Clinical trial NCT03269344
Conditions: Oropharynx Cancer
Sponsor: Henry Ford Health System
Start date: 2017-06-05; Completion date: 2020-12-09
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Strategies to minimize and mitigate external beam radiation therapy related mucositis and pain during the treatment of head and neck cancer remain limited. The investigators hypothesize that gabapentin could be used to delay or reduce treatment-related pain, reliance on opioid medication, and improve the quality of life for these patients.

Detailed description:
The specific aims of this proposed study include the following:

* Evaluate the reduction or delay of mucositis related pain and morbidity with the use of gabapentin in patients with stage III or IV oropharyngeal squamous cell carcinoma undergoing definitive radiation with concurrent chemotherapy as part of their cancer management, compared to standard supportive side effect mitigation - using patient reported quality of life endpoints such as the Patient-Reported Oral Mucositis Symptoms (PROMS) scale.
* Assess morphine-equivalent opioid use in both treatment arms by collecting the patient's narcotic use in the previous 24-hour period at each weekly evaluation during radiation treatment.
* Report on change in Speech and swallow performance, as measured by the Performance Status Scale (PSS) for Head and Neck Cancer Patients
* Evaluate changes in weight from baseline throughout treatment between the two arms.
* Assess feeding tube requirements during treatment.
* Evaluate the adverse events associated with gabapentin.
* Evaluate the severity of radiation mucositis (grade 3-4, CTCAE, v. 4)

Arms: arm 1: Standard supportive care during definitive treatment plus placebo arm 2: Gabapentin plus standard supportive care
Interventions: intervention 1: Gabapentin intervention 2: Placebo Oral Capsule
Intervention descriptions: intervention 1: Gabapentin is an anticonvulsant and has been used to manage neuropathic pain and is FDA-approved for the treatment of post-herpetic neuralgia and partial onset seizures intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
 
 
 
 
RANDOMIZED PHASE III, DOUBLE BLIND, PLACEBO CONTROLLED STUDY OF 
PROPHYLACTIC GABAPENTIN FOR THE REDUCTION OF RADIATION THERAPY 
INDUCED PAIN DURING THE TREATMENT OF OROPHARYNGEAL SQUAMOUS 
CELL CARCINOMA 
NCT Number: 03269344 
2/6/2017 
 


2 
 
RANDOMIZED PHASE III, DOUBLE BLIND, PLACEBO CONTROLLED STUDY OF 
PROPHYLACTIC GABAPENTIN FOR THE REDUCTION OF RADIATION THERAPY 
INDUCED PAIN DURING THE TREATMENT OF OROPHARYNGEAL SQUAMOUS 
CELL CARCINOMA 
Study Team 
 
Principal Investigator 
 
Andrew Cook MD 
Department of Radiation Oncology 
 
Scientific Advisors 
 
Farzan Siddiqui MD PhD 
Benjamin Movsas MD 
Department of Radiation Oncology 
 
Haythem Ali MD 
Department of Hematology/ Oncology 
 
Biostatistics 
 
Andrew Taylor MA 
Lonni Schultz PhD 
Department of Public Health Science 
 
Research Pharmacy 
 
Sonia Eliya Pharm D 
Jehan Jazrawi BS Pharm 
Research Pharmacy 
 
Participating Sites 
 
Henry Ford Hospital 
2799 West Grand Boulevard 
Detroit, MI 48202 
Protocol Version 1.0 1/6/2017 
 
 


3 
 
Randomized Phase III, Double-Blind, Placebo Controlled Study of Prophylactic 
Gabapentin for the Reduction of Radiation Therapy Induced Pain During the Treatment 
of Oropharyngeal Squamous Cell Carcinoma 
 
 
SCHEMA 
Pre-study: Determine eligibility 
▼ 
Signed Informed consent 
▼ 
S 
 
R 
Arm 1: (control): Standard supportive care during  
T 
 
A 
definitive treatment plus placebo 
R 
 
N 
 
A 
Smoking History: 
D 
Arm 2: 600 mg of gabapentin TID (1800 mg daily 
T 
Current smoker 
O 
total) during definitive treatment  
I 
Ex-smoker or non-smoker 
M 
Plus standard supportive care 
F 
 
I 
 
Y 
 
Z 
 
 
 
E 
 
 
 
Patient population: Patients being treated with radiation and concurrent chemotherapy for Stage 
III and IV (non-metastatic) squamous cell carcinoma of the oropharynx 
Required Sample Size: 60 
 
 


4 
 
TABLE OF CONTENTS   
 
 
 
 
 
 
 
