Single-Arm Trial Assessing the Feasibility and Acceptability of Navigation for The Management of Delays and Racial Disparities Starting Adjuvant Therapy in Adults With Surgically-Managed, Locally Advanced HNSCC (NDURE 2.0 Pilot)
Phase: NA
Conditions: Squamous Cell Carcinoma of Head and Neck
Sponsor: Medical University of South Carolina

NDURE 2.0 
 
Version 4.0  
Protocol #103161 
 
26 May 2020 
 
A Single-Site, Parallel-Group, Randomized-Controlled 
Trial of Navigation Versus Usual Care for The 
Management of Delays and Racial Disparities Starting 
Postoperative Radiation Therapy in Adults with 
Surgically-Managed, Locally Advanced Head and 
Neck Squamous Cell Carcinoma (NDURE 2.0) 
 
 
Protocol Number: 103161 
 
National Clinical Trial (NCT) Identified Numbers:  NCT04098458 (Single-
Arm NDURE Feasibility Study) and NCT04030130 (RCT of NDURE vs UC) 
 
Principal Investigator: Evan Graboyes, MD, MPH 
 
Sponsor: Hollings Cancer Center 
 
Grant Title: Improving the Timeliness and Equity of Adjuvant Therapy Following 
Surgery for Head and Neck Cancer 
 
Grant Number: K08CA237858-01A1 
 
Funded by: NCI 
 
Version Number:  v.4.0  (26 May 2020) 

NDURE 2.0 
 
Version 4.0  
Protocol #103161 
 
26 May 2020 
 
Based on the NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
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CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
NIH terms of award. 
 
 

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PROTOCOL VERSION HISTORY 
Section 1.3 Schedule of Activities (SOA): Added PORT delay nomogram to Study Visit 1 
4.2.3 Justification for Intervention: Clarified the rationale for including telemedicine NDURE sessions 
in addition to face to face NDURE sessions as a response to the COVID-19 pandemic 
6.1.1. Study Intervention Description: Added the possibility of conducting certain NDURE sessions via 
telemedicine instead of face to face as a response to the COVID-19 pandemic 
Section 8.1 Endpoints and other non-Safety Assessments: Clarified that comorbidity will be assessed 
using the ACE-27. Added PORT delay nomogram as a covariate. 
Section 10.4 Protocol Amendment History: Updated to reflect protocol revisions noted herein. 

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TABLE OF CONTENTS 
Table of Contents 
CONFIDENTIALITY STATEMENT ..................................................................................................................... 2 
PROTOCOL VERSION HISTORY ...................................................................................................................... 3 
TABLE OF CONTENTS ..................................................................................................................................... 4 
STATEMENT OF COMPLIANCE ...................................................................................................................... 7 
INVESTIGATOR’S SIGNATURE ........................................................................................................................ 8 
1 
PROTOCOL SUMMARY ....................................................................................................................... 9 
1.1 
Synopsis ................................................................................................................................... 9 
1.2 
Schema................................................................................................................................... 13 
1.2.1 
NDURE Feasibility Study 
13 
1.2.2 
RCT of NDURE Versus Usual Care 
13 
1.3 
Schedule of Activities ............................................................................................................. 14 
2 
INTRODUCTION ............................................................................................................................... 16 
2.1 
Study Rationale ...................................................................................................................... 16 
2.2 
Background ............................................................................................................................ 16 
2.2.1 
Head and Neck Squamous Cell Carcinoma 
16 
2.2.2 
Delays in Cancer Care Delivery for Patients with HNSCC 
16 
2.2.3 
Barriers to Timely, Equitable PORT After Surgery for HNSCC 
17 
2.2.4 
Interventions to Improve Timely, Equitable PORT for Patients with HNSCC 
17 
2.2.5 
Rationale for Patient Navigation to Improve Timely, Equitable PORT 
17 
2.3 
Risk/Benefit Assessment........................................................................................................ 17 
2.3.1 
Known Potential Risks 
17 
2.3.2 
Known Potential Benefits 
18 
2.3.3 
Assessment of Potential Risks and Benefits 
18 
3 
OBJECTIVES AND ENDPOINTS .......................................................................................................... 19 
4 
STUDY DESIGN ................................................................................................................................. 20 
4.1 
NDURE Feasibility Study ........................................................................................................ 20 
4.1.1 
Overall Design 
20 
4.1.2 
Scientific Rationale for Study Design 
21 
4.1.3 
End-of-Study Definition 
21 
4.2 
RCT of NDURE Versus Usual Care .......................................................................................... 21 
4.2.1 
Overall Design 
21 
4.2.2 
Scientific Rationale for Study Design 
22 
4.2.3 
Justification for Intervention 
23 
4.2.4 
End-of-Study Definition 
23 
5 
STUDY POPULATION ........................................................................................................................ 24 
5.1 
Inclusion Criteria .................................................................................................................... 24 
5.2 
Exclusion Criteria ................................................................................................................... 25 
5.3 
Lifestyle Considerations ......................................................................................................... 25 
5.4 
Screen Failures ....................................................................................................................... 25 
5.5 
Strategies for Recruitment and Retention............................................................................. 26 
6 
STUDY INTERVENTION ..................................................................................................................... 27 
6.1 
Study Intervention Administration ........................................................................................ 27 
6.1.1 
Study Intervention Description 
27 
6.1.2 
Administration and/or Dosing 
29 

