Clinical trial NCT04752384
Conditions: Head and Neck Squamous Cell Carcinoma
Keywords: Mucositis Radiation Chemoradiation visual analog scale Buprenorphine Tramadol Brief Pain Inventory Oral Mucositis Pain App
Sponsor: Medical College of Wisconsin
Start date: 2021-07-08; Completion date: 2024-04-04
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm prospective clinical trial to determine the safety and feasibility of using transdermal buprenorphine in alleviation of radiation induced mucositis pain in head and neck cancer patients.

Detailed description:
Hypothesis: Long-acting transdermal buprenorphine (FDA-approved dose from 5 mcg to 20 mcg /week) in conjunction with oral tramadol (50mg-400mg) as needed for breakthrough pain would lead to significant reduction in mucositis-related pain in locally advanced head and neck cancer patients being treated with radiation therapy by the end of treatment and follow up period of 12 weeks.

This is a single-arm, interventional, supportive care clinical trial for head and neck cancer patients evaluating role of transdermal (TD) buprenorphine and tramadol combination in alleviating radiation-induced mucositis pain. This will generate preliminary data to test the feasibility and efficacy of study drug regimen. The study will also test the clinical usefulness of the smart phone pain app in recording and reporting radiation induced mucositis pain.

Arms: arm 1: The main objective of this study is to provide preliminary evidence that FDA approved dose of transdermal buprenorphine in conjunction with oral tramadol can provide adequate analgesia of radiation-induced mucositis pain during treatment and follow up period in head and neck cancer patients.
Interventions: intervention 1: Buprenorphine intervention 2: Tramadol intervention 3: Oral Mucositis (OM) Pain App
Intervention descriptions: intervention 1: Transdermal buprenorphine will be started at 5 mcg/hr once a week. Depending on the Visual Analog Scale (VAS) score, it may be increased up to 20 mcg/hr once a week. intervention 2: Oral tramadol will be started at 50 mg/day. Depending on the Visual Analog Scale (VAS) score, it may be increased up to 400 mg/day. intervention 3: Each study participant will be issued an Android smartphone, or he or she may use his/her own compatible device (whether or not it has an active data service) to which the OM Pain App will be downloaded and installed. Subjects will receive a preprogrammed alarm four times a day from their smartphones prompting them to directly enter OM pain levels on the device. Patients may submit as many pain entries as they wish beyond the four minimum levels.

Subjects will receive a preprogrammed alarm four times a day from their smartphones prompting them to directly enter OM pain levels on the device. Patients may submit as many pain entries as they wish beyond the four minimum levels.

Protocol documents:
Prot_SAP_000.pdf: 
Date of Protocol:  01/26/2024 
OƯicial Title of Study:  Transdermal Buprenorphine for the Treatment of Radiation-Induced 
Mucositis Pain in Head and Neck Cancer Patients: A Pilot Study 
NCT04752384 


Study Short Title: Buprenorphine- Mucositis Pain- HN Study       1 
    Version No.: 8 
 
 
Version Date: 01/26/24 
 
 
 
 
 
Transdermal Buprenorphine for the Treatment of Radiation-Induced Mucositis Pain in 
Head and Neck Cancer Patients: A Pilot Study 
 
 
 
Short Title: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stuart Wong, MD (Study PI) 
Aditya Shreenivas, MD (Co-PI) 
 
Current Version Number and Date 
V 8.0 
 
 
 
01/26/2024 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons 
to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.  
Buprenorphine- 
Mucositis Pain- HN Study 


Study Short Title: Buprenorphine- Mucositis Pain- HN Study       2 
    Version No.: 8 
 
 
Version Date: 01/26/24 
Title:    Transdermal Buprenorphine for the Treatment of Radiation-Induced Mucositis 
Pain in Head and Neck Cancer Patients: A Pilot Study 
MCW Protocol No.: IIT-SHREENIVAS-
BUPRENORPHINE 
IRB Pro No.:   PRO00040100 
Clinical trials.gov No.: NCT04752384   
FDA IND No.: Not applicable 
Principal Investigator:  
Stuart J. Wong, MD 
Professor 
Department of Medicine 
Division of Hematology/Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email:  swong@mcw.edu 
Co-principal Investigator:  
Aditya Shreenivas, MD 
Assistant Professor 
Department of Medicine 
Division of Hematology/Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email:  ashreenivas@mcw.edu 
Sub-investigator:  
Musaddiq Awan, MD 
Assistant Professor 
Department of Medicine 
Division of Hematology/Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email:  mawan@mcw.edu 
Sub-investigator:  
Sean Marks, MD 
Associate Professor 
Department of Medicine 
Palliative Care  
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
414-805-4600 
Email:  smarks@mcw.edu 
  
Sub-investigator:  
Joseph Zenga, MD 
Assistant Professor 
Department of Otolaryngology and 
Communication Sciences 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-5527 
Email:   jyzenga@mcw.edu  
 
Sub-investigator:  
Monica Shukla, MD 
Assistant Professor 
Department of Radiation Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI  53226 
414-805-4493 
Sub-investigator:  
Selim Firat, MD 
Associate Professor 
Department of Radiation Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI  53226 
414-805-4453 


Study Short Title: Buprenorphine- Mucositis Pain- HN Study       3 
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Version Date: 01/26/24 
Email:   mshukla@mcw.edu 
Email:   sfirat@mcw.edu  
Sub-investigator:  
Michael Stadler, MD 
Associate Dean 
Department of Otolaryngology and 
Communication Sciences   
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-8548 
Email:   mstadler@mcw.edu 
Sub-investigator:  
Becky Massey, MD 
Associate Professor 
Department of Otolaryngology and  
Communication Sciences   
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-8325 
Email:   bmassey@mcw.edu  
 
Sub-investigator:  
Christopher Schultz, MD 
Professor 
Department of Radiation Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4472 
Email:   cschultz@mcw.edu 
 
Biostatistician: 
Aniko Szabo, PhD 
Associate Professor 
Institute for Heath and Society 
Division of Biostatistics 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-955-4096  
Email: aszabo@mcw.edu   
 
Sub-investigator:  
Yi Hu, PhD 
Associate Professor 
Electrical Engineering 
College of Engineering and Applied 
Science 
University of Wisconsin-Milwaukee 
3200 N. Cramer St. 
Milwaukee, WI 53211 
414-229-6351 
Email:   huy@uwm.edu 
Funder:  
NRG NCORP Grant 
  
 
 


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PROTOCOL SUMMARY 
Title 
Transdermal Buprenorphine for the Treatment of Radiation- 
Induced Mucositis Pain in Head and Neck Cancer Patients: A Pilot 
Study 
Principal Investigator  Stuart Wong, MD (Study PI) 
Clinical Trial Phase 
Phase II 
Study Population 
Stage I±IV by AJCC staging system 8th edition head and neck 
squamous cell carcinoma (HNSCC) patients, candidate for curative 
intent or adjuvant radiation therapy 
Primary Objectives 
To investigate the efficacy of using FDA-approved doses of 
transdermal (TD) buprenorphine in combination with oral tramadol to 
provide adequate pain control in radiation induced mucositis. 
Secondary Objectives 
1. Assess compliance of the study drug regimen.  
2. Assess use of off-protocol pain medications during treatment 
and follow-up period. 
3. Compare average weekly pain scores calculated by the oral 
mucositis (OM) pain app with the average pain scores recorded 
by the BPI short form.  
4. Correlate average weekly pain scores with physical activity as 
documented on symptoms and functional assessment tools like 
MDASI-HN.  
5. Assess use of nonopiod supportive care medications (i.e., 
laxatives, antiemetics and oral anesthetics) in conjunction with 
the study drug combination during treatment and follow-up 
period. 
6. Assess gastrointestinal and cognitive side effect profile of study 
drug combination and its impact on cognition and quality of life. 
7. Evaluate safety of the study drug combination. 
Primary Endpoint 
Establish efficacy of study regimen by showing that at least 33% of 
patients will achieve at least 30 percent decrease in visual analog scale 
(VAS) pain score of BPI questionnaire from baseline to the end of week 
9 of treatment and follow-up period. 
Secondary Endpoint 
1. Monitor compliance of study drug regimen through the OM Pain 
App and medication diary. 
2. Identify study participants that require off protocol opioids for 
pain control despite being on highest dose of study drug 
combination.  
3. Correlate cumulative mean weekly pain scores calculated by 
the pain app with the average weekly pain scores recorded by 
the BPI short form. 
4. Correlate average weekly OM Pain App scores and average 
weekly pain scores calculated from BPI short form and the MD 


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Anderson Symptom Inventory - Head & Neck (MDASI-HN), 
which is a head and neck symptom and function evaluation tool.  
5. Maintain a weekly log of use of other nonopiod medication, such 
as laxatives, antiemetics, and oral anesthetics in conjunction 
with the study drug combination during treatment and follow-up 
period through weekly questionnaires.  
6. Assess incidence and severity of gastrointestinal and cognitive 
adverse events measured by weekly PROMIS® (GI and 
cognition) questionnaires to better characterize the side effect 
profile of the drug regimen and its impact on quality of life.  
7. Safety: Assess incidence and severity of adverse events 
associated with study drug combination, using the CTCAE 
version 5. 
Main 
Inclusion 
Criteria  
 
1. Age >18 years. 
2. Histologically confirmed malignancies of Head and Neck 
involving Stage I-IV by AJCC staging system 8th edition (oral 
cavity, oropharynx, nasal or paranasal sinuses, hypopharynx 
and larynx etc.) including both squamous and non squamous 
cell histology¶s (salivary gland carcinomas and carcinomas of 
unknown primary will be included)  
3. Undergoing a course of either definitive radiation (dose of at 
least 50 Gy to the head and neck region) with or without 
chemotherapy or adjuvant radiation (at least 50 Gy to the head 
and neck region) with or without chemotherapy (patients with a 
history of prior definitive course of radiation will be allowed).  
4. ECOG Performance status  2. 
5. Concurrent enrollment on an interventional trial is allowed. 
6. English speaking and literate. 
7. Patients will be allowed to take radiotherapy mix, viscous 
lidocaine or magic mouthwash-like agents that do not contain 
opioids. Tylenol® allowed for fever. 
8. Adequate organ function:  Minor dose adjustments for tramadol 
are required in cases of severe liver and renal impairment so 
we would only include patients with adequate organ function 
outlined in table below. No dose adjustment for renal or hepatic 
impairment is required for TD buprenorphine. Some other 
parameters like hemoglobin, platelets, and WBC are required 
for administration of standard-of-care chemotherapy, such as  
cisplatin along with radiation in treatment of HNSCC. They are 
not required for administration of buprenorphine or tramadol. 
 
Organ Function Table 
Adequate hepatic function: 
total bilirubin 
< 2 mg/dL 
AST(SGOT)/ALT 
< 5 times institutional upper limit 
Adequate renal function: 


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creatinine 
clearance 
 
 
> 30 mL/min/1.73 m2 for patients with 
creatinine levels above institutional 
normal 
 
Main Exclusion 
Criteria  
1. Physical exam demonstrating pre-existing mucositis from prior 
radiotherapy treatments or other causes.  
2. Pre-existing oral infection or ongoing toxicity from prior 
radiotherapy.History of opioid abuse disorder, confirmed by 
medial history or subject disclosure. positive urine drug screen 
at screening visit.  Exceptions will be made for subjects with 
current prescriptions post-surgery or other medical intervention. 
Previous history of allergic reaction to buprenorphine and 
tramadol. 
3. Patients with multiple distant metastasis. (Patients with 
resectable oligometastasis will be allowed). 
4. Current or recent use of short or long acting mixed opioid 
agonists/antagonists or other opioid antagonists. (Treatment 
with more than 2 doses of short acting oral or intravenous 
opioids like Oxycodone, morphine or hydromorphone within 24 
hours of screening). Patients on treatment with long-acting 
opioids like fentanyl patch, methadone, oxycodone extended 
release, morphine extended release within 72 hours of 
screening would be excluded.Patients presenting with any other 
cause of pain not related to radiation-induced mucositis or head 
and neck cancer VAS >4/10 on BPI questionnaire (question 3: 
worst pain in last 24 hours) on the day of enrollment requiring 
opioid medications for pain control. 
5. Prolonged QTc greater than 450 milliseconds in males and 
greater than 470 milliseconds in females at the time of 
enrollment. 
6. Patients receiving induction chemotherapy prior to or after 
radiation/chemoradiation; such as patients with nasopharyngeal 
carcinoma.  
7. Patients with a history of abdominal surgery within 60 days of 
registration or acute gastrointestinal conditions, such as colitis 
and appendicitis within four weeks of registration.  
8. Conditions that may compromise the blood-brain barrier 
permeability. The blood-brain barrier may become leaky in 
select neurological diseases, such as amyotrophic lateral 
sclerosis, epilepsy, brain trauma, and brain edema. 
9. Patients with a history of myocardial infarction  6 months prior 
to registration.  
10. Patients with a history of significant respiratory depression; 
acute or severe bronchial asthma; known or suspected 
gastrointestinal obstruction, including paralytic ileus.  
 


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Study Design 
Single-arm prospective clinical trial to determine the efficacy of 
transdermal buprenorphine and oral tramadol drug combination in 
alleviating radiation-induced mucositis pain in head and neck cancer 
patients during treatment and the follow-up period. 
Study Agent 
Transdermal buprenorphine with oral tramadol.  
Number of Subjects 
20
Estimated Time to 
Complete Enrollment: Approximately 12 months. 


 
 
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STUDY SCHEMA 
 
 


 
 
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STUDY CALENDAR 
 
Procedure 
Screening 1 
Weeks During 
Chemoradiation 
(± 3 days) 
 
Weeks follow-up period 2 
 (± 3 days) 
Study Day/Visit Day 
 
 
1*  
 
 2 
   
 3 
 
4 
 
5 
 
6 
 
7 
 
8 
   
9 
 
10 
 
11 
 
12 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline medical conditions  
X 
 
 
 
 
 
 
 
 
 
 
 
 
WHO grade mucositis# 
          X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Oral exam for presence of other causes 
of mucositis (oral candidiasis, infections, 
trauma), etc. 
X 
X 
X 
X 
X 
X 
X 
X 
 
 X 
 
 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
   X 
CMP 3 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
   X 
Opioid use and nonopiod drug use log 4 
           
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OM Pain App assessment 5 
          X    
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain app compliance questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
 
 X 
 
 
X 
Monitor WI PDMP website for opioid use  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Medical history/stage of disease  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Performance status/ECOG 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
PROMIS® GI and cognition scoring 6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI(Brief Pain Inventory) score  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI-HN 6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review device usage and proper 
reporting 6 
 
X 
X 
X 
X 
X 
X 
X 
 
 X 
 
 
X 


 
 
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Procedure 
Screening 1 
Weeks During 
Chemoradiation 
(± 3 days) 
 
Weeks follow-up period 2 
 (± 3 days) 
Study Day/Visit Day 
 
 
1*  
 
 2 
   
 3 
 
4 
 
5 
 
6 
 
7 
 
8 
   
9 
 
10 
 
11 
 
12 
EKG7 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Digital image collection of oral cavity to 
evaluate mucositis 8 
          X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Record type of caloric intake (normal, 
soft, liquid, parental/enteral) 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
Report use of IV fluids for hydration 
          X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Adverse event recording (CTCAE v5) 
 
X 
X 
X 
X 
X 
X 
X 
 
 X 
 
 
X 
Pregnancy test (HCG) for WOCB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
*week 1 starts with the first week of radiation therapy and is continuous without adjustment.   
# WHO mucositis score will be recorded by the investigators during weekly clinic visits 
 
1. Patients found to be eligible for the study can be screened and enrolled anytime during first six weeks of radiation therapy. VAS 
pain scores will be recorded weekly using BPI questionnaires and daily using the pain app from the day of enrollment, as 
outlined in study calendar. Treatment with study regimen, collection of PROMIS®, MDASI, CTCAE and other assessments like 
opioid drug use log, as outlined in the study calendar will start once the patient develops mucositis and has VAS 
4/10 pain 
score on the OM Pain App and BPI questionnaire (question 3: your pain at its worst in last 24 hours). Patients usually develop 
mucositis by the third or fourth week of radiation therapy so we anticipate treatment would begin by fourth week in most patients, 
but it may start sooner if the patient develops mucositis and has VAS  4/10 pain. If a patient presents with radiation-induced 
mucositis pain on the day of enrollment, then, all study procedures, including PROMIS®, MDASI-HN, and CTCAE will be 
completed that day. Visit procedures that were performed as standard of care prior to consent (without the specific intent to 
make the subject eligible for the trial), may count toward screening tests and eligibility if they are within the screening window 
of two days. Clinician follow-up will be scheduled weekly (1±7) and then on weeks 9 and 12. 
2. If a subject is off the study drug regimen or the subject withdraws, then they will be followed as per follow-up requirements. 
3. Serum chemistry values will include ALT/SGPT, AST/SGOT, alkaline phosphatase, bilirubin (total, direct, and indirect) 
creatinine, LDH, sodium, potassium, chloride, bicarbonate, calcium, phosphate, magnesium, BUN/urea, albumin, glucose,. 
Serum chemistry results obtained from unscheduled visits should be entered into the electronic database. Additional serum 


 
 
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chemistry testing should be done as clinically indicated. 
4. Record of opioid pain medications,laxatives, and antiemetic use from the patient¶s drug diary will be copied by investigators on 
weekly clinic visits. This will commence after starting treatment. a) Patients will document pain and supportive medication use 
data daily in their diariesbut that information will be verified and recorded by investigator/research coordinator during weekly 
clinic visits in the electronic medical record(EMR). This data is currently being collected in a section of pain app. Patients 
average weekly VAS pain scores (question 3 of BPI questionnaire) will also be documented in EMR during weekly clinic visits 
as per standard of care and can be used for study purposes.  
5. The Oral Mucositis (OM) Pain App will be evaluated by the study team on a daily basis through a real-time pain assessment 
tool in the mobile app. Patients can start using the OM Pain App before starting therapy to familiarize themselves with the 
instrument. b) Pain app readings will be recorded up to four times/day. The daily pain data will be analyzed by the UWM 
research team on a weekly basis.  
6. All questionnaires/forms can be recorded on weekly in-person visits from weeks 1±7 then completed weekly through in-person/ 
telephone interviews by CTO staff from week 8±12. Other assessments can also be done over phone during week 8, 10 and 
11. Window period of +/-3 days will be allowed for data collection. 
7. EKG will be done at screening and then on week 7 and 12 if the patient is on treatment with Buprenorphine patch.  
8. Digital photos will be taken to document mucositis on the day of enrollment, treatment initiation, then during week 9 and week 
12 clinic visits. 
 
 
 
 
 
 
 
= 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BPI 
Brief Pain Inventory 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CDK 
cyclin-dependent kinases 
CQ 
chloroquine 
CR 
complete response 
CRC 
clinical research coordinator 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTL 
cytotoxic T cell 
CTO 
Clinical Trials Office 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
data and safety monitoring plan 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GVHD 
graft-versus-host disease 
HCT 
hematopoietic cell transplantation 
HGB 
hemoglobin 
HNSCC 
head and neck squamous cell carcinoma 
IP 
investigational product 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 


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MDASI-
HN
MD Anderson Symptom Inventory - Head & Neck Cancer 
MCWCC 
Medical College of Wisconsin Cancer Center 
MTD 
maximum-tolerated dose 
NCI 
National Cancer Institute 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
disease progression 
PK 
pharmacokinetics 
PSGL-1 
P-selectin glycoprotein ligand-1 
PR 
partial response 
PROMIS 
Patient-Reported Outcomes Measurement 
RBC 
red blood cell (count) 
ROS 
reactive oxygen species 
SAE 
serious adverse event 
SD 
stable disease 
SD 
standard deviation 
SRC 
Scientific Review Committee 
ULN 
upper limit of normal 
UP 
unanticipated problem 
UPIRSO   
unanticipated problems involving risks to subjects or others 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SUMMARY .............................................................................................................. 4
STUDY SCHEMA ......................................................................................................................... 8
LIST OF ABBREVIATIONS ....................................................................................................... 12
1 BACKGROUND ....................................................................................................................... 17
1.1 HEAD AND NECK SQUAMOUS CELL CARCINOMA ................................................................... 17
1.2 OPIOID MANAGEMENT OF MUCOSITIS-RELATED PAIN ........................................................... 17
1.3 RATIONALE FOR USING BUPRENORPHINE AND TRAMADOL TO MANAGE RADIATION-INDUCED 
MUCOSITIS PAIN ............................................................................................................ 17
1.5 SYMPTOM AND FUNCTIONAL ASSESSMENTS ........................................................................ 18
2. HYPOTHESIS, OBJECTIVES, AND ENDPOINTS ................................................................ 21
2.1 PRIMARY OBJECTIVES ......................................................................................................... 21
2.2 SECONDARY OBJECTIVES .................................................................................................... 21
2.4 PRIMARY ENDPOINT ............................................................................................................ 21
2.5 SECONDARY ENDPOINT(S) ................................................................................................... 22
2.6 RATIONALE FOR OUTCOME MEASURES SELECTION .............................................................. 22
3 STUDY DESIGN ...................................................................................................................... 23
3.1 GENERAL DESCRIPTION ....................................................................................................... 23
3.2 STUDY PROCEDURES .......................................................................................................... 23
3.3 STUDY COMPLETION ........................................................................................................... 24
4 SUBJECT PARTICIPATION, DISCONTINUATION, 
AND WITHDRAWAL .................................................................................................................. 24
4.1 SUBJECT STATUS ................................................................................................................ 24
4.2 PRESCREENING AND SCREENING LOG ................................................................................. 25
4.3 CONSENT ............................................................................................................................ 25
4.4 SCREENING PROCEDURES ................................................................................................... 25
4.5 Registration Process .............................................................................................................................. 25
4.6 STUDY PROCEDURES: ON THE DAY OF ENROLLMENT ........................................................... 26
4.7 TRAINING FOR THE INTERVENTION ....................................................................................... 26
4.9 STUDY PROCEDURES: FOLLOW-UP PERIOD (WEEK 8±12 FROM START OF RADIATION 
THERAPY) ...................................................................................................................... 27
4.10 ELIGIBILITY CONFIRMATION ................................................................................................ 29
4.11 DISCONTINUATION OF STUDY TREATMENT, WITHDRAWAL, AND COMPLIANCE ..................... 33
4.12 LOST TO FOLLOW-UP ........................................................................................................ 33
4.13 ACCRUAL SUSPENSION AND CLOSURE ............................................................................... 34
4.14 END-OF-STUDY DEFINITION ............................................................................................... 34
4.15 STUDY DISCONTINUATION AND CLOSURE ........................................................................... 34
5 TREATMENT PLAN ................................................................................................................ 34
5.1 STUDY INTERVENTION ......................................................................................................... 34
5.2 DOSE DETERMINATION FOR BUPRENORPHINE AND TRAMADOL .............................................. 37