    Page 
 
SCHEMA........................................................................................................................................2 
1. INTRODUCTION ....................................................................................................................4 
2. PATIENT SELECTION ..........................................................................................................6 
3. REGISTRATION PROCEDURES .........................................................................................7 
4. TREATMENT PLAN ...............................................................................................................7 
5. DOSING DELAYS/DOSE MODIFICATIONS ...................................................................13 
6. ADVERSE EVENT REPORTING .......................................................................................13 
7. PHARMACEUTICAL INFORMATION .............................................................................14 
8 STUDY CALENDAR ..............................................................................................................14 
9. STATISTICAL CONSIDERATIONS...................................................................................15 
REFERENCES ...........................................................................................................................18 
APPENDIX...................................................................................................................................19 
 
 


5 
 
1.1 INTRODUCTION 
1.1.1 Specific Aims 
Strategies to minimize and mitigate external beam radiation therapy related mucositis and pain 
during the treatment of head and neck cancer remain limited. We hypothesize that gabapentin 
could be used to delay or reduce treatment-related pain, reliance on opioid medication, and 
improve the quality of life for these patients. The specific aims of this proposed study include the 
following: 
• Evaluate the reduction or delay of mucositis related pain and morbidity with the use 
of gabapentin in patients with stage III or IV oropharyngeal squamous cell carcinoma 
undergoing definitive radiation with concurrent chemotherapy as part of their cancer 
management, compared to standard supportive side effect mitigation – using patient 
reported quality of life endpoints such as the Patient-Reported Oral Mucositis 
Symptoms (PROMS) scale.  
• Assess morphine-equivalent opioid use in both treatment arms by collecting the 
patient’s narcotic use in the previous 24-hour period at each weekly evaluation during 
radiation treatment. 
• Report on change in Speech and swallow performance, as measured by the 
Performance Status Scale (PSS) for Head and Neck Cancer Patients. 
• Evaluate changes in weight from baseline throughout treatment between the two 
arms. 
• Calculate the proportion of patients who end up requiring a feeding tube by the end of 
treatment in both arms. 
• Evaluate changes in patient-report quality of life using the Functional Assessment of 
Cancer Therapy Head &Neck (FACT-HN) and PRO-CTCAE metrics. 
• Evaluate the adverse events associated with gabapentin. 
• Evaluate the severity of radiation mucositis (grade 3-4, CTCAE, v. 4). 
 
1.2 Background and Significance 
1.2.1 Head and Neck Cancer/ Treatment Related Morbidity 
There are an estimated 55,070 patients with head and neck cancer in the United States, with an 
estimated 12,000 deaths annually and a rising incidence of Human Papilloma Virus-related 
oropharyngeal cancer. [1, 2] Unfortunately, a large portion of these patients present with locally 
advanced disease. [3] Definitive radiation with concurrent platinum-based chemotherapy is the 
primary treatment for stage III and IV oropharyngeal carcinoma.  
Chemotherapy has been evaluated in multiple trials in conjunction with radiation therapy to treat 
a variety of head and neck cancers. A comprehensive meta-analysis revealed an overall survival 


6 
 
benefit of 7% at 2 years and 8% at 5 years with the concurrent use of cisplatin-based 
chemotherapy. [4] This, however, has not come without major treatment related toxicity and 
morbidity. The addition of chemotherapy to radiation has been shown to potentially increase 
short-term toxicity burden by 300% (increased relative risk). [5] 
Strategies to minimize and mitigate treatment related mucositis and pain remain limited. Most 
practitioners utilize a combination of oral anesthetic mouthwashes, opioid medication, infection 
control, and lifestyle modification. [6] 
1.2.2 Gabapentin 
Gabapentin is an anticonvulsant and has been used to manage neuropathic pain and is FDA-
approved for the treatment of post-herpetic neuralgia and partial onset seizures. While opioids 
are effective in treating nociceptive pain, head and neck patients experience both neuropathic 
(burning, aching, stabbing) and nociceptive (dull, sore, tender) pain. [7] Opioid medications have 
adverse effects including constipation, nausea, vomiting, sedation, impaired psychomotor 
function, urinary retention, hyperalgesia, as well as the potential for dependence. [8] Gabapentin 
is thought to provide neuropathic relief of pain by inhibition of alpha-2-delta-1 receptor 
upregulation in the dorsal horn, reversing pain mediated regulators of pain. [9] It is generally 
well tolerated, although common adverse effects include somnolence, dizziness, peripheral 
edema, and fatigue. [10] 
Gabapentin has evolved as a strategy to reduce morbidity in patients undergoing radiation 
treatment. Bar-Ad et al. retrospectively evaluated their experience using gabapentin and found 
less opioid use and less treatment breaks when using this strategy for patients undergoing 
chemoradiation treatment to the head and neck. Similar findings were reported for patients 
undergoing post-operative radiation therapy without chemotherapy. [11] Similarly, Starmer et al 
retrospectively analyzed 23 patients with oropharyngeal SCC treated with chemoradiation and 
found that patients used their PEG tubes later, had their PEG tubes removed earlier, and reported 
less pain and duration of pain in those that used gabapentin. [1] Lastly, Yang et al in their 
retrospective analysis of their head and neck database found gabapentin use to be associated with 
reduced PEG tube dependence. [12] 
All of these reports are small, single institution, retrospective experiences and are subject to 
patient selection biases. Given the advantages of gabapentin use during chemoradiation in 
reducing treatment related pain and PEG tube dependence, we seek to prospectively evaluate this 
drug in a randomized, blinded setting. This will validate these findings with a greater level of 
evidence. 
1.2.3 Summary and Rationale for This Study: 
Given the lack of effective strategies to mitigate treatment related pain from mucositis during 
head and neck cancer treatment as well as lack of randomized, prospectively evaluated evidence 