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6.2 
Fidelity ................................................................................................................................... 30 
6.2.1 
Interventionist Training and Tracking 
30 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................... 30 
6.4 
Study Intervention/Experimental Manipulation Adherence ................................................. 30 
6.5 
Concomitant Therapy ............................................................................................................ 30 
6.5.1 
Rescue Therapy 
31 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
 
31 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ..................................... 31 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................... 31 
7.3 
Lost to Follow-Up ................................................................................................................... 31 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................... 32 
8.1 
Endpoint and Other Non-Safety Assessment ........................................................................ 32 
8.2 
Adverse Events and Serious Adverse Events ......................................................................... 35 
8.2.1 
Definition of Adverse Events 
35 
8.2.2 
Definition of Serious Adverse Events 
35 
8.2.3 
Classification of an Adverse Event 
35 
8.3 
Unanticipated Problems ........................................................................................................ 37 
8.3.1 
Definition of Unanticipated Problems 
37 
8.3.2 
Unanticipated Problems Reporting 
37 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................... 38 
9.1 
Statistical Hypotheses ............................................................................................................ 38 
9.2 
Sample Size Determination.................................................................................................... 39 
9.2.1 
NDURE Feasibility Study 
39 
9.2.2 
RCT of NDURE Versus Usual Care 
39 
9.3 
Populations for Analyses ....................................................................................................... 40 
9.4 
Statistical Analyses................................................................................................................. 41 
9.4.1 
General Approach 
41 
9.4.2 
Analysis of the Primary Endpoint 
41 
9.4.3 
Analysis of the Secondary Endpoints 
42 
9.4.4 
Baseline Descriptive Statistics 
43 
9.4.5 
Planned Interim Analyses 
43 
9.4.6 
Sub-Group Analyses 
43 
9.4.7 
Tabulation of Individual Participant Data 
43 
9.4.8 
Exploratory Analyses 
43 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................................... 43 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 43 
10.1.1 
Informed Consent Process 
43 
10.1.2 
Study Discontinuation and Closure 
44 
10.1.3 
Confidentiality and Privacy 
44 
10.1.4 
Future Use of Stored Specimens and Data 
45 
10.1.5 
Key Roles and Study Governance 
45 
10.1.6 
Safety Oversight 
45 
10.1.7 
Clinical Monitoring 
46 
10.1.8 
Quality Assurance (QA) and Quality Control (QC) 
46 
10.1.9 
Data Handling and Record Keeping 
46 
10.1.10 
Protocol Deviations 
47 
10.1.11 
Publication and Data Sharing Policy 
47 

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10.1.12 
Conflict of Interest Policy 
47 
10.2 
Additional Considerations ..................................................................................................... 47 
10.3 
Abbreviations and Special Terms ........................................................................................... 47 
10.4 
Protocol Amendment History ................................................................................................ 50 
11 
REFERENCES..................................................................................................................................... 52 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the National 
Cancer Institute (NCI) Terms and Conditions of Award. The Principal Investigator (PI) will assure that no 
deviation from, or changes to the protocol will take place without prior agreement from the funding 
agency and documented approval from the Institutional Review Board (IRB), and the Investigational New 
Drug (IND) or Investigational Device Exemption (IDE) sponsor, if applicable, except where necessary to 
eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct of this 
study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form(s) 
must be obtained before any participant is consented. Any amendment to the protocol will require review 
and approval by the IRB before the changes are implemented to the study. All changes to the consent 
form(s) will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances that 
this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above. 
 