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5.3 MORPHINE DAILY DOSE EQUIVALENT OF TD BUPRENORPHINE ............................................. 37
5.4 DRUG REGIMEN TITRATION SCHEDULE ................................................................................ 38
5.5 AVAILABILITY ...................................................................................................................... 39
5.6 USAGE OF CONCURRENT/CONCOMITANT MEDICATIONS ........................................................ 39
5.8 MONITORING SUBJECT COMPLIANCE .................................................................................... 40
5.9 OM PAIN APP ...................................................................................................................... 40
5.11 OTHER FUNCTIONAL, SYMPTOM ASSESSMENTS ................................................................. 43
5.12 OPIOID AND NON-OPIOID DRUG USE ASSESSMENTS .......................................................... 43
6 ADVERSE EVENTS: DEFINITIONS, COLLECTION 
AND REPORTING REQUIREMENTS ........................................................................................ 43
6.1 DEFINITIONS ....................................................................................................................... 43
6.1.1 Adverse Event ............................................................................................................................................ 43
6.1.2 Serious Adverse Event (SAE) ................................................................................................................... 45
6.1.3 Attribution of an Adverse Event ............................................................................................................... 45
6.1.4 Expectedness of an Adverse Event ........................................................................................................... 46
6.2 COLLECTION AND REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND SERIOUS ADVERSE         
EVENTS ......................................................................................................................... 46
6.2.1 Collection of Adverse Events .................................................................................................................... 46
6.2.2 REPORTING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................... 46
6.3 UNANTICIPATED PROBLEM INVOLVING RISK TO SUBJECT OR OTHER (UPIRSO) ................... 47
6.4 SUBJECT COMPLAINTS ........................................................................................................ 47
7 PHARMACEUTICAL INFORMATION ..................................................................................... 48
7.1 BUPRENORPHINE ................................................................................................................ 48
7.2 TRAMADOL ......................................................................................................................... 51
8 STATISTICAL CONSIDERATIONS ........................................................................................ 52
8.1 STUDY ENDPOINTS .............................................................................................................. 52
8.2 STUDY DESIGN .................................................................................................................... 53
8.3 STUDY POPULATIONS .......................................................................................................... 53
8.5 FEASIBILITY ......................................................................................................................... 54
8.6 DATA ANALYSIS .................................................................................................................. 54
8.8 MISSING DATA .................................................................................................................... 55
8.9 RESEARCH ENVIRONMENT................................................................................................... 55
9 DATA AND SAFETY MONITORING PLAN (DSMP) .............................................................. 55
9.1 DATA AND SAFETY MANAGEMENT OVERVIEW ...................................................................... 55
9.2 STUDY TEAM ....................................................................................................................... 55
9.3 QUALITY ASSURANCE .......................................................................................................... 56
9.4 CLINICAL TRIALS OFFICE ..................................................................................................... 56
9.5 DSMC ................................................................................................................................ 56
10 REGULATORY COMPLIANCE, ETHICS, AND 
STUDY MANAGEMENT ............................................................................................................. 56
10.1 REGULATORY COMPLIANCE ............................................................................................... 57
10.2 PRESTUDY DOCUMENTATION ............................................................................................. 57
10.4 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ........................... 58
10.5 PROTECTION OF HUMAN SUBJECTS ................................................................................... 59
10.5.1 
Protection from Unnecessary Harm ................................................................................................ 59
10.5.2 
Protection of Privacy ........................................................................................................................ 59


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10.5.3
Changes in the Protocol ................................................................................................................... 59
10.6 INVESTIGATOR COMPLIANCE .............................................................................................. 59
11 DATA HANDLING AND RECORD KEEPING....................................................................... 60
11.1 OVERVIEW ........................................................................................................................ 60
11.2 DATA MANAGEMENT RESPONSIBILITIES............................................................................. 60
11.3 SOURCE DOCUMENTS ....................................................................................................... 61
11.4 CASE REPORT FORMS ....................................................................................................... 62
11.5 STUDY RECORD RETENTION .............................................................................................. 62
APPENDIX 1. PERFORMANCE STATUS CRITERIA ............................................................... 64
APPENDIX 2. LOST TO FOLLOW-UP LETTER ....................................................................... 65
APPENDIX 3: WHO MUCOSITIS GRADING SCALE................................................................ 66
APPENDIX 4.  QUESTIONNAIRES ........................................................................................... 67
PROMIS®± COGNITIVE FUNCTION- SHORT FORM ............................................................... 67
PROMIS® 
GASTROINTESTINAL 
NAUSEA 
AND 
VOMITING .................................................................................................................................. 72
REFERENCES ........................................................................................................................... 77
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 BACKGROUND 
1.1 Head and Neck Squamous Cell Carcinoma 
Head and neck squamous cell carcinoma (HNSCC) is the eighth most common cancer in the 
United States with more than 53,600 new cases diagnosed annually.(1) Early-stage or locally 
advanced head and neck cancer patients are typically treated by a multimodality approach 
including surgery, radiation and chemotherapy. Mucositis-related pain and dysphagia are two of 
the most common primary toxicities associated with head and neck radiation. Around 80±100% 
of head and neck cancer patients being treated with radiation therapy suffer from oral mucositis 
pain. Severe mucositis (WHO grades 3 and 4) occurs in 25% of patients when standard 
fractionated radiation (once-daily dose) is used as a single modality. The incidence of severe 
mucositis can be as high as 50%±75% when radiation is used in conjunction with concurrent 
radio-sensitizing chemotherapy. (2, 3)
1.2 Opioid Management of Mucositis-Related Pain 
Mucositis is the most common and feared side effect for head and neck cancer patients 
undergoing definitive radiation or chemoradiation. It is commonly clinically evident by the third 
week of therapy, or after approximately 30 Gy of radiation has been delivered. It may develop 
earlier when concomitant chemotherapy is being given or if an altered fractionation schedule is 
used.(4) The vast majority of patients require treatment with strong pain relief medications like 
morphine, fentanyl, and oxycodone as they experience moderate-to-severe mucositis-related 
pain. Exposure to strong opioids during radiation therapy may sometimes lead to long-term opioid 
dependence and adverse effects.(5, 6) Opioid naïve patients are apprehensive about using this 
class of drugs because of fear of habit-forming properties and drug-related side effects. As a 
result, this causes reduced pain medication compliance and may also contribute to poor pain 
control.(7, 8) 
 
1.3 Rationale for Using Buprenorphine and Tramadol to Manage Radiation-Induced 
Mucositis Pain 
Buprenorphine is a potent pain medication with a more favorable side effect profile and lower 
habit-forming potential compared to other opioids.(9, 10) It is a derivative of the thebaine, which 
has mixed opioid agonistic activities (agonistic effect on µ opioid and the OR L1 receptors but the 
antagonistic effect on kappa and delta opioid receptors).(11) Transdermal buprenorphine, with its 
active polymeric matrix, is superior to some of the other long-acting opioids in terms of therapeutic 
efficacy and compliance. Unlike other opioids, it has a ceiling effect, which means its effects 
increase until the person takes a certain amount; then, these effects level off, which limits 
euphoria, confusion, and respiratory depression.(12) Earlier studies have shown that 
buprenorphine suppresses opioid withdrawal and craving, and reduces illicit opioid use.(13) 
Furthermore, it can safely be administered with no dose adjustments in patients suffering from 
chronic kidney disease or those who develop chemotherapy-related acute renal failure. This 
unique characteristic of buprenorphine makes it a good option for mucositis-related pain control 
in HNSCC patients being treated with commonly used cisplatin-based chemotherapy, which is 
often associated with acute kidney injury.(14) With appropriate education, patients may perceive 
buprenorphine to be less addictive than other opioids and its use may be more acceptable. As a 
result, this may contribute to better pain control and compliance during treatment. Tramadol is a 
short-acting, weak opioid, which works by both monoaminergic and opioid mechanisms and has 


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synergistic activity with other long-acting opioids.(15) It is associated with lower incidence of 
cardiorespiratory depression and reduced dependence compared to strong opioids. 
It can be used to treat breakthrough pain in combination with long-acting TD buprenorphine. 
Furthermore, it has been safely used in combination with both fentanyl and buprenorphine 
patches in earlier studies to alleviate cancer related pain.(9, 16) European studies have shown 
that buprenorphine patches used at higher doses (>35 µg/hour) in combination with Tylenol® or 
tramadol for breakthrough pain can provide adequate analgesia in cancer patients and is 
associated with fewer adverse effects compared to other opioids.(9) However, there is a paucity 
of similar studies with FDA-approved doses (5 µg to 20 µg/hour) of buprenorphine patches in the 
United States. In fact, to our knowledge, there are no active or completed studies of FDA- 
approved doses of buprenorphine in the treatment of mucositis in head and neck cancer. The 
goal of this study is to show efficacy of using FDA-approved doses of buprenorphine patches with 
oral tramadol in providing adequate pain relief in patients suffering from moderate to severe 
radiation-induced mucositis pain. This is an innovative and timely study question as several head 
and neck cancer patients continue to suffer from opioid addiction and opioid-related toxicities.  
 
1.4 Safety data on studies using this drug combination.   
 
Multiple studies have utilized a combination of transdermal buprenorphine and oral tramadol for 
cancer-related pain.(17-19). In a study by Pace et al., a group of 52 cancer patients with chronic 
pain were randomized 1:1 between two groups. Twenty-six patients were treated with a titratable 
dose of TD buprenorphine (35 µg/hour) with oral tramadol (200 mg/day) for breakthrough pain 
and 26 patients were treated with 60 mg/day of oral morphine. Final analysis of this study revealed 
that buprenorphine-based regimen was more effective in providing pain relief and was better 
tolerated than oral morphine. The incidence and severity of side effects were significantly lower 
in the buprenorphine arm compared to the morphine arm. Overall, common side effects reported 
in the buprenorphine arm of 26 patients were vertigo (12%), drowsiness (12%), headache (12%), 
constipation (8%), confusion (4%), and nausea (12%). No serious adverse event was 
observed.(9) In another 40-patient study of cancer patients, oral tramadol was safely used in 
combination with TD buprenorphine. Side effects, including nausea, buprenorphine patch 
insertion site pruritus and erythema, constipation, and headache were observed but were for the 
most part self-limiting.(18) Overall, there is some evidence in the literature to prove the safety of 
buprenorphine and tramadol drug combination regimen in cancer patients. However, there are no 
large randomized trials with this combination. Details on the dose justification of the study drug 
regimen are included in Section 5.2.  
 
1.5 Symptom and Functional Assessments  
Several validated metrics are available to measure treatment-related symptoms. We plan to use 
some of these patient-reported outcome measures and symptom and functional assessment tools 
in our study. We also plan to use a novel smartphone-based pain app to evaluate and monitor 
radiation-induced mucositis pain. 
 1.5.1 MD Anderson Symptom Inventory 
U.S. and European phase I through IV trials have used and validated the MD Anderson Symptom 
Inventory (MDASI). This tool can be used in clinical and research settings. The Visual Analog 
Scale (0±10) measures symptom severity and interference with daily activities.(20-22) The 13-
core MDASI symptom items are based on an extensive evaluation related to cancer and cancer-


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treatment symptoms. MDASI symptoms include pain, fatigue, and appetite changes that the head 
and neck cancer population typically experiences. Patients easily complete it as a self-report tool 
in five minutes. Alternatively, research staff may assist patients in completing it in the clinic or by 
telephone with an interactive voice response system. 
The instrument was developed in a manner that allows individuals to add items relevant to specific 
cancers and cancer treatments to patient-completed modules. The head and neck module 
(MDASI-HN) (21) was created with focus group input. These groups comprised head and neck 
cancer patients; surgical, medical, dental, and radiation oncology specialists; and symptom 
researchers. This instrument includes 12 to 14 head- and neck-specific items, including at least 
five that do not appear in the Functional Assessment of Cancer Therapy for Patients with Head 
and Neck Cancer (FACT-HN) ² another commonly used quality of life tool. The coefficient alpha, 
a measure primarily used as a means of describing the reliability of multiitem scales, is highly 
reliable with the MDASI-HN. It  was validated in a cohort of more than 200 patients in multiple 
studies.(3, 23)  It  was validated in several languages. In our trial, we plan to use the   MDASI-HN 
tool to study the impact of radiation-induced mucositis pain on head- and neck-related symptoms 
and physical activity. 
1.5.2 Brief Pain Inventory  
The Brief Pain Inventory (BPI) asks patients to rate their pain for the last week on a 0 to 10 scale 
at its ³worst,´ ³least,´ ³average´ and ³now.´  The scales are presented on a 10-cm line with each 
number equidistant from the next. Each scale is bounded by the words ³no pain´ at the 0 end and 
³pain as bad as you can imagine´ at the other. Patients are also asked to rate how pain interferes 
with several quality of life domains, including activity, walking, mood, sleep, work and relations 
with others. These scales are bounded by ³does not interfere´ at the 0 end and ³interferes 
completely´ at the other. Patients also are asked to estimate pain relief related to their pain 
treatment (by percentage), to locate areas of pain on a human figure and to estimate pain cause 
(cancer disease, cancer treatment, or non-cancer). The patient can complete the BPI in 
approximately five minutes, and the assessment is available in 12 languages. 
BPI validity and reliability issues have been examined in detail.(24) In clinical trials where pain 
reduction (or prevention) represents primary or secondary outcome measures, professionals 
frequently use the BPI due to its ease of translation and brief administration. As a pain assessment 
tool, it is the FDA standard. The typical standard deviation for the item ³worst pain´ in most cancer 
populations is 2.4. Therefore, the finding of a one-point difference in the ³worst pain´ item at 
different times or between two comparative groups is considered significant. We plan to use the 
Brief Pain Inventory to assess and quantify radiation-induced mucositis pain. 
1.5.3 MDASI and BPI Limitations and Rationale for the Smartphone Pain App 
While the above-mentioned pain assessment tools measure oral mucositis pain, they only provide 
pain severity snapshots. In a head and neck cancer clinical trial, mucositis pain questionnaires 
are typically administered only once or twice per week. Other pain assessment tools require the 
patient to rate pain by memory recall of pain severity, thereby introducing a variable prone to 
inaccuracy.(22) Patients with severe oral mucositis experience unrelenting pain. It is often 
characterized by wide fluctuations with pain peaks occurring with swallowing saliva, eating, 
talking, and with waning analgesic medication effects. The limitation of most pain assessment 
tools in failing to capture fluctuating pain is well recognized. Momentary self-reporting of chronic 
pain with an electronic diary has been shown to overcome this limitation without undue burden. 


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Pain questionnaires also fail to capture patterns of pain unique to the head and neck cancer  
population, such as pain related to the timing of radiation (early in the week versus later in the 
week versus weekend). Pain, occurring at night and interfering with sleep, is likewise not 
accounted for in typical pain surveys for mucositis. 
The difficulty of measuring radiation-induced oral mucositis pain under optimal conditions of a 
clinical trial is put into perspective by pointing out that in the non-research setting oncologists do 
not routinely use any assessment tools for measuring mucositis pain. This may be in part due to 
the shortcomings of the available tools described above. More likely, however, it is due to logistical 
restrictions ² the availability of trained personnel to administer surveys, time constraints of the 
doctors¶ office schedules and the difficulty of documenting paper surveys and integrating them 
into the electronic medical record. Instead, most commonly, patients simply are asked to verbally 
report an assessment of their pain, such as worst pain level or average level of pain. The head 
and neck cancer patient population is predisposed to specific problems that further limit the ability 
to assess pain, such as the ability to articulate and accurately describe pain, language and 
physical communication barriers, cultural influences, as well as fear of the appearance of drug-
seeking or difficult behavior. 
To address the difficulty of accurately monitoring patients¶ mucositis pain, we developed a new 
method for assessing radiation-induced oral mucositis pain by adopting widely available cell 
phone technology.  
1.5.4 Oral Mucositis (OM) Pain App  
Under the auspices of an existing protocol  approved by the Medical College of Wisconsin 
Institutional Review Board (NCT02727062), we are planning to use the OM Pain App in our study. 
The OM Pain App is a smartphone application that was designed to permit patients to key in pain 
severity, using a visual analog 0±10 scale (VAS). The app is programed with an alarm to prompt 
the patient to record pain severity at prescribed intervals daily and through spontaneous patient 
input. Deidentified data collected on each patient¶s smartphone will be backed up wirelessly to 
cloud storage where the data can be analyzed remotely or viewed on the device. The software 
can generate a time-weighted measure of pain, total area under the pain curve (AUC), a summary 
measure that integrates serial assessments of a patient¶s pain over the duration of the study. The 
OM Pain App may be a significant improvement over the current standard of care, which is 
essentially nonexistent. The validated OM Pain App has the potential to significantly improve the 
management of pain in head and neck cancer patients. As noted, at the  Medical College of 
Wisconsin, we developed an oral mucositis pain app (OM Pain App) and implemented a clinical 
trial (NCT02727062) to accurately assess pain requirements of head and neck cancer patients 
undergoing radiation. Preliminary data from 16 patients currently enrolled in the pain app study 
shows feasibility of using this application for real-time pain assessments. We are currently 
analyzing this data and hope to report these findings very soon. This app has potential applicability 
to other types of cancers in which treatment-associated pain is encountered.   
1.5.5 Outcome Measure Tools to Identify Gastrointestinal, Cognitive Side Effects of the 
Study Regimen.  
Radiation-induced mucositis pain treated with strong opioids often leads to gastrointestinal and 
cognitive side effects, which limit drug adherence and affect the quality of life of patients. A study 
by Pace et al. showed that buprenorphine is associated with lesser gastrointestinal side effects 
compared to other conventional opioids.(9) However, to our knowledge the gastrointestinal and 


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cognitive side effect profile of transdermal buprenorphine has not been studied extensively in 
patients being treated for mucositis pain in head and neck cancer patients. We plan to use a 
highly intuitive patient-reported outcome measurement information system tool called PROMIS® 
to assess the side effect profile of the study drug regimen. All scales of PROMIS® have been 
validated in cancer patients. PROMIS® is a set of person-centered outcome measures that 
evaluates and monitors physical, mental, and social health in adults and children. It is very 
sensitive, easy to use and available in multiple languages. Patients can also take assessments 
at home or through paper forms in clinic. Thus, there is less disruption to clinic flow with this 
methodology. We plan to use PROMIS® questionnaires to evaluate cognitive and gastrointestinal 
side effect profiles of the drug regimen and collect data to make appropriate and timely symptom-
related interventions. Both PROMIS® GI and PROMIS® Cognition scores have been validated in 
multiple studies. (25, 26). We plan to use PROMIS® scores to evaluate the gastrointestinal and 
cognitive side effects of the study regimen and its impact on the quality of life of patients. 
2. HYPOTHESIS, OBJECTIVES, AND ENDPOINTS 
We hypothesize that the use of long-acting transdermal buprenorphine (FDA-approved dose from 
5 mcg to 20 mcg/week) in conjunction with oral tramadol (50 mg to 400 mg/day) as needed for 
breakthrough pain will lead to a significant reduction in mucositis-related pain in locally advanced 
head and neck cancer patients being treated with radiation therapy by the end of treatment and 
the follow-up period of nine weeks.  
2.1 Primary Objectives 
To investigate the efficacy of using FDA-approved doses of TD buprenorphine in combination 
with oral tramadol to provide adequate pain control in radiation-induced mucositis.  
 
2.2 Secondary Objectives 
1. Assess compliance of the study drug regimen.  
2. Assess use of off-protocol pain medications during treatment and follow-up period. 
3. Compare the average weekly pain scores calculated by the pain app with the average 
pain scores recorded on the BPI short form.  
4. Correlate average weekly pain scores with physical activity as documented on symptom 
and functional assessment tools, such as the MDASI-HN.  
5. Assess the use of nonopiod supportive care medications (i.e., laxatives, antiemetics, and 
oral anesthetics) in conjunction with the study drug combination during treatment and 
follow-up period. 
6. Assess gastrointestinal and cognitive side effect profiles of the study drug combination 
and their impact on cognition and quality of life. 
7. Evaluate safety of the study drug combination. 
 
2.4 Primary Endpoint 
Establish the efficacy of the study regimen by showing that at least 33% of the patients will 
achieve at least a 30 percent decrease in the VAS pain score on the BPI questionnaire 
(question 3: worst pain in last 24 hours) from baseline to the end of week 9 of treatment and the 
follow-up period. Earlier studies have shown that the VAS pain score( 4/10) on the day of 


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treatment initiation may be used as the baseline in this setting and a 30% or higher reduction in 
the baseline pain score is a sign of a meaningful drug response.(27-29)   
2.5 Secondary Endpoint(s) 
1. Monitor compliance of the study drug regimen through the OM Pain App and medication 
diary. 
2. Identify study participants who require off-protocol opioids for pain control despite being 
on the highest dose of the study drug combination.  
3. Correlate the cumulative mean weekly pain scores calculated by the pain app with the 
average weekly pain scores recorded on the BPI short form.  
4. Correlate the average weekly OM Pain App scores and average weekly pain scores 
calculated from BPI short form with head and neck symptom and functional evaluation tool 
MDASI-HN. The cumulative average area under the curve (AUC) weekly pain scores are 
expected to be inversely proportion to MDASI-HN average weekly AUC physical activity 
scores.  
5. Maintain a weekly log of the use of other nonopiod medication, such as laxatives, 
antiemetics, and oral anesthetics in conjunction with the study drug combination during 
the treatment and follow-up period through weekly questionnaires. The average weekly 
use of laxatives and antiemetics is expected to decrease by the end of the follow-up 
period.  
6. Assess the incidence and severity of gastrointestinal and cognitive side effects of the study 
drug regimen and their impact on the quality of life as measured by weekly PROMIS® (GI 
and cognition) questionnaires. 
7. Safety: Assess incidence and severity of other adverse events associated with study drug 
combination, using the CTCAE version 5. 
 