7 
 
supporting gabapentin use in this setting, we hereby propose this randomized clinical trial to 
evaluate the effectiveness of gabapentin in delaying or reducing treatment-related pain, reliance 
on opioid medication, and improving the quality of life for these patients.  
 
2. PATIENT SELECTION 
2.1 Conditions for Patient Eligibility: 
 
2.1.1 Patients being treated with combination radiation and chemotherapy (definitive) 
therapy for locally advanced (Stage III and IV) squamous cell carcinoma of the 
oropharynx. 
2.1.2 Age ≥ 18. 
2.1.3 ECOG performance status 0-1. 
2.1.4 Patients must provide study specific informed consent prior to study entry and be able 
to fill out toxicity and quality of life related questionnaires. 
2.1.5 Patients should be concurrently treated with any of the following chemotherapy 
regimens: high-dose every three week cisplatin, low dose weekly cisplatin, or weekly 
carboplatin. 
 
2.2 Conditions for Patient Ineligibility: 
 
2.2.1 Patients may not be receiving gabapentin, any other investigational agents, or other 
anticonvulsants. 
2.2.2 Patients with metastatic disease are excluded from this clinical trial. 
2.2.3 Patient with allergies or hypersensitivity to gabapentin. 
2.2.4 Patients receiving surgery as part of their definitive management. 
2.2.5 Patients who have received prior chemotherapy or radiation therapy for head and 
neck cancer. 
2.2.6 Patients unable to complete the required forms; however, verbal completion is 
adequate if recorded on the form daily. 
2.2.7 Uncontrolled serious illness including, but not limited to, ongoing or serious active 
infection requiring IV antibiotics for over 30 days, symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia other than chronic, stable atrial 
fibrillation, immunocompromised state, significant hepatic insufficiency, significant 
hematological disease, and any serious or unstable psychological condition.  
2.2.8 Patients on any of the following medication that cannot find a suitable substitute 
during the study period: azelastine, orphenadrine, paraldehyde, thalidomide. 
2.2.9 Patients with severe renal insufficiency (creatinine clearance of  < 60 ml/minute) 
 
2.3 Required laboratory data (to be done at time of enrollement): 


8 
 
2.3.1 Creatinine 
 
2.4 Inclusion of Women and Minorities: Both men and women and members of all races 
and ethnic groups are eligible for this trial. 
3. REGISTRATION PROCEDURES 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria 
have been met, and the study site has Institutional Review Board approval. Patients must have 
signed and dated all applicable consents and authorization forms. To register a patient to this 
study, the signed and dated eligibility checklist, along with any necessary supporting 
documentation, and the signed patient consent form will be forwarded to the responsible data 
manager. To complete the registration process, the data manager will assign a patient study 
number, in sequential order of consent, register the patient to the study, and contact the treating 
investigator and responsible research nurse to confirm registration. 
 
4. TREATMENT PLAN 
4.1 Chemotherapeutic Agent Administration 
Chemotherapy, delivered concurrently with radiation therapy, will ultimately be determined by 
the treating medical oncologist. Patients receiving any of the following regimens will be eligible: 
 
High-dose cisplatin - Cisplatin: 100 mg/m2/day, every 3 weeks during radiation treatment, for a 
maximum of 3 doses. 
 
Carboplatin  - Carboplatin: Target area under curve (AUC) 2 once weekly for a maximum of 6 
doses. 
 