Principal Investigator: 
 
Signed: 
 
Date: 
5/26/2020 
 
Name: Evan Graboyes 
 
Title: A Single-Site, Parallel-Group, Randomized-Controlled Trial of Navigation Versus 
Usual Care for The Management of Delays and Racial Disparities Starting Postoperative 
Radiation Therapy in Adults with Surgically-Managed, Locally Advanced Head and Neck 
Squamous Cell Carcinoma (NDURE 2.0) 
 
Investigator Contact Information 
Affiliation: Medical University of South Carolina 
Address: 135 Rutledge Avenue, MSC 550, Charleston, SC 29425 
Telephone: (843)-792-0719 
Email: graboyes@musc.edu 
 
CO-INVESTIGATORS: 
Chanita Hughes-Halbert PhD 
Hong Li, PhD 
Katherine Sterba, PhD, MPH 
Graham Warren, MD, PhD 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
A Single-Site, Parallel-Group, Randomized-Controlled Trial of 
Navigation Versus Usual Care for The Management of Delays and 
Racial Disparities Starting Postoperative Radiation Therapy in Adults 
with Surgically-Managed, Locally Advanced Head and Neck Squamous 
Cell Carcinoma (NDURE 2.0) 
 
 
Grant Number: 
K08CA237858-01A1 
 
 
Study Description: 
In this study, we evaluate the feasibility, acceptability, preliminary 
clinical impact, and preliminary behavioral impact of NDURE 
(Navigation for Disparities and Untimely Radiation thErapy), a multi-
level, theory-based navigation intervention to improve timely, equitable 
post-operative radiation treatment (PORT) among patients with Head 
and Neck Squamous Cell Carcinoma (HNSCC). We hypothesize that 
NDURE will be feasible, acceptable, improve the timeliness of PORT 
for white and African American (AA) HNSCC patients and decrease 
disparities in delay between the two groups by improving system-, 
interpersonal-, and individual-level health behavior constructs. 

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Objectives: 
 
 
Primary Objective (NDURE feasibility study): 
1. To assess the feasibility of NDURE among white and AA HNSCC 
patients. 
 
Secondary Objectives (NDURE feasibility study): 
1. To assess the acceptability of NDURE to white and AA HNSCC 
patients and providers. 
2. To determine the feasibility of a single dedicated navigator to manage 
a caseload of patients for the NDURE intervention 
3. To evaluate the feasibility of collecting pre- and post-NDURE 
intervention outcome measures in this patient population 
 
Primary Objective (RCT of NDURE vs Usual Care): 
1. To evaluate the preliminary clinical impact of NDURE compared 
with usual care (UC) on delays starting PORT among white and AA 
HNSCC patients. 
 
Secondary Objectives (RCT of NDURE vs Usual Care): 
1. To evaluate the preliminary clinical impact of NDURE compared 
with UC on racial disparities in delays starting PORT among white and 
AA HNSCC patients. 
2. To assess the preliminary clinical impact of NDURE compared with 
UC on barriers to care 
3. To determine the preliminary impact of NDURE compared with UC 
on cancer care delivery processes. 
4. To evaluate the preliminary behavioral mechanism of action of 
NDURE. 
 

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Endpoints: 
Primary Endpoint: 
PORT Delay 
 
Secondary Endpoints: 
NDURE Accrual Rate 
NDURE Completion Rate 
Navigation Session Completion Rate 
Questionnaire Completion Rate 
 
Navigator Caseload 
Navigator Time Allocation (Direct) 
Navigator Time Allocation (Indirect) 
 
Patient Satisfaction with the Interpersonal Relationship with the 
Navigator Scale Score 
Patient Satisfaction with Logistical Aspects of Navigation Scale Score 
 
Time-to-PORT Initiation 
 
Rate of Barrier Resolution 
Unresolved Barriers Rate 
 
Pre-Surgical Radiation Consultation 
Pre-Radiation Therapy Dental Extractions 
Surgery to Pathology Report < 7 days 
Surgery to PORT Referral < 10 days 
RT Referral to Consult < 10 days 
RT Consult to Initiation < 21 days 
 