2.6 Rationale for Outcome Measures Selection 
A. Primary objectives: We plan to use the average daily and weekly pain scores determined 
by the OM Pain App and the average weekly pain scores determined by the BPI short 
form to assess the efficacy of the study drug combination. Cancer and cancer therapy-
related pain estimates vary widely and there is a lack of standardization of pain 
assessment tools in this area. Studies have shown that real-time assessment of patient-
reported pain outcomes improves provider awareness and leads to better management of 
pain. Further, real-time assessment is very important for the head and neck cancer patient 
population as these patients are predisposed to specific problems, such as  difficulty in 
articulating and accurately describing pain due to severe mucositis. These issues can be 
resolved with real-time assessment of pain by a smartphone-based application. To our 
knowledge, app-based pain assessment of buprenorphine has never been studied on 
head and neck cancer patients suffering from radiation-induced mucositis pain. Our goal 
will be to use the VAS-based pain assessment tools on the OM Pain App and BPI short 
form to evaluate the pain response of the buprenorphine and tramadol combination 
regimen.  
Painful mucositis usually manifests by the third to fourth week of starting radiation and 
continues four to five weeks after the termination of therapy. Therefore, we decided to 
follow patients up to 12 weeks after they begin radiation therapy.(4, 17, 30) Mild-intensity 
mucositis pain can be effectively managed with low-potency pain medications like 
Tylenol®, NSAIDS, and oral lidocaine. Thus, we plan to initiate treatment with the tramadol 


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and buprenorphine combination once the patient develops mucositis and a VAS pain 
score  4/10.  Earlier pain management studies in radiation-induced mucositis have 
acknowledged that the pain curve follows a nonlinear pattern during radiation therapy and 
starts to peak by the fourth to fifth week of radiation therapy. It then plateaus and later 
drops to a lower level after initiation of long-acting effective pain medications, such as 
fentanyl or oxycodone. Hence, it is reasonable to use the pain score on the day of 
treatment initiation as our baseline pain score. (27, 29, 31) 
B. Secondary Objectives: Adherence to the prescribed dose and frequency of pain 
medications is vital to symptom management of radiation-induced mucositis pain. Poor 
adherence is often associated with worse symptom control and inaccurate assessment of 
the potency of pain medications. Greater clinical support and research are needed to 
overcome the challenges of fragmentation in care from clinic to home, with specific 
attention to adherence and symptom management. We plan to use our pain app to make 
accurate and real-time assessments of compliance and efficacy of the pain regimen. We 
will also assess the use of off-protocol pain medications during study period.  
We plan to study the impact of radiation-induced mucositis pain on head- and neck-related 
symptoms and physical activity. This data will be further characterized and evaluated by 
the MDASI-HN symptom and function tool. Use of other medication like laxatives and 
antiemetics in conjunction with the study drug combination during treatment can be used 
as surrogate markers of gastrointestinal side effects associated with the drug regimen. 
We plan to record these values on a weekly basis and expect its use to decrease by the 
end of follow-up period. To study the gastrointestinal and cognitive side effect profile of 
transdermal buprenorphine and tramadol regimen, we plan to use a highly intuitive patient-
reported outcome measurement information system tool called PROMIS®. All PROMIS® 
scales have been validated in cancer patients. We plan to use PROMIS® questionnaires 
to evaluate the cognitive and gastrointestinal side effect profile of the drug regimen and 
its impact on quality of life of patients. Incidence and severity of adverse events associated 
with the study drug regimen, such as constipation, sedation, respiratory depression, and 
others will also be evaluated, using the CTCAE version 5. We will collect this data to make 
appropriate and timely symptom-related interventions. 
3 STUDY DESIGN 
3.1 General Description 
This is a single-arm, interventional, supportive care clinical trial for head and neck cancer 
patients evaluating the role of a TD buprenorphine and tramadol combination in alleviating 
radiation-induced mucositis pain. This will generate preliminary data to test the feasibility and 
efficacy of the study drug regimen. The study will also test the clinical usefulness of the 
smartphone pain app in recording and reporting radiation-induced mucositis pain. Additionally, it 
will also evaluate the role of symptom and function assessment tools, such as MDASI-HN and 
PROMIS® in identifying adverse effects related to the study regimen in the setting of 
chemoradiation therapy.  
3.2 Study Procedures  


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Patients found to be eligible for the study can be screened and enrolled anytime during the first 
six weeks of radiation therapy. VAS pain scores will be recorded weekly using the BPI 
questionnaires. They will also be recorded daily, using the pain app from the day of enrollment 
as outlined in study calendar. Treatment with the study regimen, collection of data from the 
PROMIS®, MDASI, CTCAE evaluation, and other assessments, such as the opioid drug use log 
as outlined in study calendar will start once patient develops mucositis and has VAS >4/10 pain 
score on the OM Pain App and the BPI questionnaire (question 3: your pain at its worst in last 
24 hours). Patients usually develop mucositis by the third to fourth week of radiation therapy so 
we anticipate treatment would begin by fourth week in most patients, but it can start sooner if 
the patient develops mucositis and has VAS 4/10 pain. If a patient presents with radiation-
induced mucositis pain on the day of enrollment, then, all study procedures, including 
administering the PROMIS® and MDASI-HN questionnaires, in addition to CTCAE evaluation, 
will be completed on that day. Visit procedures that were performed as standard of care prior to 
consent (without the specific intent to make the subject eligible for the trial), may count toward 
screening tests and eligibility if they are within the screening window of two days. Clinician 
follow-up will be scheduled weekly (weeks 1±7) and then on weeks 9 and 12. Data can also be 
collected over phone during the follow-up period (weeks 8±12 from the start of radiation 
therapy). If a subject stops radiation therapy within the first 7 weeks, weekly visits will continue 
as scheduled if he/she is on treatment.   
3.3 Study Completion 
The study is expected to complete its accrual goal in 12 months. The study will reach study 
completion approximately 18 months from the time the study opens to accrual. 
4 SUBJECT PARTICIPATION, DISCONTINUATION, AND WITHDRAWAL  
 
Investigators must follow all MCW IRB requirements and policies regarding subject participation, 
found here: 
https://www.mcw.edu/HRPP/Policies-Procedures.htm 
4.1 Subject Status 
Subject statuses throughout the trial are defined as follows:   
 
Prescreening: preconsent (subject considering trial or study staff considering a patient 
for the trial per institutional recruitment methods). 
 
Screening: the period after the consent, but prior to eligibility confirmation. 
 
Consented: consented, prior to eligibility confirmation. 
 
Eligible: the local investigator confirms all eligibility criteria apply. 
 
On study/enrolled: date eligibility is confirmed. 
 
On arm: date of enrollment. 
 
On treatment: first-day treatment with study drug regimen while undergoing radiation   
 
Off treatment: last day of treatment with study drug regimen  
 
On follow-up: from the last day of treatment to the end of the follow-up period. 
 
Off study: follow-up period completed, with no additional data gathered. 


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Withdrawn: subject fully withdraws consent (i.e., refuses ALL follow-up, even survival) or 
is taken off the study by the local principal investigator. 
 
4.2 Prescreening and Screening Log 
 
The MCW study principal investigator regularly reviews screen failure reasons to understand 
barriers to accrual and consider amending eligibility criteria. Screen failures are defined as 
participants who were considered for the trial to participate in the clinical trial with or without 
consent but are not subsequently assigned to the study intervention or enrolled in the study. 
MCWCC CTO will follow its SOPs regarding prescreening and screening tracking. 
 
4.3 Consent  
 
Investigators or their appropriate designees will identify potentially eligible subjects from their 
clinics, subject self-referrals, referrals from other clinicians, and/or other IRB-approved 
recruitment methods. No study conduct, including subject prescreening, can occur until after IRB 
approval. 
 
A written signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record (per local IRB policies and SOPs). The original will be kept on file with the 
study records.  
 
4.4 Screening Procedures 
 
Refer to the study calendar of events for details. Patients found to be eligible for the study will 
be screened and enrolled anytime during first six weeks of radiation therapy. EKG, lab, urine 
drug screen, medical history and other assessments as per study calendar will be collected on 
the day of enrollment. This day, patients will complete the BPI questionnaire and the OM Pain 
App will be installed on their cell phones. Those who do not have a smartphone will be provided 
with a wifi enabled device with OM Pain App installed on it. Going forward, BPI questionnaire 
will be completed during weekly clinic visits and daily OM Pain App data monitoring will continue 
throughout the rest of the treatment and follow up period of 12 weeks. Treatment with the study 
drug regimen will commence once the patient develops mucositis and has a VAS pain score 
4/10 on the BPI and pain app. Additional data from PROMIS®, MDASI-HN, opioid and 
nonopiod drug use log, CTCAE evaluation, calorie requirements, the need for IV hydration, and 
other assessments will also be recorded as per study calendar.  
 
Based on earlier studies and our clinical practice, we anticipate that most patients will develop 
moderate intensity pain and require an opioid-based pain regimen by the third to fourth week of 
radiation therapy.(4, 30) As we will be using the pain score on the day of treatment initiation and 
not the date of enrollment as our baseline, we don¶t expect that timing of initiation of drug 
regimen would have a significant impact on our results. 
 
4.5 Registration Process 
Recruitment 
Potential study participants will be identified by routine care in the MCW Cancer Center clinics.  


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Subjects will sign the informed consent form in the cancer center clinics. A team approach will 
be used whereby physician sub-investigators will discuss and describe the clinical trial with 
study candidates. The study coordinator will obtain the informed consent from participants and 
perform study registration. For women of childbearing potential, a negative pregnancy test must 
be obtained within 24 hours prior to starting radiation therapy. Visit procedures that were 
performed as standard of care prior to consent (without the specific intent to make the subject 
eligible for the trial), may count toward screening tests and eligibility if they are within the 
screening window of two days.  
4.6 Study Procedures: On the Day of Enrollment  
 Screening Assessments 
 
Record WHO mucositis grade. 
 
Brief Pain Inventory.  
 
ECOG/Zubrod Performance Status. 
 
Oral cavity digital image collection to evaluate mucositis will be done on the day of 
enrollment, treatment initiation, end of week 9 and then week 12. 
 
Physical examination (demonstrating no pre-existing mucositis). 
 
Record mucositis due to other causes (oral candidiasis, infections, trauma, etc.). 
 
OM pain data monitoring (VAS included in pain app). 
 
Review bloodwork, including CBC and CMP during clinic visits. 
 
Record type of calorie intake (normal, liquid, soft, parental/enteral). 
 
Report use of IV fluids for hydration.  
 
EKG.  
 
Urine drug screen. 
 
Pregnancy test for women of childbearing age.   
 
4.7 Training for the Intervention 
Study investigators and/or study coordinator will train subjects for use of devices (OM Pain App) 
and study procedures during treatment. 
 
Study procedures as per study calendar will continue until treatment with the study drug 
regimen is started.  
 
4.8 Study Procedures: After starting study drug regimen(Weeks 1±7) 
 
These procedures must be completed weekly during the study. These will be recorded once the 
patient starts the drug regimen when radiation-induced mucositis pain VAS is greater than 4/10 
on the BPI and pain app. The following procedures, such as MDASI and PROMIS® 
questionnaire administration, and adverse event evaluation, using CTCAE, will also be 
completed if the patient presents with radiation-induced mucositis pain (VAS 4/10) on the day 
of enrollment.  
 
 
Record WHO mucositis grade. 
 
Brief Pain Inventory.  
 
ECOG/Zubrod Performance status. 


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MD Anderson Symptom Inventory. 
 
PROMIS® cognition and GI questionnaires.  
 
Oral cavity digital image collection to evaluate mucositis will be done on the day of 
treatment initiation, the end of week 9, and then week 12. 
 
Record mucositis due to other causes (oral candidiasis, infections, trauma, etc.). 
 
Record adverse events, using CTCAE v.5.0. 
 
Record type of calorie intake (normal, liquid, soft, parental/enteral). 
 
Report use of IV fluids for hydration. 
 
OM Pain App data monitoring (VAS included in pain app). 
 
Review OM Pain App device usage and proper reporting. 
 
Review opioid log and record use of oral anesthetics, laxatives, and antiemetics at 
home. This data is currently being collected in a section of pain app. Patients average 
weekly VAS pain scores (question 3 of BPI questionnaire) because of radiation induced 
mucositis will also be documented in EMR during weekly clinic visits as per standard of 
care. 
 
 
Monitor opioid usage through WIPDMP,  
 
Review bloodwork, including CBC and CMP.  
 
EKG will be performed at screening,  week 7 and 12 for patients on buprenorphine patch  
If a subject stops radiation therapy prior to week 7, visits will remain on the same schedule, 
Subjects will need to come in for a weekly visit(s).  
4.9 Study Procedures: Follow-up Period (Week 8±12 from start of radiation therapy) 
   End-of-Treatment Procedures 
       To be completed by the CRC between week 8 to week 12. Refer to the study calendar for 
details. 
 
Record WHO mucositis grade. 
 
Brief Pain Inventory.  
 
ECOG/Zubrod Performance status. 
 
Evaluate and record potential other causes of mucositis (oral candidiasis, aphthous 
ulcer, infections, trauma, etc.). 
 
PROMIS® GI and cognition questionnaires recorded over phone or in person weekly.  
 
MD Anderson Symptom Inventory recorded over the phone or in person weekly.  
 
Oral cavity digital image collection to evaluate mucositis will be done on the day of 
treatment initiation, the end of week 9, and then week 12. 
 
Physical examination (demonstrating no pre-existing mucositis). 
 


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Record adverse events, using CTCAE v.5.0. 
 
Record type of calorie intake (normal, liquid, soft, parental/enteral). 
 
Report IV fluids for hydration. 
 
Review OM Pain App device usage and proper reporting. 
 
OM pain data monitoring (VAS included in pain app). Data from week 9 will be used for 
primary endpoint analysis. 
 
 
Review bloodwork, including CBC and CMP. 
 
 
Review opioid log and record use of oral anesthetics, laxatives, and antiemetics at 
home. This data is currently being collected in a section of pain app. Patients average 
weekly VAS pain scores (question 3 of BPI questionnaire) because of radiation induced 
mucositis will also be documented in EMR during weekly clinic visits as per standard of 
care. 
 
  
 
Monitor opioid usage through WIPDMP.  
 
 
EKG will be performed at screening, week 7 and 12 for patients on buprenorphine patch  


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4.10 Eligibility Confirmation 
Study staff must adhere to MCWCC CTO SOPs regarding eligibility review/confirmation.  
No waivers of protocol eligibility will be granted. When clinical factors relating to an eligibility item 
are unclear or questionable, the MCW PI can only provide guidance or clarification on eligibility. 
Any eligibility questions should be directed to Dr. Wong at  swong@mcw.edu.  
Study Population  Locally advanced (stage I to IV) head and neck cancer patients being 
treated with either definitive or adjuvant radiation with or without chemotherapy who fulfill all 
eligibility criteria will be enrolled in this study. Patients deemed eligible for the study will be 
screened and enrolled in the study; treatment with study regimen will start once mucositis-
related pain measured by VAS 4/10 anytime during first six weeks of radiation therapy. 
Inclusion Criteria 
1. Age > 18 years. 
2. Histologically confirmed malignancies of Head and Neck Stage I-IV by American Joint 
committee on cancer (AJCC) staging criteria 8th edition involving(oral cavity, oropharynx, 
nasal or paranasal sinuses, hypopharynx and larynx etc.) including both squamous and 
non-squamous cell histology¶s (salivary gland carcinomas and carcinomas of unknown 
primary will be included) 
3. Undergoing a course of either definitive radiation (dose of at least 50 Gy to the head and 
neck region) with or without chemotherapy or adjuvant radiation (at least 50 Gy to the 
head and neck region) with or without chemotherapy. (Patients with a history of prior 
definitive course of radiation will be allowed).  
4. ECOG Performance status  2.  
5. Concurrent enrollment on interventional trial is allowed. 
6. English speaking and literate. 
7. Patients will be allowed to take radiotherapy mix, viscous lidocaine or magic mouthwash-
like agents that do not contain opioids. Tylenol® is allowed for fever or mild pain before 
starting drug regimen. It can be used for fever anytime during the study. Use of Tylenol 
for non-radiation mucositis related pain may be allowed in rare circumstances at 
investigators discretion. 
8. Adequate organ function:  Minor dose adjustments for tramadol are required in severe 
liver and renal impairment so we would only include patients with adequate organ function 
outlined in the table below. No dose adjustment for renal or hepatic impairment is required 
for TD buprenorphine. Some other parameters like hemoglobin, platelets and WBC are 
required for administration of standard of care chemotherapy like cisplatin along with 
radiation in treatment of HNSCC. They are not required for administration of 
buprenorphine or tramadol. 
 
Organ Function Table 
Adequate hepatic function: 
total bilirubin 
< 2 mg/dL 
AST(SGOT)/ALT 
< 5 times institutional upper limit 
Adequate renal function: 


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Organ Function Table 
creatinine clearance  
 
> 30 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal 
 
9. Pregnancy: It is known that standard-of-care treatments of HNSCC radiation therapy and 
chemotherapy have detrimental effects on human pregnancy or development of the 
embryo or fetus. Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner. Non-
sterilized female patients of reproductive age and male patients should use effective 
methods of contraception through defined periods during and after study treatment as 
specified below.  
Female patients must meet one of the following:  
 
Postmenopausal for at least one year before the screening visit, or 
 
Surgically sterile, or 
 
If they are of childbearing potential, agree to practice two effective methods of 
contraception from the time of signing of the informed consent form through three 
months after the last dose of study drug, AND 
 
Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, or 
 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post ovulation methods] and withdrawal are not acceptable 
contraception methods.) 
 
Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to 
one of the following: 
 
Practice effective barrier contraception during the entire study treatment period and 
through 90 days after the last study drug dose, OR 
 
Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR 
 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post ovulation methods] and withdrawal are not acceptable methods 
of contraception.)  
10. Ability to understand a written informed consent document, and the willingness to sign it. 
11. Ability to operate and key in information on OM Pain App (a smartphone application).  
 
Exclusion Criteria 
A potential subject who meets any of the following exclusion criteria is ineligible to participate in 
the study. 
1. Physical exam demonstrating pre-existing mucositis from prior radiotherapy treatments 
or other causes.  
2. Pre-existing oral infection or ongoing toxicity from prior radiotherapy.  
3. History of opioid abuse disorder, confirmed by medial history or subject disclosure. 
positive urine drug screen at screening visit.  Exceptions will be made for subjects with 
current prescriptions post-surgery or other medical intervention.  


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4. Patients with multiple distant metastasis (patients with resectable oligometastasis will be 
allowed). 
5. Current or recent use of short acting mixed opioid agonists/antagonists or other opioid 
antagonists. (Treatment with more than 2 doses of short acting oral or intravenous 
opioids like Oxycodone, morphine or hydromorphone within 24 hours of screening). 
Patients on treatment with long-acting opioids like fentanyl patch, methadone, 
oxycodone extended release, morphine extended release within 72 hours of screening 
would be excluded. 
6. Prolonged QTc greater than 450 milliseconds in males and greater than 470 
milliseconds in females at the time of enrollment 
7. Patients on systemic therapy (chemotherapy or immunotherapy) for another cancer 
subtype.  
8. Patients receiving induction chemotherapy prior to or after radiation/chemoradiation, 
such as patients with nasopharyngeal carcinoma. 
9. Patients with a history of abdominal surgery within 60 days of registration, acute 
gastrointestinal conditions like colitis and appendicitis within four weeks of screening.  
10. Patients with conditions that may compromise the blood-brain barrier permeability. The 
blood-brain barrier may become leaky in select neurological diseases, such as 
amyotrophic lateral sclerosis, epilepsy, brain trauma, and edema. 
11. Patients presenting with any other cause of pain not related to radiation-induced 
mucositis or head and neck cancer, VAS >4/10 on BPI questionnaire (question 3: worst 
pain in last 24 hours) on the day of enrollment requiring opioid medications for pain 
control 
12. Patients with a history of myocardial infarction  6 months prior to registration.  
13. Patients with a history of significant respiratory depression; acute or severe bronchial 
asthma; known or suspected gastrointestinal obstruction, including paralytic ileus.  
14. History of serious or severe hypersensitivity reaction to buprenorphine, tramadol or any 
of its excipients. 
15. Use of the following drugs will not be permitted after initiation of study drug regimen:  
capsaicin, NSAIDS, tetrahydrocannabinol, and cannabinoids. Refer to Section 7 for 
details on contraindication of drug regimen. Patients will be allowed to participate in the 
study if they have been using antidepressants like SSRI¶S, other antipsychotics and 
antiseizure medications for at least 4 weeks prior to enrollment on the study. Chronic 
use of these agents will not affect our primary endpoint of assessing impact of study 
regimen of Buprenorphine and Tramadol on alleviating acute radiation induced mucositis 
pain.  As per package insert of buprenorphine and tramadol concomitant use of the 
above-mentioned agents with study pain regimen is not contraindicated. However, 
clinicians are advised to exercise caution as there have been some rare incidences of 
serotonin release syndrome (SRS) with concurrent administration of SSRI¶s and 
Tramadol. Buprenorphine is also not contraindicated but should be used with caution in 
patients with h/o seizure disorders. Study regimen can be stopped if SRS or any other 
adverse event occurs as a consequence of this combination. Periodic EKG¶s will also be 
performed to monitor for QTc prolongation. 
16. Pregnant and lactating women are excluded from this study because chemotherapy and 
radiation given for the treatment of HNSCC have a potential for teratogenic or 
abortifacient effects. Additionally, buprenorphine is classified as category C for use 
during pregnancy, which means that the risk of adverse effects on the fetus cannot be 
ruled out. Buprenorphine does cross the placenta, and the use of opioids during 
pregnancy may result in neonatal withdrawals soon after birth. Symptoms of this may 
include irritability, apnea, increased tone, tremor, convulsions, or respiratory depression 


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in the neonate. The onset of withdrawal in a neonate whose mother has taken 
buprenorphine during the pregnancy could be anywhere from the first day of life to the 
eighth day of life. 
17. Patients with history of seizure disorder as oral tramadol may reduce seizure threshold.  
18. Patient with history of opioid use disorder as defined by Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition. The Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition describes opioid use disorder as a problematic pattern of opioid 
use leading to problems or distress, with at least two of the following occurring within a 
12-month period: 1.Taking larger amounts or taking drugs over a longer period than 
intended. 2. Persistent desire or unsuccessful efforts to cut down or control opioid use. 
3. Spending a great deal of time obtaining or using the opioid or recovering from its 
effects. 4. Craving, or a strong desire or urge to use opioids 5. Problems fulfilling 
obligations at work, school or home. 6. Continued opioid use despite having recurring 
social or interpersonal problems. 7. Giving up or reducing activities because of opioid 
use Using opioids in physically hazardous situations. 8.Continued opioid use despite 
ongoing physical or psychological problem likely to have been caused or worsened by 
opioids.9Tolerance (i.e., need for increased amounts or diminished effect with continued 
use of the same amount) 10. Experiencing withdrawal (opioid withdrawal syndrome) or 
taking opioids (or a closely related substance) to relieve or avoid withdrawal symptoms. 
 