Weekly cisplatin - Cisplatin: 40 mg/m2/day, weekly during radiation treatment for a maximum of 
6 doses. 
 
4.2 Radiation Therapy 
Radiation therapy, delivered concurrently with chemotherapy, will ultimately be determined by 
the treating radiation oncologist. The following guidelines should be followed: 
4.2.1 Dose specifications:  
Volumes and Lymph node levels should be defined as per the RTOG Head and Neck atlas 
http://www.rtog.org/CoreLab/ContouringAtlases/HN.aspx.  


9 
 
Definitive treatment (all primary treatment should be delivered with concurrent chemotherapy as 
per the treating medical oncologist) will be done with simultaneous integrated dosing (SID) in 35 
fractions to a total dose of 70 Gy, 63 Gy and 56 Gy to the high-risk, intermediate-risk and low-
risk CTVs, respectively.  
4.2.2 Physical Factors: 
All subjects will undergo radiographic imaging required for radiation treatment planning 
purposes using a CT scanner. Digitally reconstructed radiographs from the CT will simulate the 
patient geometry during radiation treatment, including the localization and immobilization 
methods. A virtual treatment planning procedure is used to design treatment fields 
mathematically from the CT images. 
4.2.3 Target Volumes 
The GTV will be treated as the PTV70 (CTV 70+margin) will receive 70 Gy in 35 fractions (2 
Gy per fraction) 
Creation of the PTV70 is as follows: GTV70 defined from CT-sim and diagnostic CT fusion. 
GTV-p (primary tumor) and GTV-n (positive lymph nodes) are to be delineated.  
CTV70-p=GTV-p with 1 cm expansion, except when the GTV-p is at the base of tongue, then 
the CTV70-p will be the GTVp with a 1.5 cm expansion.   
CTV70-n will be created using the GTV-n with a 1 cm expansion.  
CTV70 will then be defined using the CTV70p+ CTV70n. The CTV70 should be modified so as 
not to cross fascial plains or vertebral bodies.  
PTV70 will be defined as the CTV70 with a 0.5 cm expansion. PTV70 should be modified to be 
cropped 3 mm from the skin surface.  
High risk PTV63 (CTV63+margin) areas will receive 63 Gy in 35 fractions (1.8 Gy per fraction) 
The CTV63 delineated to include the involved lymph node level, and any adjacent lymph node 
levels. For example for a right sided level 2 lymph node, CTV63 will include right sided level-2, 
level-3, level-5, and level-1b. Level-2 should be defined to the base of skull on the involved side 
(sacrificing parotid on involved side).  
PTV63 will be defined as CTV63 with a 0.5 cm expansion.  
Low risk PTV56 (CTV56+ margin) regions will receive 56 Gy in 35 fractions (1.6 Gy per 
fraction) 
The CTV56 will include the uninvolved neck, if clinically indicated to be treated. Level-2 in the 
uninvolved neck should be treated to the level of C1, allowing for parotid sparing. Also included 


10 
 
in the CTV56 is any lymph node level on the involved side that is not included in the CTV63, 
and is still at low risk of tumor involvement. Such that if right side level-2 LN is involved, then 
right sided level-4 would be defined as CTV 56. Right sided Level-1a would be included only if 
clinically indicated.  
PTV56 will be defined as CTV56 with a 0.5 cm expansion. 
4.2.4 Field Arrangement: 
IMRT will be used to cover the primary or planning target volume (PTV), provided that the 
normal tissue constraints described below are met. 
4.2.5 Beam Shaping: 
A multileaf collimation system will be used to comply with field margin and normal tissue dose 
requirements. 
4.2.6 Treatment Equipment: 
Treatment will be administered on an isocentrically mounted megavoltage linear accelerator with 
photon energy ≥ 6 MV. Typically, the source-to-axis distance (SAD) will be 100 cm. IMRT will 
be delivered using volumetric modulated arc therapy (VMAT) technique. 
4.2.7 Beam Verification: 
Standard IMRT QA procedures developed at our institution will be performed, including monitor 
units verification, intensity map verification, as well as point dose measurements. Cone beam CT 
scans will be obtained daily prior to radiation delivery to ensure proper patient positioning. 
4.2.8 Dosimetry: 
The uniformity requirement will be +/- 5% of the total dose at the prescription point within the 
planning target volume. 
4.2.9 Critical Normal Structures:  
QUANTEC Dose Constraint Parameters will be used. Modifications to allow for adequate tumor 
coverage are allowed at the discretion of the treating physician.  
4.2.10 Radiation Therapy Adverse Events and Treatment Modifications 
Grade 3-4 (CTCAE, v. 4) therapy-induced mucositis and/or dysphagia, which are enhanced by 
cisplatin, are expected to develop in about two thirds of patients. Nutritional evaluation prior to 
the initiation of therapy is highly recommended. Placement of a feeding tube should be recorded, 
as should use of a feeding tube during and after treatment . Other common radiation adverse 