Care Transition Measure-15 Score 
Change from Baseline in Interpersonal Support Evaluation List-12 
Score 
Change from Baseline in Perceived Susceptibility Questionnaire Scores 
Change from Baseline in Illness Perception Questionnaire-Revised 
Consequences Sub-Scale Score 
Change from Baseline in Perceived Barriers Scale 
Change from Baseline in Communication & Attitudinal Self-Efficacy 
Scale-Cancer Score 
 
 
Study Population: 
The study population will consist of patients 18 years of age or older, 
male and female sex, and self-identified white and AA race, with locally 
advanced HNSCC undergoing curative intent surgery followed by 
PORT with or without concurrent chemotherapy 
 
 
Phase or Stage: 
N/A 

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Description of 
Sites/Facilities Enrolling 
Participants: 
The study will be conducted, and participants enrolled, at the Medical 
University of South Carolina (MUSC) Hollings Cancer Center (HCC) 
Head and Neck Tumor Center. The Head and Neck Tumor Center is a 
high-volume, multidisciplinary center designed for unsurpassed clinical 
care and optimized for integration of research activities. The Head and 
Neck Tumor Center is a regional center of excellence for HNSCC 
clinical care. 
 
Description of Study 
Intervention/Experimental 
Manipulation: 
NDURE is a theory-based, multi-level patient navigation (PN) 
intervention consisting of three sessions of manualized PN with multiple 
intervention components that target system-(care coordination), 
interpersonal-(social support), and individual- (health belief model); 
perceived susceptibility, severity, barriers, self-efficacy) level health 
behavior theoretical constructs to reduce barriers to care, enhance 
HNSCC care delivery, and improve clinical outcomes (timely, equitable 
PORT). NDURE will be delivered from surgical consultation to PORT 
initiation (~3 months). The three NDURE navigation sessions, which 
are expected to take 30-60 minutes each, will coincide with the 
presurgical consult, hospital discharge, and 1st postoperative clinic visit, 
time points chosen to facilitate case identification and coordination 
across key care transitions. 
 
 
Study Duration: 
NDURE Feasibility: 7 months 
NDURE vs Usual Care RCT: 42 months 
 
Participant Duration: 
 
3 months 
 
 
 
 

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1.2 
SCHEMA 
1.2.1 NDURE FEASIBILITY STUDY 
 
1.2.2 RCT OF NDURE VERSUS USUAL CARE 
Figure 2. RCT Schema. HNSCC patients undergoing surgery and PORT will be enrolled into a pilot 
RCT comparing NDURE to usual care to evaluate the preliminary clinical impact of NDURE on delays 
and racial disparities starting PORT after HNSCC surgery. 
 
 
Figure 1. Feasibility Study Schema. Following completion of baseline questionnaires, 
participants (n=15) will be enrolled into NDURE. Measures of feasibility (enrollment, 
dropout, missed patient navigation (PN) encounters, navigator caseload and time allocation) 
will be assessed during the intervention delivery. Following completion of NDURE, patients 
will complete validated measures of acceptability related to Satisfaction with PN, and 
patients and providers will undergo semi-structured interview to help refine NDURE. 

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1.3 
SCHEDULE OF ACTIVITIES  
 
Table 1. Schedule of Activities for NDURE and Usual Care and Follow-up 
 
Pre-
screening 
 
Visit 1 
Visit 2 
(Pre-Op) 
Visit  3 
(Pre-
Discharge) 
Visit  4 
(Post-
Discharge)
Visit  5 
(Start of 
PORT) 
Informed Consent 
Electronic Medical Record 
(EMR) Review Eligibility 
X 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
Study Procedures 
Randomization 
 
X 
 
 
 
 
Demographics 
 
X 
 
 
 
 
Clinical and Oncologic 
History 
 
X 
 
 
X 
X 
PORT Delay Nomogram 
 
X 
 
 
 
 
Cultural Factor Survey 
 
X 
 
 
 
 
Monitoring 
AE/SAE Assessment 
 
 
X 
X 
X 
X 
Intervention Administration 
NDURE or UC 
 
 
X 
X 
X 
 
Efficacy Evaluation 
PORT Delay 
 
 
 
 
 
X 
Feasibility 
NDURE Accrual 
X 
 
 
 
 
 
NDURE Completion 
 
 
 
 
 
X 
Navigator Caseload 
 
<------------------------------------------------------> 
Navigator Time Allocation 
 