³I have reviewed all inclusion/exclusion criteria and confirm the subject is eligible.´ 
 
 
CRC Name and Initials 
Date 
 
 
Enrolling Investigator Name (print) 
 
 
Enrolling Investigator Signature 
Date 


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4.11 Discontinuation of Study Treatment, Withdrawal, and Compliance 
Discontinuation from the study treatment does not mean discontinuation from the study. The 
subject will be considered in follow-up, study procedures should still be completed as indicated 
by the study protocol, and AEs/SAEs will continue to be reported according to this protocol. 
In the absence of treatment delays due to adverse events, study treatment/intervention may 
continue until:  
 
 
General or specific changes in the subject¶s condition renders the subject unacceptable 
for further treatment in the investigator¶s judgment.  
 
An inter-current illness that prevents further treatment administration.  
 
The subject decides to withdraw from the study.  
 
The subject has significant noncompliance with the protocol (see below).   
 
Unacceptable adverse event(s) and/or dose level reduction beyond requirements as 
detailed in this protocol.  
 
The clinical need for concomitant therapy that is not permitted in the study. 
 
Subjects who sign the informed consent form, enroll, and receive the study intervention, 
but subsequently withdraw, or are withdrawn or discontinued from the study will not be 
replaced.  
 
Consent Withdrawal 
A subject may decide to withdraw from the study at any time. MCWCC CTO will follow their IRB 
of record¶s SOPs regarding consent withdrawal.  
If a subject intends on withdrawing consent, staff should confirm which of the following options 
the subject chooses and document the discussion: 
 
Full consent withdrawal, with no study follow-up. 
 
Selective consent withdrawal from the interventional portion of the study but agree to 
continued follow-up of associated clinical outcome information.         
Investigator-initiated Withdrawal 
The investigator will withdraw a subject whenever continued participation is no longer in the 
subject¶s best interests. Reasons for withdrawing a subject include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a subject¶s request to 
end participation, a subject¶s noncompliance, or simply significant uncertainty on the part of the 
investigator that continued participation is prudent. The reason for study withdrawal and the date 
the subject was removed from the study must be documented. 
4.12 Lost to Follow-up 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit and/or is unable to be reached for follow-up: 
 


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The investigator or designee must make every effort to regain contact and/or reschedule a 
missed visit with the participant. 
 
A participant is deemed lost to follow-up if his/her status cannot be obtained after all of the 
following occurs at two consecutive scheduled protocol calendar timepoints: 
o Three telephone calls (at least one day apart) from the study team are unanswered,  
                  AND  
o A letter (Appendix 2) to the participant¶s last known mailing address goes unanswered, 
AND 
o These contact attempts must be documented in the participant¶s medical record or 
study file.  
 
Update OnCore® (Follow-up tab and eCRF) when a participant is officially considered lost to 
follow-up. 
 
If a subject is considered lost to follow-up, but subsequently contacts the study team, the 
subject should be considered in follow-up again. 
 
4.13 Accrual Suspension and Closure 
The MCW PI facilitates the suspension and closing of accrual in the following manner: 
 
 
OnCore® tracks accrual throughout the study. 
 
If the study must be suspended, OnCore® is updated to ³suspended´ status. 
 
When the accrual number is reached, OnCore® notifies staff of study closure. 
 
4.14 End-of-Study Definition 
A participant is considered to have completed the study if he or she completed all phases of the 
study, including the last visit or the last scheduled procedure shown in the calendar of events or 
has been discontinued. 
 
4.15 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause (as determined by the MCW study PI, DSMC, sponsor, and/or IRB). Written 
notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigator, funding agency, the 
investigational new drug (IND) sponsor, and regulatory authorities. If the study is prematurely 
terminated or suspended, the MCW principal investigator (PI) will promptly inform the MCW 
Institutional Review Board (IRB), and the sponsor and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed 
of changes. 
5 TREATMENT PLAN 
 
5.1 Study Intervention  
 
The main objective of this study is to provide preliminary evidence that the FDA-approved dose 
of transdermal buprenorphine in conjunction with oral tramadol can provide adequate analgesia 
of radiation-induced mucositis pain during treatment and the follow-up period in head and neck 


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cancer patients. There is no clear consensus definition of adequate pain relief in this setting. For 
the purpose of our trial, we have defined adequate analgesia as VAS  3/10 for 72 hours. 
Inadequate analgesia is defined as VAS>3/10 for 72 hours and unbearable pain as VAS>3/10 
for 96 hours based on some prior studies and titratability requirements of a TD buprenorphine 
dose. (16, 17). Patients found to be eligible for the study can be screened and enrolled anytime 
during first six weeks of radiation therapy. Pain app data monitoring, BPI, base line labs, and 
medical history as outlined in study calendar will be collected on the day of enrollment. 
Treatment with study regimen, collection of PROMIS®, MDASI, and other assessment data, as 
outlined in the study calendar will start once the patient develops mucositis and has a VAS 
4/10 pain score on the OM Pain App and BPI questionnaire (question 3: your pain at its worst 
in last 24 hours). Patients usually develop mucositis by the third to fourth of radiation therapy. 
Therefore, we anticipate treatment would begin by the fourth week in most patients, but it can 
start sooner if the patient develops mucositis and has VAS 4/10 pain. If a patient presents with 
radiation-induced mucositis pain on the day of enrollment, then all study procedures, including 
administration of the PROMIS® and MDASI will be completed that day. 
 
The OM Pain App will be installed on their smartphone. Subjects who do not have a smartphone 
will be provided with a wifi-enabled device with a pre-installed OM Pain App. Treatment with the 
study regimen will commence once at least grade 1 radiation-related mucositis is observed and 
mucositis-related pain measured by the visual analog scale (VAS) on BPI questionnaire  
(4/10) anytime during radiation therapy. Pain scores will be evaluated according to the visual 
analog scale (VAS), with 0 indicating no pain, 10 indicating the worst pain, 1±3 indicating mild 
pain, 4±6 indicating moderate pain, and scores 7 indicating severe pain. Investigators in earlier 
studies on radiation-induced mucositis pain have used Tylenol®, NSAIDS, and viscous lidocaine 
to manage mild pain and initiated long-acting pain medications like buprenorphine and fentanyl 
patch to treat moderate to severe pain. For the study purposes, we decided to start the 
treatment regimen once radiation mucositis pain  4/10 VAS pain score on the BPI and pain 
app. The study drug combination, including transdermal buprenorphine 5 mcg to 20 mcg/week 
with oral tramadol 50 mg to 400 mg/day as needed for breakthrough pain (details in Table 2),  
will be provided to the study population. Drug will be dispensed by investigators after verifying 
opioid use information on WIPDMP. Radiation-induced mucositis begins to heal approximately 
two weeks after the last dose of stomatotoxic chemotherapy or radiation therapy.(30, 32) We 
will assess a percentage decrease in pain score by the end of week 9 of treatment to show a 
drug response. This way, we will try to avoid any bias of the normal healing process on pain 
alleviation. Based on our clinical practice experience and earlier studies, most HN patients will  
continue to have moderate to severe mucositis pain until 12 weeks of the follow-up period. 
Thus, we decided to monitor these patients for 12 weeks in our study.(32) Moreover, it would be 
easier to focus on the side effect profile of the study drug combination after completion of 
radiation therapy, as both chemotherapy and radiation may confound adverse event 
assessment of study drug regimen.  
 
We will quantify and evaluate mucositis-related pain through the serial VAS-based pain app and 
BPI short form during a 12-week period (including first seven weeks of radiation and five weeks 
of the follow-up period). Real-time pain assessments will be done through the OM Pain App. The 
pain app will record pain readings up to four times daily. Pain scores will also be recorded through 
BPI short form questionnaires. The clinical research coordinator or investigator will also record 
symptom severity and functional assessments through the MD Anderson Symptom Inventory- 
Head and Neck (MDASI-HN) questionnaires. PROMIS® gastrointestinal and cognitive 
questionnaires will be used to evaluate gastrointestinal and cognitive side effects of the study 
regimen. These assessments will be completed during weekly clinic visits as per study calendar. 


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Study assessments can also be completed virtually through a video/telephone visit during the 
post-treatment follow-up period (weeks 8±12). Dose titration of pain medications as per study 
protocol will be made over the telephone by investigators or sub-investigators. Patients will leave 
a MyChart message on EPIC (electronic medical record) if their pain remains uncontrolled on the 
prescribed dose of pain medications. These changes will be documented as a telephone 
encounter in the patient¶s EMR.  
We expect that adequate pain control will be achieved with a titratable dose of the (buprenorphine 
and tramadol) study regimen throughout the treatment and follow-up period of 12 weeks, using 
the above-mentioned pain assessment tools. We are planning to use a smartphone application 
(oral mucositis pain app) designed to permit patients to key in pain severity, using a visual analog 
0±10 scale in a real-time setting. Deidentified data collected on each patient¶s smartphone will be 
backed up wirelessly to secure cloud storage where the data can be analyzed remotely. The 
software can generate a time-weighted measure of pain, total area under the pain curve (AUC). 
It also monitors drug compliance and use of rescue pain medications. Head and neck cancer 
patients being treated with radiation with or without chemotherapy endure maximum radiation-
related toxicities during first seven weeks of treatment. During this period, the pain curve often 
follows an unpredictable nonlinear pattern; hence, it is difficult to predict peaks and troughs of the 
pain curve of an individual during radiation. We will study the radiation-induced mucositis pain 
curve patterns during the therapy and follow-up period. We hypothesize that at least 33% of 
patients being treated with the drug regimen will have a 30% decrease from the highest baseline 
mean weekly AUC pain score by end of week 9. Earlier studies have shown that a 30% drop in 
mean AUC pain score from baseline value was significant and suggestive of drug efficacy.(28, 
33). 
As noted earlier, radiation-induced mucositis begins to heal approximately two weeks after the 
last dose of stomatotoxic chemotherapy or radiation therapy.(30, 32) Hence, we will assess a 
percentage drop in pain score by the end of week 9 of treatment to show a drug response. This 
way we will be able to avoid any bias of the normal healing process on pain alleviation. Studies 
have also shown that painful mucositis continues four to five weeks after the termination of 
radiation therapy. Thus, we plan to continue the study drug regimen up to 12 weeks. (17) (32) 
Recording of data will cease after 12 weeks, at which time mucositis-related pain symptoms 
substantially abate in many individuals. Details on buprenorphine and tramadol dose 
determination and titration are included in Section 5.2 of this protocol. Post-marketing data of 
buprenorphine, other opioid studies, and clinical experience have shown that around 20 percent 
of the patients receiving  transdermal buprenorphine may have inadequate pain control and 
require rescue off-protocol pain medications despite being on the highest titratable dose of 
buprenorphine. Therefore, we have allowed the use of oxycodone in situations where pain is 
uncontrolled on highest titratable doses of the drug regimen and plan to monitor the use off-
protocol pain oxycodone in our study.(17, 34) 
Details for the use and logistics of the OM Pain App, as well as the measure of the patient¶s 
compliance to the use of the pain app are detailed below. This study will not interfere with or 
cause adjustments to the standard-of-care treatments each patient will receive as determined by 
their multidisciplinary team of cancer doctors. To this end, basic treatment descriptions and 
standards are briefly described as a reference to ensure proper patient selection and to verify that 
patients observed on the trial will be somewhat homogeneous from a treatment perspective. A 
short description of possible supportive treatments that could be needed during treatment is also 
included. All study interventions and treatments will be administered on an outpatient basis. 


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5.2 Dose Determination for Buprenorphine and Tramadol 
Based on our clinical experience and earlier studies barring exceptions, the typical MEDD dose 
of standard-of-care regimens, such as oxycodone, morphine and fentanyl patch used in the 
treatment of radiation-induced mucositis can range from 20 to 90 mg. Buprenorphine is a potent 
opioid substitute but there is no consensus at equipotency ratio for morphine to transdermal 
buprenorphine. Some authors have reported that it lies somewhere between 75:1 to 100:1.(34) 
This makes finding the appropriate morphine equivalent daily dose (MEDD) for buprenorphine in 
controlling mucositis-related pain a challenging task. For our study, we used 75:1 equipotency 
ratio to calculate our morphine equivalent daily dose (Table 1). As transdermal buprenorphine is 
a long-acting medication, we plan to allow tramadol 50 mg (total daily dose) as needed for 
breakthrough pain up to 400 mg/day (total daily dose), which roughly translates to 5 mg to 40 mg 
MEDD. Steady-state plasma buprenorphine concentration levels are achieved by day 3, during 
the first application of buprenorphine. Therefore, it can be titrated after a minimum of 72 hours. 
We hope to evaluate the possibility of using tramadol to facilitate dose adjustment of 
buprenorphine. With the buprenorphine and tramadol combination, we hope to provide MEDD to 
patients which is comparable to other standard-of-care opioids. There is no clear consensus 
definition of adequate and inadequate pain relief in this setting. However, it is well known that a 
VAS pain score of  3/10 is considered mild intensity pain in multiple settings. Based on some 
earlier studies and the titratability of TD buprenorphine dose, we have defined  adequate 
analgesia as VAS  3/10 for 72 hours, inadequate analgesia as VAS>3/10 for 72 hours, and 
unbearable pain as VAS>3/10 for 96 hours.(16, 17) If patients have unbearable pain (VAS > 3/10 
x 96 hours) despite being on highest dose of the buprenorphine patch and tramadol, then,  we 
will switch from tramadol to oxycodone for breakthrough pain and continue treatment with 
buprenorphine. We will titrate this combination as needed for pain control until study completion.  
Some authors have also shown the benefit and safety of using immediate-release oxycodone in 
conjunction with transdermal buprenorphine for moderate to severe pain.(35)  If the pain is still 
uncontrolled >3/10 for 72 hours, even after using oxycodone 90 mg/day with buprenorphine 20 
g/hour, then, the patient will be taken off the study regimen. However, data monitoring will 
continue. Patients suffering intolerable side effects (severe constipation, vomiting, headache, 
pruritis, sedation, or respiratory depression, etc.) or those who wish to switch to standard-of-care 
oxycodone due to ineffective pain control or unclear reasons at any time during the study will be 
taken off study regimen. However, data monitoring through the pain app and questionnaires will 
continue. The dose titration schedule is illustrated in Table 2. 
 
5.3 Morphine Daily Dose Equivalent of TD Buprenorphine 
 
 
 
 
 
 
 
Table 1:  
Buprenorphine patch  
Morphine equivalent daily dose  
5 mcg/hr  
9 mg  
10 mcg/hr  
18 mg  
15 mcg/hr 
27 mg  
20 mcg/hr 
36 mg 


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5.4 Drug Regimen Titration Schedule  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2  Drug Titration Schedule 
Drug: Buprenorphine with tramadol for breakthrough pain (First seven weeks of study) T = 0±
7 weeks;  
Start TD buprenorphine 5 g/hour along with oral tramadol 50 mg to 150 mg (total dose over 24 
hours) as needed for breakthrough pain when mucositis related pain is 4/10 on VAS 
measured on OM Pain App and BPI. Further dose adjustments will be made through pain app. 
 
If VAS is >3/10 for 72 hours on tramadol 150 mg (total dose over 24 hours) and 
buprenorphine 5 g/hour, then, increase tramadol to 250 mg (total dose over 24 hours).   
 
If VAS is >3/10 for 72 hours, even with tramadol 250 mg (total dose over 24 hours) and 
buprenorphine 5 g/hour, then, increase dose of buprenorphine to 10 g/hour.  
 
If the pain persists VAS>3/10 for 72 hours on tramadol 250 mg (total dose over 24 
hours) and 10 g/hour, then, increase the dose of tramadol to 350 mg (total dose over 
24 hours).  
 
If VAS pain is >3/10 x 72 hours with both tramadol 350 mg (total dose over 24 hours) 
and buprenorphine 10 g/hour, then, increase dose of buprenorphine to 15 g/hour.  
 
If VAS pain >3/10 x 72 hours on tramadol 350 mg (total dose over 24 hours) and 15 
g/hour of buprenorphine, then, increase the dose of tramadol to 400 mg (total dose 
over 24 hours) and buprenorphine to 20 g/hour. 
 
If the pain persists and is unbearable at >3/10 for 96 hours, despite being on highest 
dose of both drugs, then, replace tramadol with oxycodone at the clinician¶s discretion 
up to 90 mg (total dose over 24-hour period) for pain relief.  
 
If VAS is 3/10 maintained for 72 hours, then, we can start tapering off total daily 
tramadol dose by 50 mg every day, but not change the buprenorphine dose during the 
first seven weeks of treatment, as mucosal injury from ongoing radiation may increase 
pain later.    
 
(Post-radiation period) T = 8±12 weeks:  if necessary, increase dose of buprenorphine up to 
20 mcg along with tramadol up to 400 mg/day as per titration schedule used in the first seven 
weeks until VAS is 
3/10. If pain is well controlled (VAS 3/10 x 72 hours), start weekly 
tapering of buprenorphine by 5 mcg and tramadol by 50 mg daily. 
 
Special Circumstances 
If pain is uncontrolled with VAS >3/10 x 72 hours on 90 mg oxycodone (total dose over 24-hour 
period) and 20 g/hour of buprenorphine, then, buprenorphine patch can be taken off and other 
stronger pain medications can be started at clinician¶s discretion. If the patient is admitted and 
requires IV pain medication for pain control, then, the study drug regimen will be held, and data 
monitoring will stop for that time. The patient can be discharged on the study regimen (tramadol 
and buprenorphine) or a combination of oxycodone and buprenorphine patch or any other 
combination at clinician¶s discretion, and data monitoring will resume.  
 


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5.5 Availability 
Both tramadol and buprenorphine are FDA approved and commercially available 
5.6 Usage of Concurrent/Concomitant Medications 
Use of all the medications mentioned below are allowed  
 
Antidiarrheal like loperamide and Lomotil (atropine and diphenoxylate). 
 
Antiemetics like prochlorperazine, steroids or serotonin antagonists may be used if 
clinically indicated. 
 
Antihistamines. 
 
Topical steroid creams. 
 
Anticoagulants. 
 
Viscous lidocaine. 
 
NSAIDS before starting study regimen.  
 
Tylenol® before starting study drug regimen or any time for fever.   
 
CYP3A4 inhibitors and inducers: Buprenorphine is mainly a substrate of CYP3A4, and the 
manufacturers and others advise caution in its concurrent use with CYP3A4 inhibitors (e.g., 
cimetidine, clarithromycin, erythromycin, itraconazole, ketoconazole, protease inhibitors), 
because it may cause decreased clearance of buprenorphine, which could lead to an increase 
in buprenorphine plasma concentrations and result in increased or prolonged opioid effects. If 
coadministration with TD buprenorphine is necessary, monitor patients for respiratory 
depression and sedation at frequent intervals and consider dose adjustments until stable drug 
effects are achieved. Similarly, CYP3A4 inducers (e.g., carbamazepine, phenobarbital, 
phenytoin, rifampin) could reduce buprenorphine levels. These agents should be avoided during 
treatment with study regimen. If coadministration or discontinuation of a CYP3A4 inducer with 
TD buprenorphine is necessary, monitor for signs of opioid withdrawal and consider dose 
adjustments until stable drug effects are achieved. 
 
Anticholinergics: Anticholinergics or other drugs with anticholinergic activity when used 
concurrently with opioid analgesics may result in increased risk of urinary retention and/or 
severe constipation. Monitor patients for signs of urinary retention or reduced gastric motility 
when TD buprenorphine is used concurrently with anticholinergic drugs. 
 
5.7 Prohibited Medications 
 
Alcohol, and use of other opioids, such as fentanyl or morphine or hydromorphone will not be 
allowed with study drug regimen. CNS depressants, such as benzodiazepines, antidepressants, 
antipsychotics should be used with caution as concurrent use of these agents with any opioids 
including buprenorphine can increase the risk of respiratory depression, profound sedation and 
in rare cases even coma and death. 
 