11 
 
events include: fatigue, weight loss, regional alopecia, xerostomia, hoarseness, transient ear 
discomfort, dysgeusia, and skin erythema and desquamation within the treatment fields.  
Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, 
chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. Much 
less common radiation adverse events include: mandibular osteoradionecrosis (< 5% incidence 
with attention to the dental recommendations), and cervical myelopathy (< 1% with restriction of 
spinal cord dose to ≤ 45 Gy). 
 
4.3 Protocol Treatment 
 
Figure 1: Treatment schema, as described below.  
4.3.1 Arm 1 
 Patients will receive a placebo along the same dosing schedule as the experimental arm (patients 
randomized to placebo will take the same number of capsules as those assigned to gabapentin).  
This will also include standard supportive care for treatment-related pain and mucositis as 
needed during concurrent chemotherapy and radiation treatment, consisting of the following: 


12 
 
• Viscous lidocaine 2% oral solution 
• Oral liquid or solid opioid medications- e.g., morphine, oxycodone. These will be introduced 
and titrated at the discretion of the treating physician when the patient-reported pain score is ≥ 4 
on a 0-10 scale. 
4.3.2 Arm 2 
Gabapentin will be initiated at a dose of 300 mg to be taken at bedtime of the night prior to the 
first radiation treatment. During week 1, the dose will be 300 mg three times a day for a total 
daily dose of 900 mg. Starting week 2, the dose will be 600 mg taken 3 times per day for a total 
daily dose of 1800 mg. This will continue until one week after the end radiation treatment (week 
8). Therapy will then be titrated down to 300 mg three times a day for 1 day, and then 
discontinued all together. The standard supporting care for treatment-related pain and mucositis 
described above will also be included. 
4.3.3 Adverse Events 
Side effects of gabapentin include somnolence, dizziness, peripheral edema, and fatigue. Rarely, 
patients experience changes in behavior or suicidal ideation. These effects will be evaluated on a 
weekly basis. 
4.3.4 Study medication accountability 
Patient compliance with be evaluated weekly during clinic visits. Patients are expected to receive 
3 doses per day (21 per week), 7 days a week during radiation. Patients who take at least 12 
doses a week will be considered compliant. Patients that do not begin gabapentin or require a 
feeding tube  will be followed for the endpoints measured in the protocol for an intent-to-treat 
analysis. 
The investigator is required to maintain adequate records of the disposition of the investigational 
products. Participants will be asked to return unused tablets at the end of radiation treatment and 
at first follow-up. The unused tablets will be counted by pharmacy.  
 
4.4 Duration of Follow Up 
 
Patients will be followed for 6 weeks after completion of definitive treatment or until removal 
(or) termination from study, or until death, whichever occurs first. Patients removed from study 
for unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event.  
Toxicity notations, quality of life information, and disease status will be recorded. If it is not 
possible to coordinate a follow-up evaluation at 2 ± 1 months, then a follow-up phone call will 


13 
 
be made to the patient by the treating physician, or clinical trials office designee, in lieu of a 
visit. 
 
4.5 Assignment of interventions 
4.5.1 Allocation sequence generation 
Separate randomization lists will be produced by a statistician for current smokers as well as for 
former/ non-smokers with a goal of 1:1 allocation to both treatment arms.  
4.5.2 Allocation concealment mechanism 
The sequence of the randomization numbers is kept in sealed envelopes independent of the 
investigators. 
4.5.3 Implementation 
The Henry Ford Research Pharmacy will label the tablet packages according to the 
randomization list. Single sealed envelopes containing the participants’ randomization code will 
be located and the Radiation Oncology Clinic. 
4.5.4 Unblinding 
Blinding of the investigators, outcome assessors, pharmacists, data analysts and trial participants 
will be maintained throughout the study. Adverse events (AEs) that are considered serious, 
unexpected and at least possibly related to the medication would have to be unblinded. The study 
will be unblinded by the trial statistician after the final visit of the primary endpoint assessment. 
4.5.5 Withdrawal of participants/stopping rules and urgent safety 
Participants have a right to withdraw at any time and may be withdrawn at the investigator’s 
discretion. Reasonable effort should be made to contact any participant lost to follow-up. The 
information collected before the withdrawal will be included in analysis. Participants will not be 
replaced. The PI will have the authority to deviate from the protocol if doing so relates to the 
immediate safety of a participant, where continuing to follow protocol would put that participant 
at risk. If any of the following criteria are met, study enrolment and study therapy will be 
suspended: death in any participant, where death is attributed in any way to study therapy or 
intervention; grade 4 anaphylaxis as defined by the World Allergy Organization (WAO).  
Study therapies will be discontinued for any of the following reasons: two or more occurrences 
of grade 3 or above systemic allergic reactions as defined by the WAO; any AE that presents an 
unacceptable consequence to the participant; an illness that requires treatment not consistent with 
protocol requirements; inability to comply with the study protocol and pregnancy. 