<------------------------------------------------------> 
Acceptability 
 
 
 
 
 
 
Satisfaction with the 
Interpersonal Relationship 
with the Navigator Scale 
 
 
 
 
 
X 
Satisfaction with Logistical 
Aspects of Navigation 
Scale 
 
 
 
 
 
X 
Program Evaluation 
 
 
 
 
 
X 
Cancer Care Delivery Processes 
Timely Care Processes 
 
<------------------------------------------------------> 
Health Behavior Constructs 
Barrier Reduction 
 
 
 
X 
X 
X 
Unresolved Barriers 
 
 
X 
X 
X 
X 
Care Transition Measure-15 
 
 
 
X 
X 
 

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Interpersonal Support 
Evaluation List-12 
 
X 
 
 
 
X 
Perceived Susceptibility 
Questionnaire 
 
X 
 
X 
X 
 
Illness Perception 
Questionnaire-Revise 
Consequences Subscale 
 
X 
 
X 
X 
 
Perceived Barriers 
Questionnaire 
 
X 
 
X 
X 
X 
Communication & 
Attitudinal Self-Efficacy 
Scale-Cancer 
 
X 
 
 
 
X 
Navigator Barrier Log 
 
X 
 
X 
X 
X 

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2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE 
Head and neck squamous cell carcinoma (HNSCC) is responsible for 14,000 deaths annually in the US 
and has poor survival (50% at 5 years) despite intense treatment including surgery, radiation, and 
chemotherapy1. HNSCC is also a disease with significant racial disparities in mortality; African 
Americans (AAs) have a 51% relative decrease in survival compared with whites2. Delays starting 
postoperative radiation therapy (PORT) after HNSCC surgery are a key driver of high mortality for all 
HNSCC patients and racial disparities in survival for AAs. As such, the delivery of timely PORT is an 
appealing therapeutic target to address both issues3,4. We have shown that delayed, non-guideline-
adherent PORT initiation (> 6 weeks after surgery5) affects 56% of HNSCC patients6, is 31% more 
common in AA HNSCC patients than whites6, is associated with an 11% absolute decrease in 5-year 
survival7, and is a key driver of racial differences in mortality3. Our pilot qualitative data suggest that 
treatment toxicity, travel distance, care coordination, finances, support, knowledge, and communication 
are barriers to timely, equitable PORT. Delivering timely PORT to all HNSCC patients is critical to 
prevent excess mortality and racial disparities in survival. Unfortunately, effective interventions to 
decrease delays and racial disparities starting PORT are unknown8,9, due in part to the lack of 
understanding of the relevant barriers in this clinical setting. One potential strategy to improve timely, 
equitable PORT is patient navigation (PN), a barrier-focused intervention that improves the timeliness 
and racial equity of initial cancer care (screening, treatment initiation)10,11. However, the impact of PN on 
delays and racial disparities starting PORT, a different point on the cancer care continuum than screening 
and treatment initiation, is unknown12. In this proposal, we extend our work to develop and evaluate the 
feasibility, acceptability, and preliminary clinical impact of NDURE (Navigation for Disparities and 
Untimely Radiation thErapy), our multi-level, theory-based PN intervention to improve timely, equitable 
PORT among HNSCC patients. 
 
2.2 
BACKGROUND 
2.2.1 HEAD AND NECK SQUAMOUS CELL CARCINOMA 
HNSCC, which affects the tongue, pharynx, larynx, and neck, is diagnosed in 65,000 patients in the US 
annually and causes 14,000 deaths per year1. No screening tests exist for HNSCC, and as a result, more 
than two-thirds of patients present with locally advanced disease1. Despite aggressive multimodal therapy 
consisting of surgery followed by PORT and concurrent chemotherapy5, outcomes remain poor with only 
50% of patients with locally-advanced HNSCC surviving 5 years1. HNSCC is also a disease with 
significant racial disparities in mortality; AAs with HNSCC have a 19% absolute decrease in 5-year 
survival relative to white HNSCC patients13 and a 51% relative decrease in survival2.  
 