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5.8 Monitoring Subject Compliance  
Study drug can be dispensed only to eligible patients under the supervision of the investigator or 
identified sub-investigator(s). The appropriate study personnel will maintain records of study 
drug receipt through WIPDMP website.  
5.9 OM Pain App  
5.9.1 Device Description/Overview 
The Oral Mucositis (OM) Pain App is a smartphone application that was designed to permit 
patients to key in pain severity using a visual analog 0±10 scale. The app is programed with an 
alarm to prompt the patient to record pain severity at prescribed intervals daily and through 
spontaneous patient input. Time intervals for prompted pain queries can be customized, when,  
for instance, patients work a night shift or have specific sleep/wake cycle preferences. 
Deidentified data collected on each patient¶s smartphone will be transferred wirelessly to cloud 
storage.  Data transmitted wirelessly will use HTTP secure (HTTPS) sessions and JSON/XML 
protocols, such as the security used in online banking. Security measures and only deidentified 
data will be transmitted. Study participants will be encouraged not to update the  smartphone 
operating system during the conduct of the study. Study PIs and/or study coordinator will 
perform OM Pain App software updates on smartphones. 
Analysis of data collected from smartphones will be performed from cloud-stored data on 
deidentified sources only. This would be done in collaboration with our co-investigators at 
University of Wisconsin Milwaukee (UWM). The raw pain scores will be used to generate a time-
weighted measure of pain called total area under the pain curve (AUC). Average weekly pain 
scores will also be calculated. This is a summary measure that integrates serial assessments of 
a patient¶s pain over the duration of the study. Architecture of the pain app is illustrated in 
figures 1 and 2.  
5.9.2 Device Distribution to Subjects 
The OM Pain App will be installed on the smartphone of each participant. If during the conduct 
of the study, a smartphone is lost, stolen, or broken, the subject will not be responsible for the 
cost of the device.   
The study is designed for Android platform. However, an iOS app will be developed for the 
iPhone and will also be tested during this project. See figures 1 and 2 for further illustration and 
description of architecture, framework, and IT network for mobile platforms.  
Deidentified data will be transmitted by wifi to a cloud storage server. Patients who do not have 
a smartphone will be issued a device with the OM Pain App installed on it at the initiation of their 
participation in the study. These phones will not have an active cellular phone service; but will 
have active wifi. Syncing of data from the phone will occur by hardwire connection (during initial 
testing) or by wifi (later during software testing). The device will be collected from participants at 
the end of the study period.  
5.9.3 Daily Intervention 


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If enrolled, patients can start using the app up to one week prior to radiation therapy for training 
and practice. Formal data monitoring would only start once patients start study drug regimen. As 
noted,subjects will receive a preprogrammed alarm four times a day from their smartphones 
prompting them to directly enter OM pain levels on the device. Patients may submit as many pain 
entries as they wish beyond the four minimum levels. The software also allows patients to 
document self-administration of breakthrough pain medication. This event will prompt immediate 
entry of a pain level and an automatic pain assessment one-half hour later. Because symptoms 
of mucositis do not commence typically until the third week of radiation therapy, and no sooner 
than week 2, we don¶t expect to start data recording earlier than that. Recording of data will cease 
five weeks (week 12) after the end of radiation therapy at which time mucositis symptoms typically 
start to resolve and pain symptoms substantially abate (see the schema). 
5.9.4 Avoiding Bias: A viewable graphic summary of pain scores will be a functionality of the app 
but will be disabled in this study to avoid bias of care provider or participant. For the feasibility 
phase, patients and providers will be blinded to the pain scores and symptoms will be managed 
with supportive treatments during routine weekly provider visits and symptom-initiated clinical 
visits.    


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5.9.5 Monitoring Compliance: The study coordinator will download data and check the 
equipment weekly for proper functioning and compliance. Patients will be interviewed weekly to 
assure the device is functioning correctly and that data are being recorded. Compliance with the 
device use will be assessed by the percent adherence to the device prompted four times daily 
pain assessment.  
5.10 Patient-Reported Outcomes Measurement Information System (PROMIS®) 
To study the side effect profile of patients treated with transdermal buprenorphine and tramadol,  
we will use (PROMIS®) questionnaires. We will use PROMIS® cognition and gastrointestinal side 
effect assessment questionnaires for our secondary outcome analysis. For example, PROMIS® 
GI Symptom instrument has 60 items and assesses eight domains: gastroesophageal reflux (13 


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items), disrupted swallowing (seven items), diarrhea (five items), bowel incontinence/soilage (four 
items), nausea and vomiting (four items), constipation (nine items), belly pain (six items), and gas 
/bloating /flatulence (12 items). For the study purposes, we will only be using disrupted 
swallowing, constipation and nausea/vomiting forms. A higher score denotes more GI symptoms. 
Similarly, the PROMIS® Applied Cognition short form has four questions. A higher cognition score 
would denote more cognitive impairment. The recall period for PROMIS® GI Symptom items is 
around one week. We will be collecting PROMIS® data weekly through an in-person visit or 
through telephone interviews for up to 12 weeks. We hope to quantify and measure severity of 
study regimen-related side effects. We also plan to record frequency of antinausea, laxative and 
oral anesthetic use. We expect that buprenorphine will have manageable GI and cognitive side 
effect profile. (25, 26) The PROMIS® GI and cognition forms are included in appendix section of 
this protocol.  
5.11 Other Functional, Symptom Assessments 
A compliance questionnaire that has been previously used to test an electronic pain diary will be 
administered periodically by the study coordinator, as per study calendar. The coordinator who is 
trained in using the WHO mucositis scale will grade mucositis weekly during radiation therapy. 
The Brief Pain Inventory questionnaire and MDASI-HN will also be administered weekly during 
radiation therapy and the follow-up period, as per study calendar. These questionnaires can also 
be administered through a telephone interview by a provider or CRC. All responses in the BPI 
(24) short form will be recorded, including severity of pain, impact of pain on daily function, location 
of pain, pain medications, and amount of pain relief in the past 24 hours or the past week 
MDASI consists of 28 question items. Along with the core MDASI¶s 13 symptom items and 
six interference items, the MDASI-HN (21) also assesses nine symptoms relevant to head and 
neck cancer, such as mucus in the mouth and throat, difficulty swallowing or chewing, choking or 
coughing, difficulty with voice or speech, skin pain/burning/rash, constipation, problems with 
tasting food, mouth/throat sores and problems with teeth or gums. Copies of the BPI and MDASI 
forms are included in appendix section of this protocol.  
5.12 Opioid and Non-Opioid Drug Use Assessments 
Patients and family members will be asked to maintain a drug diary at home to document use of 
opioids, laxatives, antiemetics, and oral anesthetics. Record of the opioid pain medications, 
laxatives, and antiemetics from patient drug diary will be copied by the investigators / CRC on 
weekly clinic visits. Opioid drug use will also be monitored by investigators through Wisconsin 
Prescription Drug Monitoring Program - WI (PDMP). 
6 ADVERSE EVENTS: DEFINITIONS, COLLECTION AND REPORTING REQUIREMENTS 
 
6.1 Definitions 
6.1.1 Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. (International Conference on Harmonization [ICH], E2A, E6). 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0, located on the CTEP web site: 


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https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Adverse events (AEs) may be spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures. 
For the purpose of the study, only the adverse events related to the study intervention will be 
reported for regulatory oversight (e.g., related to OM Pain App, drug regimen of buprenorphine 
and tramadol, etc.).   
Adverse events related to anticancer therapy will not be reported, as these treatments are 
considered standard of care and are not the focus of investigation of this trial.   
Some patients who are enrolled in a therapeutic clinical trial may also be eligible for the present 
study. Adverse events related to cancer treatment in these patients will be reported under the 
umbrella of their active treatment clinical trial.   
For this study, adverse events may be defined as follows:  
 
Loss of device (including theft,). AirWatch will be loaded on each mobile device that is 
provided to participants. MCW Information Service agrees to provide oversight and 
assistance to deactivate lost or stolen devices.  
 
Loss of protected health information.  
 
Established side effects of tramadol and buprenorphine for example: skin reaction to 
transdermal patch, central nervous system depression, respiratory compromise or 
hypercapnia due to drug regimen use, prolonged QTc> 500 ms, new onset seizures, and 
gastrointestinal side effects not attributable to standard-of-care radiation and 
chemotherapy. For details, refer to Section 7.   
 
Radiation related Adverse Events  
 
Radiation toxicity data will be used to associate with OM pain data. All acute and late adverse 
events from radiation therapy will be recorded and scored for severity using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. As noted, a copy of the CTCAE 
v5.0 can be downloaded from the CTEP home page ( https://ctep.cancer.gov/). While radiation 
therapy side effects will be recorded, they will not be reported as adverse events for the purpose 
of the study, because its purpose is to evaluate the efficacy of the study drug regimen.  The 
radiation therapy will be delivered according to the standard of care and not directed by this 
protocol.  
Chemotherapy Adverse Events  
Chemotherapy-related toxicity data will be used to associate with OM pain data. All acute and late 
adverse events from chemotherapy will be recorded and scored for severity using the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicity data will be 
recorded because cumulative toxicity may have indirect effects on pain perception.   


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While chemotherapy side effects will be recorded, they will not be reported as adverse events for 
the purpose of the study, because the purpose of this study is to evaluate the efficacy of 
buprenorphine and tramadol combination regimen.  
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to adverse event reporting. This information may be found on the Human Research Protection 
Program website.   
6.1.2 Serious Adverse Event (SAE)  
Serious Adverse Event (SAE) means any untoward medical occurrence that results in any of the 
following outcomes: 
 
Death. Results in death. 
 
Life-threatening. Is life-threatening (refers to an AE in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (see clarification in the paragraph below on planned hospitalizations). 
 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person¶s ability to conduct normal life 
functions). 
 
Pregnancy 
 
Medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious 
when based on appropriate medical judgment, may jeopardize the patient, require medical 
or surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse; any organism, virus, or infectious 
particle (e.g., prion protein transmitting transmissible spongiform encephalopathy), 
pathogenic or nonpathogenic, is considered an infectious agent. 
 
6.1.3 Attribution of an Adverse Event 
An assessment of the relationship between the adverse event and the medical intervention, using 
the following categories: 
Related: The AE is clearly related to the intervention. There is clear evidence to suggest a causal 
relationship, and other possible contributing factors can be ruled out. The AE is likely related to 
the intervention. There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The AE may be related to the intervention. There is some evidence to suggest 
a causal relationship (e.g., the event occurred within a reasonable time after administration of the 
trial medication). However, the influence of other factors may have contributed to the event (e.g., 
the subject¶s clinical condition, other concomitant events).  
 
Unrelated: The AE is doubtfully related to the intervention. A clinical event, including an abnormal 
laboratory test result, whose temporal relationship to drug administration makes a causal 


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relationship improbable (e.g., the event did not occur within a reasonable time after administration 
of the trial medication) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the subject¶s clinical condition, other concomitant treatments). The 
AE is clearly NOT related to the intervention. The AE is completely independent of study drug 
administration, and/or evidence exists that the event is definitely related to another etiology.  
 
6.1.4 Expectedness of an Adverse Event 
Study Investigator or treating Physician will be responsible for determining whether an AE is 
expected or unexpected as indicated in Reference Safety Information within drug information 
brochure. An AE will be considered unexpected if the nature, severity, or frequency of the event 
is NOT consistent with the risk information previously described in the reference safety 
information for the investigational product for the study intervention. 
 
6.2 Collection and Reporting Requirements for Adverse Events and Serious Adverse   
      Events 
6.2.1 Collection of Adverse Events 
All adverse events (including SAEs) must be recorded in OnCore® and/or an adverse event log. 
All AEs required to be collected must be graded according to the CTCAE v5. When possible, 
signs and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event. Investigator¶s or treating physician¶s assessment of AE attributions must 
also be documented.  
 
AEs will be collected from the time of initiation of drug regimen to the end of follow up period. AEs 
will be tracked and followed until resolution, subject withdraws consent, or is lost to follow-up 
(including subjects who discontinue early). All adverse events collected per the protocol will be 
followed with appropriate medical management until they are resolved, if they are related to the 
study treatment, or until the investigator deems the event to be chronic.  
 
Please see sections 6.1.1, 6.2.2 and Table 3 to identify the adverse events that need to be 
reported.  
 
6.2.2 Reporting of Adverse Events and Serious Adverse Events 
Please refer to Table 3 below to identify adverse events that meet reporting requirements. All 
serious adverse events (SAEs) that occur after the subject has signed the consent form through 
30 days post last dose of study drug(s) will be reported. All SAEs will be followed until satisfactory 
resolution, or until the investigator deems the event to be chronic. All serious adverse events 
(SAEs) must also be documented in OnCore®. 
 
 
 
 
 
 
 


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Table 3: Adverse Events and Serious Adverse Events Reporting Requirements. 
Attribution 
SAE 
AE 
Grade 1, 2 & 3 
Grade 4 and 5 
Grade 3 
Grade 4 
Expected 
Unexpected 
Expected 
Unexpected 
Unexpected 
Expected 
Unexpected 
Unrelated 
Unlikely 
IRB1 and 
DSMC- 
Routine 
Review2 
IRB1 and 
DSMC- 
Routine 
Review2 
IRB1- 
Routine 
Review2
DSMC3-
Within 5 
calendar 
days 
IRB1- 
Routine 
Review2 
DSMC3-
Within 5 
calendar 
days 
DSMC2- 
Routine 
Review 
DSMC3-
Within 5 
calendar 
days 
DSMC3-
Within 5 
calendar 
days 
Possible 
Probable 
Definite 
IRB1 and 
DSMC3- 
Within 5 
calendar 
days 
IRB1 and 
DSMC3- 
Within 5 
calendar 
days 
Footnotes 
1 Guidance on adverse event reporting to the IRB will follow the current MCW IRB Policies and Procedures. 
2 For routine reporting, the events will be reported to IRB as part of the annual continuing progress report, and the 
DSMC will review events entered in OnCore at the time of scheduled monitoring. 
3 For expedited DSMC reporting, study coordinator/research nurse must notify the DSMC via email. For AEs, include 
the subject ID, date of event, grade, relatedness, expectedness, and a short narrative. For SAEs, DSMC will review 
the SAE report entered into OnCore. 
 
6.3 Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found on 
the Human Research Protection Program website.  
6.4 Subject Complaints 
If a complaint is received by anyone on the study staff, it will be discussed with the study staff and 
will be addressed on a case-by-case basis. The PI will be notified of any complaints. Complaints 
will be reported to the IRB if indicated.  
If the subject has questions about his or her rights as a study subject, wants to report any 
problems or complaints, obtain information about the study, or offer input, the subject can call the 
Medical College of Wisconsin/Froedtert Hospital research subject advocate at 414-955-8844. 
This information is provided to the subject in their consent.  


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A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately contact the drug manufacturer 
and report the event. Whenever possible, the associated product should be maintained in 
accordance with the label instructions pending further guidance from a drug manufacturer 
representative. Product complaints in and of themselves are not reportable events. If a product 
complaint results in an SAE, an SAE form should be completed. 
7 PHARMACEUTICAL INFORMATION 
7.1 Buprenorphine  
7.7.1 Mechanism of Action 
Buprenorphine is a derivative of the thebaine, which has mixed agonistic activities. It exerts an 
agonistic effect on µ opioid and the OR L1 receptors, but it has antagonistic effect on kappa and 
delta opioid receptors.(13, 36) It is also a low-molecular weight compound (467 g/mol), has a 
low melting point, is lipophilic and water soluble, making it an ideal candidate for transdermal 
administration. (37) 
7.1.2 Formulation Used 
Transdermal buprenorphine with a polymeric active matrix is superior to some of the other long-
acting opioids in terms of therapeutic efficacy and compliance. Continuous and controlled release 
of drug by passive diffusion through polymeric matrix maintains a constant level of buprenorphine 
in plasma. This effect gives transdermal buprenorphine an edge over some of the other long-
acting opioids, as there is less likelihood of side effects related to periodic plasma drug level 
surges associated with some of the other opioids. The longer half-life of buprenorphine and its 
high affinity to the µ-receptor make it longer lasting and up to 100 times more efficacious (per mg) 
as an analgesic than morphine. For usage as a transdermal patch, buprenorphine is incorporated 
into an adhesive polymer matrix (acrylate vinyl acetate), from which it is continuously released 
into the systemic circulation over a period of seven days. Buprenorphine transdermal patch (BTP) 
is available in three strengths ² 5, 10, and 20 mg ² with a rate of drug release of 5, 10, and 20 
mg/h, respectively. Following removal of the patch, concentrations decrease to about one-half in 
12 hours, and then decline more gradually with an apparent half-life of about 26 hours.(38) 
Unlike other opioids, it has a ceiling effect, which means its effects increase until the person takes 
a certain amount; then, these effects level off. This limits euphoria and respiratory depression. 
7.1.3 Metabolism 
Buprenorphine is metabolized by the liver, via CYP3A4 (also CYP2C8 seems to be involved) 
isozymes of the cytochrome P450 enzyme system into norbuprenorphine (by N-dealkylation). The 
glucuronidation of buprenorphine is primarily carried out by UGT1A1 and UGT2B7, and that of 
norbuprenorphine by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly 
through excretion into bile. The elimination half-life of buprenorphine is 20 to 73 hours (mean 37 
hours). Due to the mainly hepatic elimination, there is no risk of accumulation in people with renal 
impairment.(39) One of the major active metabolites of buprenorphine is norbuprenorphine, 
which, in contrast to buprenorphine itself, is a full agonist of the MOR, DOR, and ORL-1, and a 
partial agonist at the KOR. However, relative to buprenorphine, norbuprenorphine has extremely 
little antinociceptive potency (1/50th that of buprenorphine), but markedly depresses respiration 
(10-fold more than buprenorphine). This may be explained by very poor brain penetration of 


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norbuprenorphine due to a high affinity of the compound for P-glycoprotein. In contrast to 
norbuprenorphine, buprenorphine and its glucuronide metabolites are negligibly transported by 
P-glycoprotein. The glucuronides of buprenorphine and norbuprenorphine are also biologically 
active and represent major active metabolites of buprenorphine. Buprenorphine-3-glucuronide 
has affinity for the MOR, DOR, and ORL-, and no affinity for the KOR. It has a small 
antinociceptive effect and no effect on respiration. Norbuprenorphine-3-glucuronide has no affinity 
for the MOR or DOR but does bind to the KOR (Ki = 300 nm.) and ORL-1 (Ki = 18 M). It has a 
sedative effect but no effect on respiration.(40, 41) 
 
7.1.4 Contraindications 
The only true contraindication to buprenorphine use is a hypersensitivity reaction to it. Its use 
requires caution in patients with respiratory depression, seizure disorder, and gastrointestinal 
obstruction. It should be avoided in patients with gastrointestinal obstruction and surgical 
abdomen, such as pancreatitis or appendicitis. Patients with significant respiratory depression, 
such as severe chronic COPD, asthma, or myasthenia gravis should not be given buprenorphine. 
Buprenorphine is also not a recommended agent for patients who are currently using full opioid 
agonists, such as heroin or morphine, because the concurrent use of a full and partial agonist 
may result in acute withdrawal (see "Monitoring"), thus, defeating the purpose of buprenorphine 
administration. Concurrent use of benzodiazepines, other CNS depressants and alcohol is 
prohibited. (42) 
 
7.1.5 Side Effects  
Common side effects (>5%) of buprenorphine include nausea, vomiting, constipation, drowsiness, 
dizziness, headache, and sweating. It may also cause central nervous system depression, 
respiratory depression, and QT prolongation. Anticholinergic side effects like dry mouth, miosis, 
orthostatic hypotension, and urinary retention are also seen. Transdermal patches are also 
associated with contact dermatitis in some individuals. (42) If QTc prolongation of more than 500 
ms is noticed, then, buprenorphine should be held until it is less than 470 ms. If respiratory 
depression is observed, then, remove buprenorphine patch, give oxygen, administer IV naloxone 
2 mg stat over 90 secs in the hospital or urgent care setting.  
 
7.1.6 Special Considerations  
It is not recommended in pregnant and lactating women, as it is category C medication, and it 
does pass into breast milk.  
HIV: 
Since many HAART drugs also affect the liver microsomal enzymes, healthcare workers should 
closely monitor liver function and drug levels in patients who have buprenorphine prescribed at 
the same time. In some patients, the dose of buprenorphine may require alteration. 
Hepatitis:  
Both hepatitis B and C are common comorbid conditions in opioid-dependent patients. Since 
buprenorphine break down occurs in the liver, these patients should have their liver function and 
drug levels closely monitored. Clinicians should caution patients with hepatitis that intravenous 
use of buprenorphine has correlations with liver damage. 
Complete and updated information is available in the investigational drug brochure and/or product 
package insert.  


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Others: Specific patient populations, such as the elderly, debilitated patients, or those with pre-
existing pulmonary disease are at greater risk of respiratory depression with buprenorphine. It 
should be used with extreme caution in these individuals.  
7.1.7 Dose Adjustments: No dose adjustments for liver or renal impairment required for TD 
buprenorphine. Refer to Table 3.  
7.1.8 Drug Administration and Handling: Instruct patients to apply it immediately after 
removal from the individually sealed pouch. Instruct patients not to use TD buprenorphine if the 
pouch seal is broken or the patch is cut, damaged, or changed in any way. See the instructions 
for use for step-by-step instructions for applying TD buprenorphine. TD buprenorphine can be 
applied to any of these sites, including the upper outer arm, upper chest, upper back or the side 
of the chest. These four sites (each present on both sides of the body) provide eight possible 
application sites. The patients should be advised as follows: Rotate TD buprenorphine among 
the eight described skin sites. After TD buprenorphine removal, wait a minimum of 21 days 
before reapplying to the same skin site. Apply the patch to a hairless or nearly hairless skin site. 
If none are available, the hair at the site should be clipped, not shaven. Do not apply the TD 
buprenorphine to irritated skin. If the application site must be cleaned, clean the site with water 
only. Do not use soaps, alcohol, oils, lotions, or abrasive devices. Allow the skin to dry before 
applying TD buprenorphine. Incidental exposure of the TD buprenorphine patch to water, such 
as while bathing or showering is acceptable based on experience during clinical studies. If 
problems with adhesion of TD buprenorphine occur, the edges may be taped with first aid tape. 
If problems with lack of adhesion continue, the patch may be covered with waterproof or 
semipermeable adhesive dressings suitable for seven days of wear. If the TD buprenorphine 
patch falls off during the seven-day dosing interval, dispose of the transdermal system properly 
and place a new drug patch on at a different skin site. When changing the system, instruct 
patients to remove TD buprenorphine and dispose of it properly. If the buprenorphine-containing 
adhesive matrix accidentally contacts the skin, instruct patients or caregivers to wash the area 
with water and not to use soap, alcohol, or other solvents to remove the adhesive because they 
may enhance the absorption of the drug.  
 