14 
 
An internal data safety committee will be formed through the Clinical Trials Office and will 
meet quarterly to review potential adverse effects from the study medication. 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
version 4.0 for toxicity and Serious Adverse Event (SAE) reporting. 
5.1 General Considerations 
5.1.1 Dose Modifications for Gabapentin 
If patient cannot tolerate gabapentin at the dose specified in this protocol, dose can be reduced in 
300 mg (or 1 pill) decrements until side effects subside. If intolerance continues, therapy should 
be discontinued. Patients who are unable to tolerate the medication will be withdrawn from the 
study. Patient should be continued to be followed as specified on the protocol, however, for 
intent-to-treat analysis purposes. 
 
6. ADVERSE EVENT REPORTING: 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 for reporting of adverse events (AEs). 
Serious Adverse Events (SAE) and adverse events will be carefully recorded, and SAEs will be 
reported to Henry Ford Hospital’s IRB if they meet the IRB’s SAE reporting criteria. 
Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite). 
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment 
and 30 days after that results in any of the following outcomes: 
 Death; 
 A life-threatening adverse drug experience; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 A persistent or significant disability/incapacity; 


15 
 
 Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. Any pregnancy, including a male patient’s impregnation of his 
partner, occurring on study must be reported to the IRB as a medically significant event. SAEs 
(more than 30 days after last treatment) attributed to the protocol treatment (possible, probable, 
or definite) should be reported to the IRB if the reporting criteria is met. 
 
7. PHARMACEUTICAL INFORMATION 
7.1 Gabapentin 
Please refer to the FDA-approved package insert for additional information. 
a. Description –   Anticonvulsant, Miscellaneous; GABA Analog 
b. Pharmaceutical Data (as taken from UpToDate) – 
Absorption: Variable, from proximal small bowel by L-amino transport system; saturable 
process; dose-dependent 
Distribution: Vd: 58 ± 6 L; CSF concentrations are ~20% of plasma concentrations 
Protein binding: <3% 
Metabolism: Not metabolized 
Bioavailability: Inversely proportional to dose due to saturable absorption: 
Immediate release: 
900 mg/day: 60% 
1,200 mg/day: 47% 
2,400 mg/day: 34% 
3,600 mg/day: 33% 
4,800 mg/day: 27% 
Half-life elimination: 
Adults, normal: 5 to 7 hours; increased half-life with decreased renal function; anuric adult 
patients: 132 hours; adults during hemodialysis: 3.8 hours 
Time to peak: Adults: 2 to 4 hours. 
Excretion: Proportional to renal function; urine (as unchanged drug) 
Clearance: Apparent oral clearance is directly proportional to CrCl. 
c. Administration – Orally 
d. Storage and Stability - : Store vials at room temperature and protect from light. 
e. Supplier – Gabapentin is commercially available. 
 
 
8. STUDY CALENDAR 


16 
 
The institutional review board (IRB) approval process is expected to be completed by March of 
2017. The trial will start accrual of patients subsequently. Given the typical volume of patients 
treated at our institution, it is expected to take 1-1.5 years to accrue the required 60 patients to 
complete this study. Patients will be followed up until the first follow-up after completion of 
radiation treatment (6 weeks). The trial is expected to conclude January of 2019 with data 
analysis and reporting to take place subsequently. 
 