2.2.2 DELAYS IN CANCER CARE DELIVERY FOR PATIENTS WITH HNSCC 
Delays starting PORT contribute to high mortality in HNSCC and racial disparities in survival. Delays in 
cancer care delivery are a key driver of mortality for HNSCC patients14 and a source of racial disparities 
in survival for AAs3. The critical time period for HNSCC patients is the time from surgery to the start of 
PORT8,15, the only aspect of timely HNSCC care incorporated in National Comprehensive Cancer 
Network (NCCN) Guidelines (< 6 weeks after surgery)5. Delays starting PORT are associated with 
increased recurrence and decreased survival7,16,17. The 11% improved 5-year survival seen with timely 
PORT7 is large, comparable in magnitude to the benefit seen from adding Cisplatin to PORT in landmark 
HNSCC trials18,19. Unfortunately, delays starting PORT affect 56% of HNSCC patients6. Delays starting 
PORT also disproportionately affect AAs, who are 31% more likely to experience delays than whites after 

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adjusting for insurance, income, education, and stage6. The high rate of delayed PORT among AA 
HNSCC patients is a source of preventable mortality and contributes to racial disparities in survival7. 
 
2.2.3 BARRIERS TO TIMELY, EQUITABLE PORT AFTER SURGERY FOR HNSCC 
The barriers that contribute to delays and racial disparities starting PORT after HNSCC surgery are 
unknown. AA race, insurance status, prolonged travel distance, and care fragmentation are associated 
with delayed PORT6,20-22. However, the barriers to timely care delivery at the patient-, provider-, and 
system-level remain unknown. As a result, the development of targeted, multi-level interventions to 
address barriers and improve the delivery of timely, equitable PORT for HNSCC patients has been 
impeded. To prevent continued treatment delays, it is critically important to identify the barriers to 
delivering timely, equitable PORT. 
 
2.2.4 INTERVENTIONS TO IMPROVE TIMELY, EQUITABLE PORT FOR PATIENTS 
WITH HNSCC 
The care delivery pathway for PORT, which is potentially modifiable through a multi-level intervention, 
represents an appealing target to decrease mortality and racial disparities in survival for HNSCC 
patients3,4,8. Unfortunately, despite the large clinical impact of delayed PORT on mortality and racial 
disparities in survival, no effective interventions have been described8,9,23. A prior study using an 
atheoretical, provider-centric approach did not find a decrease in the rate of PORT delay24. Improving the 
timeliness of PORT for white and AA HNSCC patients is crucial to improving survival for all HNSCC 
patients and decreasing racial disparities in mortality. 
 
2.2.5 RATIONALE FOR PATIENT NAVIGATION TO IMPROVE TIMELY, 
EQUITABLE PORT 
PN is a patient-centered intervention that addresses barriers to cancer care, thereby improving the delivery 
of timely, equitable cancer screening, decreasing racial differences in post-screening diagnostic 
resolution, and decreasing care fragmentation10,11,25-27. However, the efficacy of PN in the sequential 
multimodal cancer care setting (e.g. surgery then PORT) is unknown12; care transitions following surgery 
involve unique care barriers and care coordination challenges28. To address the lack of effective 
interventions to decrease delays and racial disparities starting PORT after HNSCC surgery8, we will 
develop and test NDURE, our multi-level, theory-based PN intervention to improve timely, equitable 
PORT among HNSCC patients. The underlying scientific premise is that our NDURE PN intervention 
has the potential to decrease delays starting PORT among HNSCC patients because PN is most effective 
in 1) populations with low adherence rates10 (timely PORT adherence is < 50% overall and <40% among 
AAs6); 2) racial minority populations10,29 (delays starting PORT are 31% more common in AAs6); and 3) 
the setting of fragmented care10,27 (PORT delivery involves coordinating consults with seven medical 
specialties23, care transitions from inpatient to outpatient, and care transitions across healthcare systems 
[in 51% of cases6]). 
 
2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
Overall, this research study poses no more than minimal risks to participants. There are no physical, 
financial, legal, social, or cultural, risks to the study participants by joining this study. There are slight 

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psychological risks, as described below. There is a slight risk that subjects may experience adverse 
psychological reactions such as anxiety or stress as a result of discussing issues related to cancer or 
barriers to cancer care. We believe that this risk is minimal. We are using survey items that are commonly 
used in clinical settings and subjects are likely to have had prior exposure to similar types of questions as 
part of their medical care. Furthermore, in our past studies with white and AA men and women with 
HNSCC, the overwhelming majority of respondents have said they found the questions that we have 
asked related to care have not been upsetting. 
 