Disposal Instructions:  Patients should refer to the instructions for use for proper disposal of 
TD buprenorphine. Dispose of used and unused patches by following the instructions on the 
Patch-Disposal Unit that is packaged with the TD buprenorphine patches. Alternatively, patients 
can dispose of used patches by folding the adhesive side of the patch to itself, then flushing the 
patch down the toilet immediately upon removal. Unused patches should be removed from their 
pouches, the protective liners removed, the patches folded so that the adhesive side of the 
patch adheres to itself, and immediately flushed down the toilet. Patients should dispose of any 
patches remaining from a prescription as soon as they are no longer needed.  
 
Rash Related to TD buprenorphine:  
Erythema and mild pruritis from TD buprenorphine are common. If localized erythema or rash is 
observed, then, the site of application of patch should be changed. In rare cases, if severe 
application site skin reactions with signs of marked inflammation including ³burn,´ ³discharge,´ 
and ³vesicles´ are noticed, then, the patch should be discontinued. If severe anaphylactic 
reaction, bronchospasm or angioedema occurs from the study drug regimen then it should be 
discontinued.   


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Refer to package insert for details on management of other adverse events 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021306s015s019lbl.pdf 
7.2 Tramadol  
7.2.1 Mechanism of Action 
Tramadol is an atypical synthetic compound that acts as a -opioid receptor agonist, serotonin 
releasing agent norepinephrine reuptake inhibitor, NMDA receptor antagonist (IC50=16.5 M), 5-
HT2C receptor antagonist (EC50=26 nM), ( 7)5 nicotinic acetylcholine receptor antagonist, 
TRPV1 receptor agonist, and M1 and M3 muscarinic acetylcholine receptor antagonist. (43, 44) 
7.2.2 Formulation 
It is administered orally. Immediate release tablet formulation will be used. Its analgesic effects 
take about one hour to come into effect and two to four hours to peak after oral administration 
with an immediate-release formulation. On a dose-by-dose basis, tramadol has about one-tenth 
the potency of morphine and is approximately equally potent when compared to pethidine and 
codeine.(45) 
7.2.3 Metabolism 
Tramadol is extensively metabolized in the liver by O- and N-demethylation and by conjugation 
reactions to form glucuronides and sulfate metabolites. The O-demethylation of tramadol to its 
main active metabolite, O-desmethyltramadol (M1), is catalyzed mainly by cytochrome P450 
(CYP) 2D6  enzyme. (46) 
 
7.2.4 Contraindications 
- Patients who have previously demonstrated hypersensitivity to tramadol, any other component 
of this product or opioids.  
- GI obstruction, surgical abdomen like pancreatitis or appendicitis.  
- Patients with significant respiratory depression like severe chronic COPD/asthma or myasthenia 
gravis. 
- Patients with acute or severe bronchial asthma or hypercapnia in unmonitored settings or the 
absence of resuscitative equipment. 
- It also decreases seizure threshold by antagonizing 5HTc receptors.(47)  
- All other opioid contraindications, including intoxication with alcohol, hypnotics, narcotics, 
centrally acting analgesics, opioids or psychotropic drugs. 
 
7.2.5 Side Effects 
Most common adverse reactions (incidence > 10%) are nausea, constipation, dry mouth, 
somnolence, dizziness, and vomiting. Complete and updated information is available in the 
investigational drug brochure and/or product package insert. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf 


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7.2.6 Rationale for Using Oral Tramadol with Transdermal Buprenorphine  
Tramadol is being used for breakthrough pain as TD buprenorphine is long acting.  
 
7.2.7 Dose adjustments in renal failure 
No dose adjustment of tramadol is required for creatinine clearance >30ml/min. Creatinine 
clearance <30ml/min:  restrict maximum daily dose of tramadol immediate release to 200 mg/day.  
 
7.2.8 Dose Adjustment in Liver Failure 
 No dose adjustment is required in mild to moderate liver failure (Child Pugh class A and B). 
Restrict dose to 50 mg q12 in severe liver impairment. Refer to Table 4  
Table 4. Dose Modifications of Buprenorphine and Tramadol  
 
8 STATISTICAL CONSIDERATIONS 
8.1 Study Endpoints 
8.1.1 Primary endpoint: Establish efficacy of study regimen by showing that at least 33% of 
patients will achieve at least a 30 percent decrease in VAS pain score from baseline to the end 
of week 9 of treatment and follow-up period. Earlier studies have shown that the VAS pain score 
( 4/10)  on the day of treatment initiation can be used as baseline in this setting and a 30% or 
higher reduction in baseline pain score is a sign of meaningful drug response.(27-29) 
8.1.2 Secondary endpoint:  
1. Monitor compliance of study drug regimen through OM Pain App and medication diary. 
Table 4: 
 
Organ Impairment  
Buprenorphine Patch  
Oral Tramadol   
Renal: Creatinine clearance >30ml/min. No dose adjustment. 
No dose adjustment. 
Renal: Creatinine clearance <30ml/min. No dose adjustment.  
Restrict maximum daily 
dose 
of 
tramadol 
immediate release to 
200 mg/day. 
Mild to moderate liver failure (Child 
Pugh class A and B). 
No dose adjustment.  
No dose adjustment. 
Severe liver failure (Child Pugh C). 
Not 
studied in severe 
impairment. 
Restrict dose to 50 mg 
q12 in severe liver 
impairment. 
Cytopenia¶s (any grade). 
No 
dose 
adjustment 
required. 
No dose adjustment 
required. 
Other side effects, such as severe 
nausea, 
vomiting, 
headache, 
respiratory depression, somnolence, 
dizziness, and constipation. 
Dose 
adjustment 
at 
clinician¶s discretion. 
Dose 
adjustment 
at 
clinician¶s discretion. 
Prolonged QTc>500 msec attributable 
to buprenorphine (other causes ruled 
out). 
Hold buprenorphine patch 
until QTc comes back to 
normal range <470 msec 
Not applicable  


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2. Identify study participants who require off-protocol opioids for pain control despite being on 
the highest dose of study drug combination.  
3. Correlate cumulative mean weekly pain scores calculated by the pain app with the average 
weekly pain scores recorded by the BPI short form. 
4. Correlate average weekly OM Pain App scores and average weekly pain scores calculated 
from the BPI short form with head and neck symptoms and function evaluation tool MDASI-
HN. The cumulative average area under the curve (AUC) weekly pain scores are expected to 
be inversely proportion to MDASI-HN average weekly AUC physical activity scores.  
5. Maintain a weekly log of use of other nonopiod supportive care medications, such as laxatives, 
antiemetics, and oral anesthetics, in conjunction with the study drug combination during 
treatment and follow-up period through weekly questionnaires. Average weekly use of 
laxatives and antiemetics is expected to decrease by the end of follow up period.  
6. Assess incidence and severity of gastrointestinal and cognitive side effects of the study drug 
regimen and their impact on quality of life, as measured by weekly PROMIS® (GI and 
cognition) questionnaires. 
7. Safety: Assess the incidence and severity of other adverse events associated with the study 
drug combination using CTCAE version 5. 
 
8.2 Study Design 
This is a single-arm prospective clinical trial to determine the safety and feasibility of using 
transdermal buprenorphine in alleviation of radiation-induced mucositis pain in head and neck 
cancer patients with 12-week follow-up. 
 
8.3 Study populations 
 
The enrolled population will consist of all enrolled patients. This population will be used 
in the CONSORT diagram, and patient disposition summaries. 
 
The treated population will consist of all enrolled patients who received at least one dose 
of the study medication. This population will be used for the efficacy and safety 
analyses. 
 
The per-protocol population will consist of all treated patients whose treatment followed 
without major protocol violations. This population will be used for sensitivity analyses. 
 
8.4 Determination of Sample Size and Accrual Rate 
 
Based on earlier studies (48) and the IMMPACT recommendations(28), a 30% or higher decrease 
in pain score from baseline to the end of the follow-up period is a sign of clinically meaningful 
efficacy of the drug regimen within a patient. A randomized trial of pregabalin for the treatment of 
radiotherapy-related pain in head-and-neck cancer patients (33) observed an at least 30% 
decrease in 33% of placebo-treated patients. This study will use a single-stage design to evaluate 
the hypothesis that patients treated with buprenorphine will achieve at least a 30% decrease in 
pain with probability exceeding 33%. Formally, the following hypotheses will be evaluated at a 
one-sided 5% significance level:  
 
H0: p ( 30% decrease) = 0.33  
versus  
 Ha p ( 30% decrease) > 0.33. 
 
With 18 subjects, the study will have at least 80% power to reject the null hypothesis if the 
probability of achieving at least 30% decrease in pain with buprenorphine is, in fact, 63%. The 
hypothesized effect is consistent with the efficacy seen with other active treatments. Specifically, 


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buprenorphine will be considered an acceptable pain control medication if 10 or more subjects 
out of the 18 experience at least 30% pain reduction. We will enroll 20 subjects to allow for 10% 
drop-out rate. 
8.5 Feasibility 
We will be able to complete protocol development and receive IRB approval in two months. Based 
on our previous experience, we normally see around 64 stage II±IV HNSCC patients annually 
who fulfill the eligibility criteria of the study. During 12 months of the potential accrual period, we 
will be able to contact 25 subjects. Under an assumed 80% consent rate, 19 to 20 subjects will 
be enrolled into the study. Assuming a 10% dropout rate, we will end up with around 18 patients 
participating in our study. Since close to 100% patients develop mucositis and develop at least 
moderate intensity pain requiring opioid medications through radiation therapy, we do not 
anticipate any screen failures. However, if a screen failure occurs for some reason then we plan 
to replace those patients to ensure an evaluation of 18 patients. Patients will be followed for 12 
weeks. Final interpretation of pain app data, standardized measurement tools and document of 
results will be done in the last month of the study period. We are confident of completing the 
accrual in 12 months.  
8.6 Data Analysis 
Serial measurements of patient-reported pain data will be analyzed throughout the follow-up 
period to look for inadequate pain control and use of off-protocol breakthrough pain medication 
use. The pain app data will be analyzed by study coordinators and our collaborators at UWM. 
Data recording will commence on the day the patient starts taking the drug regimen. We plan to 
study the daily and weekly pain score patterns during therapy. We will determine the baseline 
VAS pain score on the day of treatment initiation. Other pain management studies in radiation-
induced mucositis acknowledged the fact that the pain curve follows a nonlinear pattern during 
radiation therapy, but it plateaus and later drops down to a lower level after initiation of long-acting 
effective pain medications. Hence, it is reasonable to use the pain score on the day of treatment 
initiation as our baseline pain score. (29, 31) Radiation-induced mucositis begins to heal 
approximately two weeks after the last dose of stomatotoxic chemotherapy or radiation 
therapy.(30, 32) We will assess a percentage drop in the pain score by the end of week 9 of 
treatment to show a drug response. This way, we will try to avoid any bias of the normal healing 
process on pain alleviation. At least two-week treatment with study drug regimen will be required 
in order to be considered evaluable for study endpoints. Earlier studies and consensus guidelines 
have shown that a 30% drop in average weekly pain score by end of the follow-up period is 
significant. (28). The recording of data will cease after 12 weeks, at which time mucositis-related 
pain symptoms substantially abate in many individuals. (32) 
 
The primary analysis will compare the proportion of patients achieving a 30% drop in pain scores 
to the null-hypothesis value of 33% at a one-sided 5% significance level using a binomial test. 
The number of patients using analgesic and non-analgesic medications, as well as the occurrence 
of adverse events, will be tabulated and presented as counts with percentages. The average 
weekly pain scores, MDASI-HN, and the PROMIS® measures will be reported with descriptive 
statistics (mean, standard deviation, median, and range). Patient level summaries of the pain 
score and PRO outcomes will be created by computing area under the curve (AUC) of weekly 
averages. Scatterplots will be used to explore their relationship which will be quantified by 
Spearman¶s correlation coefficient. Further correlational analysis will be done by linear regression 
and linear fixed models.  
 
8.7 Rationale for not Having a Stopping Rule: This is a supportive care pilot study to determine 


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the efficacy of transdermal buprenorphine and oral tramadol drug combination in alleviating 
radiation-induced mucositis pain in head and neck cancer patients. These pain medications are 
FDA approved and have an established safety profile. In addition to the primary efficacy endpoint, 
we will be evaluating other secondary end points, such as real-time pain monitoring through the 
OM Pain App. This will continue, even if the study drug regimen is discontinued for lack of efficacy 
or some other unspecified reason. This would provide us invaluable pilot data for future studies 
in this setting. Moreover, we have made provisions for switching to standard-of-care pain 
medications, such as oral oxycodone in our study for patients who don¶t derive adequate pain 
relief from the study regimen. Hence, it is reasonable to exclude a formal stopping rule for this 
trial.  
8.8 Missing Data  
Missing data will be investigated, and multiple imputations will be used to account for 
missingness. Multiple imputations will be performed under the assumption that missing data are 
missing at random (MAR). If the validity of the MAR assumption is questioned, possible 
departures from MAR will be investigated by sensitivity analyses. 
 
8.9 Research Environment 
The study will be activated at the Medical College of Wisconsin (MCW) Cancer Center. The 
cancer center employs 57 full-time and two part-time staff. It is the only academic cancer center 
in Eastern Wisconsin, supporting more than 2.3 million people. The MCW Cancer Center Clinical 
Trials Office (CTO) will conduct the study and support all stages of the clinical trial process, 
including: protocol feasibility, regulatory support, compliance monitoring, consent development, 
IRB submission, budget development, contract negotiation, trial coordination and management, 
trial promotion and referrals, and patient screening, enrollment and consenting, data collection 
and management and results monitoring and reporting. The Division of Biostatistics at MCW will 
provide statistical support and perform analysis. As a recipient of a clinical and translational 
science award from NIH, with a recent five-year, $20 million renewal, the Medical College of 
Wisconsin is representing a consortium of Milwaukee institutions (Clinical and Translational 
Science Institute of Southeast Wisconsin [CTSI]) working in collaboration to advance biomedical 
research, clinical care, and education.    
9 DATA AND SAFETY MONITORING PLAN (DSMP) 
9.1 Data and Safety Management Overview 
The Medical College of Wisconsin (MCW) Data Safety Monitoring Committee (DSMC) and the 
MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans. A local, 
investigator-initiated trial will be required to be continuously monitored by the principal investigator 
of the study with safety and progress reports submitted to the DSMC.  
9.2 Study Team 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist, and the study biostatistician. While subjects are on study, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to review 
study status. This review will include but not be limited to reportable SAEs and UPIRSOs and an 
update of the ongoing study summary that describes study progress in terms of the study schema. 


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The appropriateness of further subject enrollment and the specific intervention for the next subject 
enrollment is addressed. All meetings including attendance are documented.  
9.3 Quality Assurance  
The MCWCC Clinical Trials Office provides ongoing quality assurance audits. This protocol was 
classified as intermediate risk and will be reviewed internally by the MCW Cancer Center Clinical 
Trials Office Quality Assurance Staff according to the MCW Cancer Center Data and Safety 
Monitoring Plan and current version SOP, 6.5.2 Internal Quality Assurance Reviews.  
9.4 Clinical Trials Office 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to the 
DSMC.  
9.5 DSMC 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at MCW 
includes a plan for safety and data monitoring. 
More information can be found related to the MCWCC Data and Safety Monitoring Plan at the 
MCWCC website (Data and Safety Monitoring Plan).  
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows:  
 
Review the clinical trial for data integrity and safety.  
 
Review all DSM reports. 
 
Submit a summary of any recommendations related to study conduct.  
 
Terminate the study if deemed unsafe for patients. 
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be maintained 
in the study research file and updated as membership changes. The committee will review reports 
from the study PI twice annually (or more frequently if needed) and provide recommendations on 
trial continuation, suspension, or termination as necessary.  
Any available DSMC letters will be submitted to the IRB of record as required. 
10 REGULATORY COMPLIANCE, ETHICS, AND STUDY MANAGEMENT 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
 


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10.1 Regulatory Compliance 
This study will be conducted in compliance with: 
 
The protocol. 
 
Federal regulations, as applicable, including 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and 45 CFR 46 
Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and Neonates), C 
(Prisoners), and D (Children), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
10.2 Prestudy Documentation  
Prior to implementing this protocol at MCWCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MCW IRB. 10.3 Institutional Review Board 
 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) will be reviewed and 
approved by the MCW Institutional Review Board. Before obtaining MCW approval, the protocol 
must be approved by the Medical College of Wisconsin Cancer Center Scientific Review 
Committee. The initial protocol and all protocol amendments must be approved by the IRB 
before implementation.  
 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individuals agreeing to participate in the 
study and continues throughout the individual¶s study participation. Extensive discussion of risks 
and possible benefits of this therapy will be provided to the subjects and their families. Consent 
forms describing in detail the study interventions/products, study procedures, and risks are given 
to the subject and written documentation of informed consent is required prior to starting 
intervention/administering study product. 
Consent forms will be IRB approved and the subject (and legally authorized representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the subject and answer any questions that may 
arise. In accordance with 46 CR 46.111, the subject will sign and date the informed consent 
document prior to any procedures being done specifically for the study.  
A witness should only sign when required, per FH/MCW IRB policy. If a witness signs the 
document when not required, the study staff should document in the legal medical record (or note 
to file) the relationship to the patient and why a witness signed. (i.e., ³Although not required, the 
subject¶s spouse was present during the consenting process and signed as the witness.´ Or 
³Although not required, the hospital staff was present for the consenting process and signed as a 
witness.´) 


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The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial.  
A copy of the informed consent document will be given to the subjects for their records. The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. If there are 
changes to the consent form, all revisions will be reviewed with the study subject at the next 
appropriate opportunity. Patients who require reconsenting will be defined in the IRB-approved 
amendment submission. The process for obtaining informed consent will again be performed. 
Study subjects will not be reconsented for continuing reviews. The MCWCC CTO will follow the 
MCW/FH IRB¶s policy for subjects who demonstrate limited English proficiency or limited literacy.  
After the subject¶s visit in which the consent is signed, it is documented in the clinic chart that the 
consent has been signed and that all questions have been answered to the subject¶s satisfaction 
after adequate time for the review of the consent. It is also documented that a copy of the consent 
is given to the subject. The original consent is kept with the subject¶s study file, and a copy of the 
consent is sent to the OCRICC office, which will then submit to HIM a copy of the signed consent 
to be scanned into EPIC, the legal medical record. 
10.4 Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff, [and the sponsor(s) and their agents] (include bracketed portion if 
applicable). This confidentiality includes clinical information relating to participating subjects, as 
well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the principal investigator. 
The conditions for maintaining the confidentiality of the subjects¶ records are required for the life 
of the data. These rules apply equally to any and all MCWCC projects.  
One risk of taking part in a research study is that more people will handle the personal health 
information collected for this study. The study team will make every effort to protect the information 
and keep it confidential, but it is possible that an unauthorized person might see it. Depending on 
the kind of information being collected, it might be used in a way that could embarrass the subject 
or affect his/her ability to get insurance. 
While data are being collected and after all data have been collected but are still in the process 
of being analyzed, the subject¶s data/PHI are stored in the locked clinical research office in the 
Clinical Trials Office. Databases in which the study subject information is stored and accessed 
are password protected, allowing for limited access by authorized personnel only. Data/PHI kept 
in the case report forms contain the study identifiers, subject initials, date of birth, and date of 
service.  
The principal investigator will allow access to all source data and documents for the purposes of 
monitoring, audits, IRB review, and regulatory inspections.  


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The study monitor/s or other authorized representatives of the principal investigator may inspect 
all documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this study. 
The clinical study site will permit access to such records. 
10.5 Protection of Human Subjects 
10.5.1  Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the IRB mechanism and the informed consent process. The IRB reviews 
all proposed studies involving human experimentation and ensures that the subject¶s rights and 
welfare are protected and that the potential benefits and/or the importance of the knowledge to 
be gained outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study to ensure that the consent document accurately and 
communicates the nature of the research to be done and its associated risks and benefits. 
10.5.2  Protection of Privacy 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they will 
be asked to sign informed consent documents. The original signed document will become part of 
the patient¶s medical records, and each patient will receive a copy of the signed document.  
10.5.3 Changes in the Protocol 
Once the protocol has been approved by the MCW IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the investigator 
and approved by IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
investigator must then notify the IRB in writing within five working days after implementation.  
The IRB may provide, if applicable regulatory authority(ies) permit, expedited review, and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB. The investigator will submit all protocol modifications to the sponsor 
and the regulatory authority(ies) in accordance with the governing regulations. 
Changes to the protocol may require approval from the sponsor. 
Any departures from the protocol must be fully documented in the source documents. 
10.6 Investigator Compliance  
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).  
Onsite Audits 


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Auditing is essential to ensure that research conducted at the Medical College of Wisconsin 
(MCW) Cancer Center is of the highest quality and meets MCW and regulatory agency standards.  
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, data 
capture records and other study documentation for on-site audit or inspection. Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 
11 DATA HANDLING AND RECORD KEEPING 
11.1 Overview 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity:  well-
trained data collectors/recorders to ensure consistency and quality, well-designed data collection 
protocols and ongoing monitoring. In this way, study rigor and validity are maintained. Data are 
protected from physical damage as well as from tampering, loss, or theft. This project¶s data 
management is a multidisciplinary activity that includes investigators, research coordinators and 
nurses, data mangers, support personnel, biostatisticians, and database programmers. Quality 
control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly.  
11.2 Data Management Responsibilities 
Principal Investigator 
The principal investigator oversees the management of patient records/case report forms and 
ensures that a) complete and accurate data will be obtained and provided to the sponsor; b) 
patient records are maintained to include history, prescribed medication, and investigational 
product(s), measurements, exams, evaluations, and adverse events; c) corrections are applied 
to clinical research data according to principles of good research practice (i.e., single-line delete, 
date and initial). He or she will ensure that there is a correlation between the case report forms 
and the source documents.  
Research Coordinator  
A research coordinator creates, collects, and organizes clinical trial documentation. He or she 
ensures that source documentation and data abstraction and entry are being done at protocol-
specified time points. 
 
Research Nurse/Medical Staff 
The research nurse and medical staff documents protocol-required care or assessment of the 
subject¶s outcomes, adverse events, and compliance to study procedures. 
Biostatistician 
The biostatistician may assist in CRF development (content and design), dataset specifications 
(annotation of CRFs and record layout) and validation. 