9. STATISTICAL CONSIDERATIONS 
9.1 Study Endpoints/ Analysis Plan 
9.1.1 Primary endpoint 
The primary endpoint is change in quality of life and pain, as measured by the Patient-Reported 
Oral Mucositis Symptoms (PROMS) scale over the entire study period. This will be measured at 
baseline and weekly during clinic visits. Additional measurements will be obtained at 6-weeks 
(first follow-up) from the time of radiation treatment completion. 
The PROMS scale consists of 10 questions on a visual analogue scale of 100-mm lines 
addressing oral functions affected by oral mucositis.[13] This questionnaire has been validated in 
patients undergoing radiation treatment for head and neck cancers and correlates well with 
clinician determined scores of mucositis.[14]  
Repeated measures analysis of variance (ANOVA) will be used to determine if there was a 
significant difference between the mean PROMS scores of the two groups over the entire study 
period, and t-tests will be used to examine if there was a difference in the PROMS scores for the 
two groups at each week of the study period. 
9.1.2 Sample size/ Justification of Number of Subjects 
Based on reported means and standard deviation of PROMS scores of patients undergoing 
radiation treatment, a total of 60 patients will be required to evaluate a 16% reduction in PROMS 
score at week 7 (final week) of radiation treatment, with α = 0.05 and power = 80%. This 
assumes a 10% dropout rate. 
9.2.1 Secondary Endpoints  
9.2.2 Speech and Swallow Function: 
Report on change in Speech and swallow performance, as measured by the Performance Status 
Scale (PSS) for Head and Neck Cancer Patients (see appendix). This will completed by the 
treating physician/ speech-language pathologist during the same time points as the primary 
endpoint. 


17 
 
9.2.3 Weight Loss and Feeding Tube use 
Patient weight loss will be evaluated by comparing the percent weight change per patient from 
baseline to 6 weeks post-treatment between treatment arms using the Wilcoxon-rank sum test at 
the significance level of 0.05. The feeding tube placement and use will also be documented.  
9.2.4 Opioid Use 
Patients with at least 1 reported administration of opioid analgesic will be considered to have 
received opioid analgesics. The total dose of opioid analgesics will be the sum of all opioid 
analgesic administrations that have been converted to morphine equivalents (see Appendix II). 
Use of opioid analgesics will be assessed for a 24-hour period before completing the assessment 
weekly during radiation. The relationship between analgesic use and treatment-related pain will 
be evaluated using the general linear model with (at minimum) stratification, treatment arm, and 
compliance. 
9.2.5 Adverse Events (CTCAE, v. 4) 
Adverse events related to gabapentin will be reported. Additionally, the incidence of grade 3-4 
radiation induced mucositis during treatment will be compared between treatment arms using 
Fisher’s exact test at the significance level of 0.05. 
9.2.6 Other Quality of Life Metrics 
Patients will be asked to complete the FACT-HN and PRO-CTCAE quality of life forms (see 
Appendix). The FACT-HN will be assessed at baseline and at the 7-week (final week) of 
radiation. The PRO-CTCAE will be assessed at baseline and weekly with the PROMS scale.  
The change in scores from baseline to the 6-week follow-up timepoint will be used for analysis. 
All assessments are summarized in Table 1. 
 


18 
 
Table 1. Subject assessments.  
Parameters 
Prior to Study 
Therapy 
Weekly During 
Radiation Therapy 
At First Follow-
up (6-weeks post 
completion) 
History and Physical a 
X 
 
X 
Performance status a 
X 
 
X 
Creatinine 
X 
 
 
PROMS Score b 
X 
X 
X 
HN-PSS Score a 
X 
X 
X 
FACT H&N b 
X 
 
X 
Weight 
X 
X 
X 
Daily opioid use (in 
morphine equivalents) a 
X 
X 
X 
Assess if feeding tube 
has been placed a 
X 
X 
X 
CTCAE and other 
adverse events a 
X 
X 
X 
PRO-CTCAE 
questionnaire  b 
X 
X 
X 
a Physician or evaluator reported. 
b Patient reported. 
 
 
REFERENCES 
1. 
Starmer, H.M., et al., Effect of gabapentin on swallowing during and after 
chemoradiation for oropharyngeal squamous cell cancer. Dysphagia, 2014. 29(3): p. 
396-402. 
2. 
Chaturvedi, A.K., et al., Human papillomavirus and rising oropharyngeal cancer 
incidence in the United States. Journal of Clinical Oncology, 2011. 29(32): p. 4294-4301. 
3. 
Marur, S. and A.A. Forastiere, Head and neck cancer: changing epidemiology, diagnosis, 
and treatment. Mayo Clin Proc, 2008. 83(4): p. 489-501. 
4. 
Pignon, J.-P., et al., Meta-analysis of chemotherapy in head and neck cancer (MACH-
NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and 
Oncology, 2009. 92(1): p. 4-14. 
5. 
Trotti, A., et al., TAME: development of a new method for summarising adverse events of 
cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol, 2007. 8(7): 
p. 613-24. 
6. 
Moslemi, D., et al., Management of chemo/radiation-induced oral mucositis in patients 
with head and neck cancer: A review of the current literature. Radiother Oncol, 2016. 
120(1): p. 13-20. 