There is also a slight risk that confidential information about the participant may be accidentally disclosed 
as study participants may be asked to provide information considered confidential or private during study 
interviews. The likelihood of this risk is low as all the investigators have been involved in similar research 
in the past and have not experienced this problem before due to adequate safeguards. 
 
The decision to participate in this research will be voluntary and individuals may refuse to take part or 
choose to stop taking part at any time. Participants will also be encouraged to take their time when 
answering questions and may decline to answer any question at any time. If patients become upset talking 
about their cancer and the barriers that they faced, they will be offered a referral to the Hollings Cancer 
Center (HCC) Behavioral Medicine program (which is covered by most health insurance programs) or the 
HCC Social Worker who will offer links to other HCC and community resources. 
 
2.3.2 KNOWN POTENTIAL BENEFITS 
Extrapolating from data about PN in other settings, NDURE may improve the timeliness of PORT after 
HNSCC surgery and decrease racial disparities in timely HNSCC care. However, although we 
hypothesize a direct benefit to participants in the NDURE study (in terms of timely HNSCC care), it is 
unknown whether patients will experience a direct benefit. Data generated from this study are expected to 
provide benefits to society by providing new knowledge about a practical and scalable strategy for 
addressing racial disparities in the timeliness of PORT in HNSCC patients. Because timely PORT is 
associated with decreased rates of recurrence and improved survival, it is expected that if we decrease 
racial disparities in delays starting PORT, we will improve survival and racial equity in outcomes. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
The decision to participate in this research will be voluntary. Participants will be informed that they can 
stop participating at any time and/or refrain from answering any questions that make them uncomfortable. 
The interviewers are trained researchers with experience conducting interviews related to cancer. By 
using survey items that are commonly used in clinical settings (to which subjects have likely had prior 
exposure as part of their medical care) we will minimize psychological risk. If a participant has a 
psychological adverse event (AE) talking about his/her cancer and/or the barriers that he/she faced during 
treatment, the participant will be offered a referral to the HCC Behavioral Medicine program (which is 
covered by most health insurance programs) or the HCC Social Worker who will offer links to other HCC 
and community resources as detailed in the Data and Safety Monitoring Plan. Immediate backup and 
support will be available.  
 
To help ensure and protect privacy of participants and confidentiality of research data for the study, we 
will assign a unique study ID number to each subject’s information in place of his/her name and will label 
data collection forms with the ID number. All hard copy and electronic files will be stored appropriately 
using double-locked methods and password-protection. Only the study team members will have access to 
study records. Participant data will be collected and recorded on either a password-protected electronic 
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collection data method, the data collection form will be labeled only with the participant's unique study 
ID number, and then stored within locked drawers in a locked office. 
 
The information on these paper forms will be transferred to a password-protected REDCap database. Any 
exported data for analysis will be de-identified with all privately identifiable information automatically 
removed. The key linking subject ID number to an individual will be stored in the password protected 
REDCap database. The audio recordings from the qualitative interviews will be labeled only with the 
patient’s unique study ID and stored using password-protected files only accessible by the study team 
through password-protected servers. Once data have been collected, only de-identified data will be 
exported for analysis. All study personnel will participate in training on protecting the privacy of study 
participants and personal information will not be disclosed to anyone outside of the research team. Only 
the principal investigator and study staff participating in data collection or analysis will have access to the 
data. We have no plan to use laptops, jump drives, CDs/DVDs to transport data. 
 
On the whole, given the minimal risks to the study participants and the potential benefit of the research to 
participants and society, we believe that the potential reward to participants and society substantially 
outweighs the risks to the participants. 
 
3 
OBJECTIVES AND ENDPOINTS  
Table 1. Study Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
NDURE FEASIBILITY STUDY 
Primary 
 
To assess the feasibility of NDURE among white and 
AA HNSCC patients. 
NDURE Accrual Rate 
NDURE Completion Rate 
NDURE Session Completion Rate 
Questionnaire Completion Rate 
Secondary 
To assess the acceptability of NDURE to white and 
AA HNSCC patients and HNSCC providers. 
Patient Satisfaction with the Interpersonal 
Relationship with the Navigator Scale Score 
Patient Satisfaction with Logistical Aspects of 
Navigation Scale Score 
To determine the feasibility of a single dedicated 
navigator to manage a caseload of patients for the 
NDURE intervention 
Navigator Caseload 
Navigator Time Allocation (Direct) 
Navigator Time Allocation (Indirect) 
To evaluate the feasibility of collecting pre- and post-
NDURE intervention outcome measures in this 
patient population 
Study questionnaire completion rate 
 