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11.3 Source Documents 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic test 
reports, etc.) are maintained in the patient¶s clinical file.  
All source documents will be written following ALCOA standards:  
ALCOA Attribute 
Definition 
Attributable 
Clear 
who 
has 
documented 
the 
data. 
Legible 
Readable 
and 
signatures 
identifiable. 
Contemporaneous 
Documented 
in 
the correct time 
frame along with 
the flow of events. 
If 
a 
clinical 
observation 
cannot be entered 
when 
made, 
chronology should 
be 
recorded. 
Acceptable 
amount of delay 
should be defined 
and justified. 
Original  
Original, 
if 
not 
original should be 
exact copy; the 
first record made 
by the appropriate 
person. 
The 
investigator 
should have the 
original 
source 
document. 
Accurate 
Accurate, 
consistent 
and 
real 
representation of 
facts. 
Enduring 
Long-lasting 
and 
durable. 
Available and 
accessible 
Easily available for 
review by treating 
physicians 
and 


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ALCOA Attribute 
Definition 
during 
audits/inspections. 
The 
documents 
should 
be 
retrievable 
in 
reasonable time. 
Complete 
Complete until that 
point in time. 
Consistent 
Demonstrate 
the 
required attributes 
consistently. 
Credible 
Based on real and 
reliable facts. 
Corroborated 
Data should be 
backed 
up 
by 
evidence. 
11.4 Case Report Forms  
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study-
specific Case Report Forms (CRFs) will document outcomes. All study data will be entered into 
OnCore® via standardized CRFs, in accordance with the study calendar, using single data entry 
with a secure access account. The clinical research coordinator will complete the CRFs as soon 
as possible upon completion of the study visit; the investigator will review and approve the 
completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient¶s medical records maintained by 
MCWCC personnel. All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The principal investigator will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate.  
All source documentation and data will be available for review/monitoring by the MCWCC DSMC 
and regulatory agencies. 
11.5 Study Record Retention 
The principal investigator is required to maintain adequate records. 
The principal investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 


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physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
sponsor-investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 


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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance 
without restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of the 
disease 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work) 
80 
Normal activity with effort; some 
signs or symptoms of the disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 


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APPENDIX 2. LOST TO FOLLOW-UP LETTER 
 
Date: ___________________________________ 
Dear ___________________________________, 
The research study team has been unable to contact you regarding the clinical trial 
(Transdermal Buprenorphine for the Treatment of Radiation-Induced Mucositis Pain in Head 
and Neck Cancer Patients: A Pilot Study) you participated in. 
We would like to discuss how you are doing and if we may continue contacting you. 
Please contact us at 
_____________________________________________________________ 
Sincerely, 
___________________________________ 


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APPENDIX 3: WHO MUCOSITIS GRADING SCALE 
Grade 
Description 
0 (none) 
None 
I (mild) 
Oral soreness, erythema 
II (moderate) 
 Oral erythema, ulcers, solid diet tolerated 
III (severe) 
Oral ulcers, liquid diet only 
IV (life-threatening) 
Oral alimentation impossible 


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APPENDIX 4.  QUESTIONNAIRES 
PROMIS®± COGNITIVE FUNCTION- SHORT FORM  
Please respond to each question or statement by marking one box per row in the 
past seven days.  
                  
 
 
 
 
Never  Rarely 
(Once)
 
Sometimes 
(Two or 
three 
times) 
 
 
Often 
(once 
a 
day) 
 
Very 
often 
(Several 
times) 
  
 PC2r     
My thinking has been slow 
......................  
 
5  
 
4  
 
3  
 
2  
1  
  
  
   
   
   
   
   
  
 
PC35r  
  
It has seemed like my brain was 
not working as well as usual 
..........................  
 
5  
 
4  
 
3  
 
2  
1  
 
  
   
   
   
   
   
  
 
PC36r  
  
I have had to work harder than 
usual to keep track of what I was 
doing ................  
 
5  
 
4  
 
3  
 
2  
1  
  
 
   
   
   
   
   
PC42r  
 
 
 
 
 


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I have had trouble shifting back 
and forth between different 
activities that require thinking 
...................................................  
5  
4  
3  
2  
1  
PROMIS® Gastrointestinal Disrupted Swallowing 
 
 
Please respond to each question or statement by marking one box. In the past seven 
days«  
 
 
        
 
 
Never 
Rarely 
Sometimes 
Often 
Always 
GISX31  
How often did food get stuck in 
your chest when you were 
eating? .....................  
1  
2  
3  
4  
5  
  
  
  
 
 
 
 
 
GISX32  
How often did food get stuck in 
your throat when you were 
eating? ....................   
1  
2  
3  
4  
5  
  
  
  
 
 
 
 
 
GISX33  
How often did you feel pain in your 
chest 
when 
swallowing 
food? 
.............................   
1  
2  
3  
4  
5  
  
  
  
 
 
 
 
 
GISX34  
How often did you have difficulty 
swallowing solid foods like meat, 
chicken or raw vegetables, even 
after 
lots 
of 
chewing? 
....................................................   
1  
2  
3  
4  
5  
  
  
  
  
  
  
  
GISX35  
How often did you have difficulty 
swallowing soft foods like ice 
cream, apple sauce, or mashed 
potatoes? ..............   
1  
2  
3  
4  
5  
  
  
  
  
  
  
  
GISX36  
How often did you have difficulty 
swallowing 
liquids? 
...................................   
1  
2  
3  
4  
5  
  
  
  
  
  
  
  


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GISX37  
How often did you have difficulty 
swallowing 
pills? 
.......................................   
1  
2  
3  
4  
5  
PROMIS® Gastrointestinal Constipation:  
Please respond to each question or statement by marking one box.  
In the past seven days«  
GISX 1) How often did you pass very hard or lumpy stools?  
  
  
  
  
1.  Never 
 If Never, go to #3  
 
2.   One day  
 
3.   Two ± Six days  
 
4   Once a day  
 
5 
More than once a day   
 
 
GISX 2) How much did hard or lumpy stools bother you?  
  
  
  
  
  
1. 
Not at all  
 
2. 
A little bit  
 
3. 
Somewhat  
 
4. 
Quite a bit  
 
5. 
Very much  
 
 
 
 
 
 
GISX3) How often did you strain while trying to have bowel movements?  


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1. Never 
 If Never, go to #6  
 
  
 
2. Rarely  
 
  
 
3. Sometimes  
 
  
 
4. Often  
 
  
 
5. Always  
In the past 7 days«  
GISX 4)  
 
How much did you usually strain while trying to have a bowel movement?  
  
  
  
  
  
 
1. Not at all  
  
 
2. A little bit  
 
3. Somewhat  
 
4. Quite a bit   
 
5. Very much   
 
  
GISX5)  
How much did straining during bowel movements bother you?  
 
 
 
 
 
1. Not at all  
 
2. A little bit  
 
3. Somewhat  
 
4. Quite a bit   
 
5. Very much   
 
 
 
 


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GISX6) 
 
How often did you feel pain in your rectum or anus while trying to have bowel 
movements?  
 
  
 
1. Never 
 If
Never, go to
#8  
 
  
 
2. Rarely  
 
  
 
3. Sometimes  
 
  
 
4. Often  
 
  
 
5. Always  
   In the past seven days«  
GISX7) 
  
At its worst, how would you rate the pain in your rectum or anus during bowel movements?  
 
 
 
 
 
1. Not bad at all  
 
2. A little bad  
 
3. Somewhat bad  
 
4. Quite bad  
 
5. Very bad  
 
  
GISX 8)  
  
How often after a bowel movement did you feel unfinished - that is, that you had not 
passed all your stool? 
  
 
 
1. Never   
  
 
 
2. Rarely  
  
 
 
3. Sometimes  
  
 
4. Often  
  
 
 
5. Always  
 
GISX 9) 
 
How often did you use your finger or toilet paper to get out a stool?  


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1. Never   
 
   
2. Rarely  
 
  
 
3. Sometimes 
 
  
 
4. Often  
 
5. Always  
            
 
 
PROMIS® GASTROINTESTINAL NAUSEA AND VOMITING  
 Please respond to each question or statement by marking one box.  
  
In the past seven days«  
  
GISX1) 
 
How often did you have nausea²that is, a feeling like you could vomit?  
 
 
 
 
 
1. Never 
 If Never, go to #3  
 
2. Rarely  
 
3. Sometimes   
 
4. Often  
 
5. Always   
 
GISX 2)  
How often did you know that you would have nausea before it happened?  
  
  
  
  
  
1. Never   
 
2. Rarely  
 
3. Sometimes   
 
4. Often  
 


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5. Always   
 
  
GISX 3) 
 
How often did you have a poor appetite?  
  
 
1. Never   
  
  
 
2. Rarely  
  
  
 
3. Sometimes 
  
 
4. Often  
  
5. Always   
                    
  
In the past 7 days« 
 
GISX4) How often did you throw up or vomit?  
 
1. Never 
  
  
 
2. One 
day  
  
  
 
3. 2-6 
times 
per 
day    
 
  
 
4. Once 
a day 
 
5. More 
than 
once 
a day 
                    
 
PROMIS® questionnaires can be downloaded directly from  
https://www.healthmeasures.net/explore-measurement-systems/promis/obtain-
administer-measures 
 
 
 
 


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BRIEF PAIN INVENTORY (SHORT FORM) 
Patient Initials:  
Date of Birth (dd, mm, yyyy):  
Visit Date (dd, mm, yyyy):  
1. Throughout our lives, most of us have had pain from time to time (such as minor 
headaches, sprains, and toothaches). Have you had pain other than these everyday kinds 
of pain during the last week?  
  
 
2. On the diagram, shade in the areas where you feel pain. Put an X on the area that hurts 
the most.  
  
  
  
3. Please rate your pain by circling the one number that best describes your pain at its worst 
in the last 24hours.  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
No  
Pain as bad as  
 
Pain  
you can imagine  
  
4. Please rate your pain by circling the one number that best describes your pain at its least 
in the last week.  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
No  
Pain as bad as  
 
Pain  
you can imagine  


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5. Please rate your pain by circling the one number that best describes your pain on the 
average weekly.  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
No  
Pain as bad as  
 
Pain  
you can imagine  
  
6. Please rate your pain by circling the one number that tells how much pain you have right 
now.  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
No  
Pain as bad as  
 
Pain  
you can imagine  
  
7.What treatments or medications are you receiving for your pain?  
_________________________________________________________________ _  
  
8. 
In the last week, how much relief have pain treatments or medications 
provided? Please circle the one percentage that most shows how much relief you have 
received.  
  
 
0%  
10%  
20%  
30%  
40%  
50%  
60%  
70%  
 80%  
90% 
 
100%  
 
 No  
Complete   
 
Relief  
Relief  
  
9. 
Circle the one number that describes how much, during the past week, pain 
has interfered with your:  A. General Activity  
  
 
0  
 1  
2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
Does not  
Completely  
 
Interfere  
Interferes  
  
B. Mood  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
Does not  
Completely  
 
Interfere  
Interferes  
  
C. Walking Ability  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
Does not  
Completely  
 
Interfere  
Interferes  
  
D. Normal Work (includes both work outside the home and housework)  


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0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
Does not  
Completely  
 
Interfere  
Interferes  
  
E. Relations with other people  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
Does not  
Completely  
 
Interfere  
Interferes  
  
F. Sleep  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
Does not  
Completely  
 
Interfere  
Interferes  
  
G. Enjoyment of life  
  
0 
1  2  
3  
 4  
5  
6  
7  
 8  
 9  
10  
 
Does not  
Completely  
 
Interfere  
Interferes  
  
Scoring:  
Pain Severity Score = Mean of items 3-6 (pain at its worst, pain at its least, average Pain 
Interference Score = Mean of items 9A-9G (interference of pain with: general activity, 
mood, walking, normal work, relations, sleep, enjoyment of life)  
MDASI- HN questionnaires  
Forms can be obtained from MDASI website  
https://www.mdanderson.org/research/departments-labs-institutes/departments-
divisions/symptom-research/symptom-assessment-tools/md-anderson-symptom-inventory-
head-and-neck-cancer-module.html 
 
 
 
 
 
 


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Mordarski S. Efficacy and safety of buprenorphine in patients receiving haemodialysis. 
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Rosenthal DI, Mendoza TR, Chambers MS, Asper JA, Gning I, Kies MS, et al. 
Measuring head and neck cancer symptom burden: the development and validation of the M. D. 
Anderson symptom inventory, head and neck module. Head Neck. 2007;29(10):923-31. 


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Cleeland CS, Mendoza TR, Wang XS, Chou C, Harle MT, Morrissey M, et al. Assessing 
symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer. 
2000;89(7):1634-46. 
23. 
Fu KK, Pajak TF, Trotti A, Jones CU, Spencer SA, Phillips TL, et al. A Radiation Therapy 
Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two 
variants of accelerated fractionation to standard fractionation radiotherapy for head and neck 
squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 
2000;48(1):7-16. 
24. 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann 
Acad Med Singap. 1994;23(2):129-38. 
25. 
Sinha P, Wong AWK, Kallogjeri D, Piccirillo JF. Baseline Cognition Assessment Among 
Patients With Oropharyngeal Cancer Using PROMIS and NIH Toolbox. JAMA Otolaryngol Head 
Neck Surg. 2018;144(11):978-87. 
26. 
Spiegel BM, Hays RD, Bolus R, Melmed GY, Chang L, Whitman C, et al. Development 
of the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) 
gastrointestinal symptom scales. Am J Gastroenterol. 2014;109(11):1804-14. 
27. 
Chang JT, Lin CY, Lin JC, Lee MS, Chen YJ, Wang HM. Transdermal fentanyl for pain 
caused by radiotherapy in head and neck cancer patients treated in an outpatient setting: a 
multicenter trial in Taiwan. Jpn J Clin Oncol. 2010;40(4):307-12. 
28. 
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. Core 
outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 
2005;113(1-2):9-19. 
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Xing SZ, Zhang Y. Efficacy and safety of transdermal fentanyl for the treatment of oral 
mucositis pain caused by chemoradiotherapy in patients with esophageal squamous cell 
carcinoma. Support Care Cancer. 2015;23(3):753-9. 
30. 
Maria OM, Eliopoulos N, Muanza T. Radiation-Induced Oral Mucositis. Front Oncol. 
2017;7:89. 
31. 
Guo SP, Wu SG, Zhou J, Feng HX, Li FY, Wu YJ, et al. Transdermal fentanyl for pain 
due to chemoradiotherapy-induced oral mucositis in nasopharyngeal cancer patients: evaluating 
efficacy, safety, and improvement in quality of life. Drug Des Devel Ther. 2014;8:497-503. 


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Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have 
cancer. Dent Clin North Am. 2008;52(1):61-77, viii. 
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Jiang J, Li Y, Shen Q, Rong X, Huang X, Li H, et al. Effect of Pregabalin on 
Radiotherapy-Related Neuropathic Pain in Patients With Head and Neck Cancer: A 
Randomized Controlled Trial. J Clin Oncol. 2019;37(2):135-43. 
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Sittl R. Transdermal buprenorphine in cancer pain and palliative care. Palliat Med. 
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Silverman S, Raffa RB, Cataldo MJ, Kwarcinski M, Ripa SR. Use of immediate-release 
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buprenorphine transdermal system. J Pain Res. 2017;10:1255-63. 
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Zaki PA, Keith DE, Jr., Brine GA, Carroll FI, Evans CJ. Ligand-induced changes in 
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2000;292(3):1127-34. 
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Steiner DJ, Sitar S, Wen W, Sawyerr G, Munera C, Ripa SR, et al. Efficacy and safety of 
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Breivik H, Ljosaa TM, Stengaard-Pedersen K, Persson J, Aro H, Villumsen J, et al. A 6-
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Moody DE, Fang WB, Lin SN, Weyant DM, Strom SC, Omiecinski CJ. Effect of rifampin 
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Brown SM, Holtzman M, Kim T, Kharasch ED. Buprenorphine metabolites, 
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Anesthesiology. 2011;115(6):1251-60. 
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Brown SM, Campbell SD, Crafford A, Regina KJ, Holtzman MJ, Kharasch ED. P-
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Minami K, Ogata J, Uezono Y. What is the main mechanism of tramadol? Naunyn 
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Minami K, Uezono Y, Ueta Y. Pharmacological aspects of the effects of tramadol on G-
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Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain. 
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Ogata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, et al. The 
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Farrar JT, Young JP, Jr., LaMoreaux L, Werth JL, Poole RM. Clinical importance of 
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2001;94(2):149-58. 

ICF_001.pdf: 
Date of Consent: Approval Period 1/31/2024-11/19/2024; Stamped eƯective January 31, 2024 
OƯicial Title of Study:  Transdermal Buprenorphine for the Treatment of Radiation-Induced 
Mucositis Pain in Head and Neck Cancer Patients: A Pilot Study 
NCT04752384 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 1 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
Medical College of Wisconsin  
INTRODUCTION TO THE INFORMED CONSENT 
 
IIT-SHREENIVAS-BUPRENORPHINE: Transdermal buprenorphine for the treatment of 
radiation induced mucositis pain in head & neck cancer patients: A pilot study 
Stuart Wong, MD 
Department of Medicine 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee WI 53226 
414-805-6700 
 
 
 
 
Definitions 
 
Performance Status ± an assessment of your overall health 
 
Oral Mucositis (OM) Pain App ± a mobile app to record the amount of oral mucositis pain 
you experience during radiation therapy 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 2 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
Purpose 
This project is being done to investigate the 
efficacy of using FDA approved doses of a 
Buprenorphine patch in combination with oral 
Tramadol to provide adequate pain control in 
radiation induced mucositis. 
Length 
You will be in this research project for about 3 
months or 12 weeks after starting radiation 
therapy for your cancer. This study does not 
require any follow up after this time frame. 
Risks 
This is a brief list of the most commonly seen 
side effects. The full consent form after this 
introduction contains a more complete list of 
potential research risks. 
Buprenorphine risks: 
 
Nausea 
 
Dizziness 
 
Spinning sensation (vertigo) 
 
Weakness 
 
Tired feeling 
 
Sweating 
 
Numbness or tingly feeling 
 
Headache 
 
Depression 
 
Low blood pressure (hypotension) 
 
Nausea 
 
Vomiting 
 
Constipation 
 
Blurred vision 
 
Double vision 
 
Shallow breathing 
 
Tramadol risks: 
 
Agitation 
 
Nervousness 
 
Anxiety 
 
Seizures (convulsions) 
 
Skin rash 
 
Dizziness 
 
Spinning sensation 
 
Hallucinations 
 
Fever 
 
Fast heart rate 
 
Overactive reflexes 
 
Nausea 
 
Vomiting 
Procedures 
All subjects who participate in this study will 
receive both Buprenorphine and Tramadol. 
You will continue to take the study drugs until 
your pain from radiation induced mucositis 
has resolved. 
 
 
List of visits: 
 
Screening Visit(s) 
- Total Number: approx. 1-2 
- Total Time: approx. 6-10 hours 
 
Radiation Therapy Treatment Visits 
- Total Number: approx. 7-10 
- Total Time: approx. 2-4 hours each 
 
Follow-up Visits 
- Total Number: approx. 5-7 
- Total Time: approx. 2-4 hours each 
 
Procedures that will occur at various 
visits: 
 
Invasive Procedures 
- Blood collection for routine 
laboratory tests 
 
Non-invasive Procedures 
- Weight 
- Urine collection for opioid pain 
medication testing 
- Heart monitoring by 
Electrocardiogram (EKG) 
- Performance Status 
- Quality of Life questionnaires 
- Oral exam 
- Oral Mucositis (OM) Pain App  
- Record of calorie intake and 
intravenous (IV) fluids 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 3 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
My Other Options 
You do not have to join this project. Your other 
options may include: 
1. Joining a different project 
2. Routine care for this condition  
3. Getting no treatment for this condition 
 
Benefits 
We don¶t know if this project will help you. Your 
condition may get better but it could stay the 
same or even get worse. 
 
 
If you have more questions about this project at any time, you can call Stuart Wong, MD at 
414-805-6700. 
 
If you have questions about your rights as a participant, want to report any problems or 
complaints, or offer input, you can call the MCW/Froedtert Hospital Research Subject 
Advocate at 414-955-8844. 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 4 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
CONSENT TO PARTICIPATE IN RESEARCH 
A1. INTRODUCTION ± WHY ARE WE ASKING YOU TO PARTICIPATE? 
You are being invited to participate in this research because you have Stage II-IV head and 
neck squamous cell carcinoma (HNSCC) and are a candidate for curative intent or adjuvant 
radiation therapy. 
 
A total of about 20 people are expected to participate in this research at the Medical College of 
Wisconsin/Froedtert Hospital. 
 
The Director of the project is Stuart Wong, MD in the Department of Medicine. A research team 
works with Dr. Wong. You can ask who these people are.  
 
This project is funded by a pilot grant awarded by the National Cancer Institute (NCI) 
Community Oncology Research Program (NCORP). 
 
A2. DO I HAVE TO PARTICIPATE? 
You can decide whether to take part in this research or not. You are free to say yes or no. If you 
do not agree to join, or if you leave, you will not be penalized or lose any benefits that you had 
before starting the research project. Even if you join this project, you do not have to stay in it. 
You may stop at any time. Take as much time as you need to make your choice.  
 
A research project is different from routine medical care in three ways: 1) there are extra risks 
that we will tell you about in this form; 2) you may have some extra medical tests and visits; 3) 
the research procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS PROJECT BEING DONE? 
Mucositis-related pain is a common side effect of radiation treatment of head and neck 
squamous cell carcinoma (HNSCC). The purpose of this project is to investigate the efficacy of 
using FDA approved doses of transdermal Buprenorphine in combination with oral Tramadol to 
provide adequate pain control in radiation-induced mucositis. Buprenorphine in other studies 
has shown to have a better side effect profile and less habit-forming properties than other opioid 
medications used to treat moderate to severe radiation-induced mucositis pain. 
 
We don¶t know if this study will help you. Your condition may get better, but it could stay the 
same or even get worse. We hope the information from this study will help us develop a better 
treatment for oral mucositis in the future. 
 