19 
 
7. 
Epstein, J.B., et al., Neuropathic and nociceptive pain in head and neck cancer patients 
receiving radiation therapy. Head & neck oncology, 2009. 1(1): p. 1. 
8. 
McNicol, E., et al., Management of opioid side effects in cancer-related and chronic 
noncancer pain: a systematic review. The Journal of Pain, 2003. 4(5): p. 231-256. 
9. 
Luo, Z., et al., Injury type-specific calcium channel α2δ-1 subunit up-regulation in rat 
neuropathic pain models correlates with antiallodynic effects of gabapentin. Journal of 
Pharmacology and Experimental Therapeutics, 2002. 303(3): p. 1199-1205. 
10. 
Gabapentin for Adults with Neuropathic Pain: A Review of the Clinical Efficacy and 
Safety. 2015, Ottawa ON: 2015 Canadian Agency for Drugs and Technologies in Health. 
11. 
Bar Ad, V., et al., Gabapentin for the treatment of pain related to radiation‐induced 
mucositis in patients with head and neck tumors treated with intensity‐modulated 
radiation therapy. Head & neck, 2010. 32(2): p. 173-177. 
12. 
Yang, W., et al., Predictive Factors for Prophylactic Percutaneous Endoscopic 
Gastrostomy (PEG) Tube Placement and Use in Head and Neck Patients Following 
Intensity-Modulated Radiation Therapy (IMRT) Treatment: Concordance, Discrepancies, 
and the Role of Gabapentin. Dysphagia, 2016. 31(2): p. 206-213. 
13. 
Kushner, J.A., et al., Development and validation of a Patient-Reported Oral Mucositis 
Symptom (PROMS) scale. J Can Dent Assoc, 2008. 74(1): p. 59. 
14. 
Gussgard, A.M., et al., Assessment of cancer therapy-induced oral mucositis using a 
patient-reported oral mucositis experience questionnaire. PloS one, 2014. 9(3): p. 
e91733. 
 
 
 
 


20 
 
APPENDIX I 
 
ZUBROD PERFORMANCE SCALE 
 
0 Fully active, able to carry on all predisease activities without restriction 
 
1 Restricted in physically strenuous activity but ambulatory and able to carry work of a light or 
sedentary nature. For example, light housework, office work 
 
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
 
3 Capable of only limited self-care, confined to bed or chair 50% or more of waking hours 
 
4 Completely disabled. Cannot carry on self-care. Totally confined to bed 
 
5 Death 
 
 
 


21 
 
APPENDIX II 
 
Analgesic Conversion Tables 
 
EQUIANALGESIC POTENCY CONVERSION 
Name 
Equianalgesic Dose (mg) po 
Morphine 
60 
Hydromorphone (Dilaudid) 
7.5 
Methadone (Dolophine) 
20 
Oxycodone 
30 
Levorphanol (Levo-Dromoran) 
4 
Codeine 
200 
TRANSDERMAL FENTANYL (DURAGESIC) DOSE PRESCRIPTION BASED UPON 
DAILY MORPHINE EQUIVALENCE 
Oral 24-hour morphine (mg/day) 
Duragesic Dose (ug/h) 45-134 
25 
135-224 
50 
225-314 
75 
315-404 
100 
405-494 
125 
495-584 
150 
585-674 
175 
675-764 
200 
765-854 
225 
855-944 
250 
945-1034 
275 


22 
 
NARCOTIC EQUIVALENCY INDEX 
NARCOTIC 
ROUTE 
CONVERSION FACTOR 
Morphine 
IM/IV 
1.00 
0.17 for single dose trial; 0.33 for chronic administration 
Hydromorphone 
IM 
6.67 
(Dilaudid) 
po 
1.33 
Codeine 
IM 
0.08 
po 
0.05 
Oxycodone* 
IM 
0.67 
po 
0.33 
Levorphanol 
IM 
6.25 
(Levodromoran) 
po 
3.13 
Meperidine 
IM 
0.10 
(Demerol) 
po 
0.03 
Methadone 
IM 
1.38 
(Dolophine) 
po 
0.69 
* 1 tablet of Tylox, Percocet, or Percodan contains 5 mg of oxycodone. 


23 
 
 
APPENDIX III 
Weekly Patient and Clinician Reported Questionnaires 
 
 


24 
 
 
 
 
I have taken pain medication today. 
Yes 
No 
 
The name of your pain medication: 
  
 
 
What is the dose you are taking? 
  
 
 
How do you take your pain medication? (for example, by mouth, by patch, by injection)   
 
 
How often do you take your pain medication? (for example, once a day, twice a day)   
 
 


25 
 
 
 
 


26 
 
 
 
 


27 
 
 
 


28