B1. WHAT WILL HAPPEN IF I PARTICIPATE? 
STUDY DRUGS 
 
Buprenorphine will be administered daily as a transdermal patch that will be stuck to the skin. 
Tramadol will be administered as an oral pill. You will take Buprenorphine and Tramadol for pain 
relief during your radiation therapy and for up to 4 weeks after your radiation therapy is 
completed. If your pain is well controlled, the doses of both drugs will begin to be gradually 
reduced. 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 5 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
Buprenorphine and Tramadol are in the opioid class of pain medication, but they are safer to 
use than other drugs in its class. Please tell the study doctor if you have a history of abuse or 
dependency on Buprenorphine, Tramadol, or any other opioid pain medication. Your use of the 
study drugs will be monitored during the study, as is standard policy for all patients prescribed 
opioid pain medication. 
STUDY GROUPS 
All subjects who participate in this study will receive both Buprenorphine and Tramadol. 
STUDY VISITS 
Screening  
If you agree to participate in the study, you will sign this consent form before screening 
assessments are performed to see if you are eligible. Your study doctor or a member of the 
study team will let you know if you are eligible to participate in the study. If you are unable to 
participate in the study, the study doctor will discuss other treatment options with you.  
Study Drug Regimen (treatment weeks 1-7 from the start of radiation therapy) 
If you are eligible to participate, you will take the study drugs once your pain from radiation-
induced mucositis requires medication. You will visit the doctor weekly during this period. 
Assessments to track your pain status and to monitor you for side effects will occur during these 
weekly visits. 
Follow-up (weeks 8-12) 
During the follow up phase you will return to the clinic twice (week 9 and 12) for a visit with the 
doctor. Weeks 8, 10 and 11 you will have a phone call from the research coordinator or study 
staff member.  
STUDY ASSESSMENTS 
Screening 
You will need to have all or some of the following exams, tests, or procedures to find out if you 
can be in the study. Most of them are routine and may be done even if you do not join the study. 
If some of the tests were completed recently, they may not have to be repeated. 
 
Informed consent: Prior to any study-related procedures being performed, you will be 
required to voluntarily sign and date this consent form. 
 
Medical history: You will be asked about your health status, including previous 
treatments for your cancer 
 
Weight: You will be weighed 
 
Performance status: An assessment of your overall health and ability to perform daily 
tasks 
 
Oral exam: Your mouth will be examined, and pictures of your mouth will be taken 
 
Electrocardiogram (EKG): EKG will be performed to check the activity of your heart 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 6 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
 
Urine test: A urine sample will be collected confirm you are not currently taking any other 
opioid pain medication. This is standard policy before prescribing any new opioid pain 
medications. 
 
Blood tests: Blood samples will be collected for 
 Blood cell counts, blood chemistry and clotting ability 
 Pregnancy, if you are able to have become pregnant 
 
Quality of Life questionnaires: Questions about daily activities and mental, physical, and 
emotional symptoms, etc. 
 
Record of calorie intake: The study team will ask you about the food and drink you are 
consuming and whether it is solid or liquid 
 
Study Drug Regimen (Treatment) 
You will be allowed to enroll to the study if the results of screening assessments show that you 
are eligible. The following assessments will be performed weekly once you start the study drug 
regimen: 
 
Adverse events: You will be asked about if you experienced any changes in your health 
 
Medications: You will be asked about opioids, laxatives, medications to reduce nausea 
and vomiting, and medications to relieve minor mouth pain that you take 
 
Weight: You will be weighed weekly 
 
Performance status: An assessment of your overall health and ability to perform daily 
tasks will be done at Week 7  
 
Oral exam and image collection: Your mouth will be examined at each visit, and pictures 
of your mouth will be taken at Week 4  
 
Electrocardiogram (EKG): EKG will be performed to check the activity of your heart at 
Week 7 of radiation therapy 
 
Blood tests: Blood samples will be collected weekly for 
 Blood cell counts, blood chemistry and clotting ability 
 
Quality of Life questionnaires: Questions about daily activities and mental, physical, and 
emotional symptoms, etc. These questionnaires will be completed at your study visits 
during the radiation therapy treatment period. 
 
Record of calorie intake: The study team will ask you about the food and drink you are 
consuming and whether it is solid or liquid 
 
Report of intravenous (IV) fluids: The study team will ask if you received any fluids by IV 
infusion at each visit 
 
Oral Mucositis (OM) Pain App: You will record the amount of oral mucositis pain you 
experience during radiation therapy using an app you can download on your mobile 
device. If you do not have a mobile device, a device with the OM pain app installed on it 
will be given to you. Answers you provide on the OM Pain App will be de-identified so 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 7 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
that they do not contain your personal details. You may use the OM Pain App before the 
radiation therapy treatment period begins to become familiar with it. 
 
Follow-up 
The following assessments will be performed Weeks 8-12: 
 
Adverse events: You will be asked about if you experienced any changes in your health 
at Week 9 and Week 12 from the start of radiation therapy 
 
Medications: You will be asked about opioids, laxatives, medications to reduce nausea 
and vomiting, and medications to relieve minor mouth pain that you take at Week 9 and 
Week 12 from the start of radiation therapy 
 
Weight: You will be weighed at Week 9 and Week 12 from the start of radiation therapy 
 
Performance status: An assessment of your overall health and ability to perform daily 
tasks will be done at Week 9 and Week 12 from the start of radiation therapy 
 
Oral exam and image collection: Your mouth will be examined at Week 9 and Week 12 
from the start of radiation therapy, and pictures of your mouth will be taken at Week 9 
and Week 12 
 
Electrocardiogram (EKG): EKG will be performed to check the activity of your heart at 
Week  12 from the start of radiation therapy 
 
Blood tests: Blood samples will be collected at Week 9 and Week 12 after the start of 
radiation therapy for 
 Blood cell counts, blood chemistry and clotting ability 
 
Quality of Life questionnaires: Questions about daily activities and mental, physical, and 
emotional symptoms, etc. These questionnaires will be completed weekly. 
Questionnaires will be completed by telephone call Week 8, Week 10 and Week 11 with 
the study team or on your mobile device during the follow-up period. 
 
Record of calorie intake: The study team will ask you about the food and drink you are 
consuming and whether it is solid or liquid at Week 9 and Week 12 from the start of 
radiation therapy 
 
Report of intravenous (IV) fluids: The study team will ask if you received any fluids by IV 
infusion at Week 9 and Week 12 from the start of radiation therapy 
 
Oral Mucositis (OM) Pain App: You will record the amount of oral mucositis pain you 
experience during radiation therapy using an app you can download on your mobile 
device. If you do not have a mobile device, a device with the OM pain app installed on it 
will be given to you. Answers you provide on the OM Pain App will be de-identified so 
that they do not contain your personal details. 
 
B2. HOW LONG WILL I BE IN THE PROJECT? 
You will be in this research study for up to 3 months or 12 weeks after starting radiation therapy.   
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 8 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
B3. CAN I STOP BEING IN THE PROJECT?   
You are free to withdraw from the project at any time. If you leave, your regular medical care will 
not change. If you are thinking about leaving, please tell the research doctor.  
You may stop at any time. If you decide to leave the project, please let the research team know.  
The research doctor may stop your participation in the project at any time for any reason without 
your consent.  He/she will tell you if this happens. 
The research doctor may take you out of this project at any time. This would happen if: 
 
They think it is in your best interest. 
 
You do not follow the project rules. 
 
The whole project is stopped. 
 
If this happens, the research doctor will tell you. 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE PROJECT?  
You should tell the study doctor of any changes in your current medications, including over-the-
counter medications, vitamins, and herbal supplements. Some medications are not allowed 
during the study. Your study doctor will advise about which medications these are. 
 
You should bring the mobile device containing the OM Pain App with you to all study visits. 
 
You should not make any software updates to the OM Pain App yourself. The study team will 
perform any software updates for you during study visits. 
 
You should not breastfeed a baby while receiving Buprenorphine and/or Tramadol. 
 
It is possible that the Buprenorphine patch will not stick properly to your skin. If this occurs, you 
may use a small piece of tape on the edges to help the patch consistently stick without falling off 
your skin. If you have any questions regarding adhering the patch, please contact the study 
doctor. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE PROJECT? 
There are risks to taking part in any research project. There is a risk that you may get drugs that 
do not help your condition or may make it worse.  There also may be problems (side effects) we 
do not know about yet, from the drugs themselves, or how they combine with other drugs you 
are taking. If we learn about new important side effects, we will tell you.  
 
We watch everyone in the project for problems (side effects). You need to tell the research 
doctor or a member of the research team immediately if you experience any problems, 
side effects, or changes in your health. In an emergency, call 911. 
 
C2. RISKS OF STUDY DRUGS 
The research drugs themselves may cause problems (side effects).  Side effects may be mild or 
very serious.  Some can last a long time or never go away.   


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 9 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
Buprenorphine 
Side effects of Buprenorphine include: 
 
Nausea 
 
Dizziness 
 
Spinning sensation (vertigo) 
 
Weakness 
 
Tired feeling 
 
Sweating 
 
Numbness or tingly feeling 
 
Headache 
 
Depression 
 
Low blood pressure (hypotension) 
 
Nausea 
 
Vomiting 
 
Constipation 
 
Blurred vision 
 
Double vision 
 
Shallow breathing 
 
Tell your doctor if you have serious side effects of Buprenorphine including: 
 
Weak or shallow breathing 
 
Lightheadedness 
 
Fainting 
 
Blue lips or fingernails 
 
Confusion 
 
Feelings of extreme happiness 
 
Fast or slow heart rate 
 
Urinating less than usual or not at all 
 
Tramadol 
 
Side effects of Tramadol include: 
 
Agitation 
 
Nervousness 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 10 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
 
Anxiety 
 
Seizures (convulsions) 
 
Skin rash 
 
Dizziness 
 
Spinning sensation 
 
Hallucinations 
 
Fever 
 
Fast heart rate 
 
Overactive reflexes 
 
Nausea 
 
Vomiting 
 
Upset stomach 
 
Diarrhea 
 
Constipation 
 
Loss of coordination 
 
Headache 
 
Drowsiness 
 
Fainting 
 
C3. OTHER RISKS OF THIS RESEARCH PROJECT 
Other procedures that are part of the research also involve some risks: 
 
Blood Draws 
The side effects that you might experience as a consequence of a blood draw for this project 
include possible discomfort and bruising at the needle entry site. Rare complications of any 
venipuncture (drawing blood from a vein) include fainting, arterial puncture, peripheral nerve 
injury, local infection, and local blood clot. It is likely that you may have a port-a-cath which may 
mitigate some of these problems. There may be other unanticipated risks, but every precaution 
will be taken to assure your personal safety and to minimize discomfort. The person drawing 
your blood will observe you for side effects, but please inform him or her if you experience any 
discomfort or feel faint. 
 
Electrocardiogram (ECG) 
An ECG procedure requires you to lie still for a few minutes while electrodes are attached to 
your chest, wrists, and ankles to record the activity of your heart. The ECG leads placed on your 
skin may cause slight discomfort during their placement and removal. 
 
 
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 11 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
Questions on Your Well-Being 
The answers that you give are confidential, but there is always a risk that your answers will be 
read by people who should not read your personal information. You may also feel 
uncomfortable answering some of the questions. 
Privacy and Confidentiality 
Another risk may be loss of confidentiality. Every effort will be made to keep your research 
records confidential but we cannot guarantee it. Depending on the kind of information being 
collected, if your research information were accidentally seen, it might be used in a way that 
could embarrass you or affect your ability to get insurance. If you have questions, you can talk 
to the project director about whether this could apply to you. 
C4. REPRODUCTIVE RISKS 
Risks to subjects who could become pregnant  
We know the drugs in this project affect babies, so we do not want anyone who might be 
pregnant to enter the project.  
 
You should not become pregnant or nurse a baby while in this project. You must tell the 
research doctor right away if you think you are pregnant. You will be asked to have a pregnancy 
test to be sure you are not pregnant at the start of the project.  
 
You may not donate eggs during your participation in the project or for 3 months after stopping 
the drugs. 
 
Risks to a subject who could father a child and the subject¶s partner(s) 
If you and your partner(s) are able to become pregnant, one or both of you must use some form 
of effective birth control, because we know that the drugs affect babies. You must tell the 
research doctor right away if you think your partner is pregnant. 
You may not donate sperm during your participation in the project or for 3 months after stopping 
drugs. 
Birth control methods for all subjects 
Check with the research doctor about the birth control methods needed for this project and how 
long to use them. Some methods might not be good enough for this project. If you are having 
sex that could lead to pregnancy, you should use two forms of birth control while you are in this 
project.   
This may include: 
 
Not having vaginal sex (abstinence) 
 
Taking birth control pills orally 
 
Having birth control shots or patches such as Depo-Provera 
 
Surgical sterilization (hysterectomy/tubal ligation or vasectomy) 
 
Limiting sexual activity to a partner who has undergone surgical sterilization  
 
Use of an intrauterine device (IUD) 
 
Use of diaphragm with contraceptive jelly 
 
Use of condoms with contraceptive foam 
 
Use of diaphragm with condoms (³double barrier´) 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
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You should continue using birth control for 3 months after stopping the study drugs. 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE PROJECT? 
We don¶t know if this study will help you. Your condition may get better, but it could stay the 
same or even get worse. We hope the information from this study will help us develop better 
treatments for oral mucositis. 
D1. ARE THERE ANY COSTS TO BEING IN THE PROJECT? 
Most of the medical care that you will receive in this project is considered routine care for your 
condition and would be recommended whether or not you join the project. Costs for routine care 
will be billed to you or your insurance carrier. For routine clinical care, you will be responsible for 
paying any copayment, coinsurance, or deductible that is required by your insurance carrier.  
Activities that are part of the project will not be billed to you or your insurance company. These 
are: 
 
Quality of Life questionnaires 
 
Oral Mucositis (OM) Pain App 
 
Record of calorie intake 
 
Record of intravenous (IV) fluids 
 
Some insurers will not pay for drugs, tests or hospitalization that are part of research, so check 
with your insurer before you join this project. If you have questions regarding costs, please 
contact Dr. Wong. 
 
If you participate in this research, the costs of any necessary emergency medical treatment in 
the event of a research-related injury will be billed to you or your health insurance. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE PROJECT? 
You will be paid five times during the study for your participation. A $70 stipend will be given: at 
the following times: first at the time you are found eligible for the study and study medications 
are prescribed, then on any two subsequent clinic visits during treatment with radiation therapy 
at least 1 week apart, and then during two follow up visits after completing radiation therapy on 
Week 9 and Week 12. This will come to a maximum of $350. After the screening visit, if we find 
out you are not eligible for participation in the study, we will not be able to pay you. We will 
provide you with the lab results that you can share with your doctor. This is being done to offset 
treatment related costs associated with management of radiation induced mucositis pain. 
 
Sponsor, other researchers, or research companies may patent or sell products, discoveries 
and data or information that result from this research. Neither Sponsor nor Dr. Wong will pay 
you if this happens. You will not receive any payment or commercial rights for products, data, 
discoveries, or materials gained or produced from your health information. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this project. You are free to say yes or no. If you do not join this project, 
your research doctor can discuss other healthcare choices with you.  


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 13 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
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Your other choices may include: 
 
Routine care for this condition or symptoms. 
 
Joining a different research project 
 
The procedure or drug offered to you may also be available without being in any 
research project. 
 
The research doctor can explain both the possible benefits and the risks of other options that 
are available to you. 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE PROJECT? 
If we learn any important new information about the drugs that might change your mind about 
being in the project, we will tell you about it right away.  You can then decide if you want to stay 
in the project. 
 
When research data are collected and analyzed , there is the chance of finding something 
clinically relevant. There may be benefits to learning such results (such as early detection and 
treatment of a medical condition), but there are risks as well (such as feeling worried about a 
finding for which no treatment is required or appropriate).   
 
In this study, you will be informed of any findings of possible clinical significance that may be 
discovered during review of results from your research data. The results of your research data 
will be placed in your medical record.  
 
The results from the data we collect in this research study are not the same quality as what you 
would receive as part of your health care. The data will be reviewed by a physician who 
normally reads such results. We will provide you with this information so that you may discuss it 
with your primary care physician.  
 
D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE PROJECT?  
Emergency medical treatment for injuries directly related to your participation in this research 
project will be provided to you. You or your health insurance will be billed for the costs of this 
emergency treatment.  MCW will decide on a case by case basis if they will reimburse you or 
your insurer for emergency treatment costs.  If your research-related injury requires medical 
care beyond this emergency treatment, you or your insurer will be responsible for the costs of 
this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this project, contact 
the research doctors right away.  Contact information: Stuart Wong, MD, 414-805-6700  
 
Nothing in this consent form affects any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence. 
 
 
 
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 14 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
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D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE PROJECT? 
- 
If you have more questions about this project at any time, you can call Stuart Wong, MD at 
414-805-6700. 
- 
If you have questions about your rights as a research participant, want to report any 
problems or complaints, or offer input, you can call the MCW/Froedtert Hospital Research 
Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
E1. What health information will be collected and used for this project? 
To be in this research project, the research team needs your permission to access, collect and 
use some of your health information. If you say no, you cannot be in the project. This 
information may come from questions we ask, forms we ask you to fill out, or your medical 
record, as described below. We will only collect and use information needed for the project. 
The protected health information (PHI) originates from services you will or have received at one 
or more of the following locations: the Medical College of Wisconsin (MCW); Versiti, Inc.; 
Children¶s Hospital of Wisconsin (CHW); any Froedtert Health Affiliate- Froedtert Hospital (FH), 
Inc.; Froedtert Menomonee Falls Hospital;  Froedtert West Bend Hospital;  Froedtert & The 
Medical College of Wisconsin Community Physicians Clinics, Inc. (FMCWCP); the West Bend 
Surgery Center, LLC; and the Froedtert Surgery Center, LLC.  
The health information to be collected and used for this project is:
 
Past and present medical records 
 
Records about your study visits and results of tests done during the study 
 
Records about phone calls made as part of this research 
 
Data entered in the Pain App, data collected from quality-of-life questionnaires  
 
Research records 
 
E2. Who will see the health information collected for this project? 
The only MCW/Froedtert Hospital. employees allowed to handle your health information are 
those on the research team, those on the Institutional Review Board (IRB) and those who check 
on the research activities to make sure the hospital¶s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-related 
injury are billed to your health insurance, your health information may need to be disclosed to 
the insurer for billing purposes. 
 
The research team may share your information with people who don¶t work at MCW/Froedtert 
Hospital. because they planned, pay for, or work with us on this project.  The federal Privacy 
Rule may no longer protect your health information once it leaves MCW/Froedtert Hospital.  For 
this project, we plan to share information with those doctors, researchers or government 
representatives working with us on this project at the institutions or companies listed here: 
 
 
Florence Healthcare, Inc. 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 15 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
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The funder of this study, National Cancer Institute (NCI) Community Oncology Research 
Program (NCORP); 
 
Government agencies in the U.S., such as the Food and Drug Administration (FDA), 
National Cancer Institute (NCI), and National Institutes of Health (NIH); 
 
Other federal and state agencies, such as the Office of Human Research Protections, 
(OHRP); 
 
Others required by law 
 
Because this project involves the use of drugs and/or devices, the FDA also has the right to 
inspect all project records. 
 
We may record your research information, including results of tests and procedures done for 
research, in your Froedtert Hospital and/or Medical College of Wisconsin medical record.  As a 
result, this research information may be seen by people allowed to see your medical records for 
healthcare operations or treatment, by those you allow to see your medical records by giving 
written permission, and by others when required by law. 
 
We will not use your personal health information for a different project without your permission 
or the permission of a hospital research review board (IRB). Once all personal identification is 
removed from your health information and/or biospecimens, the information and/or 
biospecimens may be used for future research or distributed to another investigator for future 
research without additional informed consent from you or your legally authorized representative. 
The information might also be used or released for other purposes without asking you. Results 
of the project may be presented in public talks or written articles, but no information will be 
presented that identifies you. 
 
E3. What are the risks of sharing this health information? 
One risk of taking part in a research project is that more people will handle your personal health 
information collected for this project. The research team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. If 
you have questions, you can talk to the research doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this project? 
If you sign this form, we plan to keep your information without any end-date in case we need to 
check it again for this project. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to Stuart Wong, MD at  
 
Department of Medicine 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee WI 53226 
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 16 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
The letter must say that you have changed your mind and do not want the researcher to collect 
and share your health information. At that time, we will decide that you cannot continue to be 
part of the project. We may still use the information we have already collected. 
 
E6. Access to records 
You may not be able to see, or copy, your project-related health information until after the 
project has been completed; otherwise, it could affect the study. 
 
F1. FOR MORE INFORMATION ABOUT THE PROJECT
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
You can look up this project by referring to the ClinicalTrials.gov number (NCT04752384) or by 
asking the research team for a printed copy.    


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: December 1, 2020 
IRB Protocol Number: PRO 40100 
IRB Approval Period: 1/31/2024 ± 11/19/2024 
Page 17 of 17 
Protocol Version: V8 v 1/26/24 
ICF Version: 1/26/24 
EFFECTIVE 
 
January 31st, 2024 
 
MCW IRB 
CONSENT TO PARTICIPATE 
By signing my name below, I confirm the following: 
 
I have read (or had read to me) this entire consent document.  
All of my questions have been answered to my satisfaction. 
 
The project¶s purpose, procedures, risks and possible benefits have been explained to me.   
 
I agree to let the research team use and share the health information and other information 
gathered for this project. 
 
I voluntarily agree to participate in this research project. I agree to follow the procedures as 
directed. I have been told that I can stop at any time. 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date    
Name of Witness, if applicable 
please print 
Signature of Witness 
 
Date
Rationale for Use of Witness 
 Subject has limited/no literacy 
 Subject has limited English 
proficiency 
 Subject has limited/no vision 
 
 Sponsor requirement 
 Other ____________________ 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date
* A member of the research team trained and authorized by the Principal Investigator to act on 
her/his behalf in obtaining informed consent according to the protocol. The Principal Investigator 
is responsible and accountable for the research project.