RCT of NDURE VERSUS USUAL CARE 
Primary 
 
To evaluate the preliminary clinical impact of 
NDURE compared with UC on delays starting PORT 
among white and AA HNSCC patients. 
PORT Delay 
Time-to-PORT (TTP) Initiation 
Secondary 
To evaluate the preliminary clinical impact of 
NDURE compared with UC on racial disparities in 
delays starting PORT among white and AA HNSCC 
PORT Delay 
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Table 1. Study Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
patients. 
To assess the preliminary clinical impact of NDURE 
compared with UC on barriers to care 
Barriers Resolution Rate 
Unresolved barriers 
To determine the preliminary clinical impact of 
NDURE compared with UC on cancer care delivery 
processes 
Pre-surgical Radiation Consultation 
Pre-RT Dental Extractions 
Surgery to Pathology Report < 7 d 
Surgery to PORT Referral < 10 d 
RT Referral to Consult < 10 d 
RT Consult to Initiation < 21 d 
To evaluate the preliminary behavioral mechanism of 
action of NDURE 
Care Transition Measure-15 (CTM-15) Score 
Change from Baseline in Interpersonal Support 
Evaluation List-12 Scale Score 
Change from Baseline in Perceived 
Susceptibility Scale Scores 
Change from Baseline in Illness Perception 
Questionnaire-Revised (IPQ-R) Consequences 
Sub-Scale Score 
Change in Baseline from Perceived Barriers 
Scale 
Change in Baseline from Communication & 
Attitudinal Self-Efficacy Scale (CASE)-Cancer 
Score 
 
4 
STUDY DESIGN 
4.1 
NDURE FEASIBILITY STUDY 
4.1.1 OVERALL DESIGN 
We will conduct a single-site, single-arm, non-blinded trial of NDURE to assess its feasibility and 
acceptability as an intervention to decrease delays and racial disparities starting PORT in adults with 
surgically-managed, locally advanced HNSCC (n=15; AA n=5; white n=10). 
 
The study is designed to test the following hypotheses: 1) NDURE is feasible as measured by accrual rate, 
completion rate, and PN caseload; and 2) NDURE is acceptable, as measured by the Patient Satisfaction 
with the Interpersonal Relationship with the Navigator30,31 and the Patient Satisfaction with Logistical 
Aspects of Navigation32. 
 
NDURE is feasible NDURE is a theory-based, multi-level PN intervention consisting of three sessions of 
manualized PN with multiple intervention components that target system- (care coordination), 
interpersonal- (social support), and individual- (health belief model [HBM]; perceived susceptibility, 
severity, barriers, self-efficacy) level health behavior theoretical constructs to reduce barriers to care, 
increase HNSCC care delivery, and improve clinical outcomes (timely, equitable PORT). NDURE will be 
delivered from surgical consultation to PORT initiation (~3 months). The three NDURE navigation 
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hospital discharge, and 1st postoperative clinic visit, time points chosen to facilitate case identification and 
coordination across key care transitions. 
 
4.1.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The single-arm study design was chosen to evaluate the feasibility and acceptability of the NDURE 
intervention. Questionnaires to be used in the RCT assessing symptom burden, interpersonal support, 
knowledge, and self-efficacy will be collected pre- and post-intervention to assess the feasibility of data 
collection procedures and monitor completion rates. Post-intervention, patients will complete validated 
measures of PN acceptability. Qualitative work with patients and providers will help refine NDURE. Our 
interdisciplinary team will consult with our scientific advisory board and community advocacy group to 
interpret the data about the feasibility and acceptability of NDURE to refine recruitment, retention, and 
the content, format, timing, and delivery of NDURE for the planned RCT. We considered other study 
designs that involve randomization. Although such a study design would allow us to evaluate feasibility 
of enrollment when there is a control group option (and thus reasons for study decline), it would dilute the 
sample size thereby minimizing the amount of information gained about feasibility of accrual to the 
intervention necessary before proceeding to the RCT. In addition, since the control group in the RCT is 
usual care, randomizing patients to usual in the feasibility and acceptability study would not add useful 
information about the acceptability of the control to the control group beyond what is already known from 
recent clinical experience in this setting. 
 
4.1.3 END-OF-STUDY DEFINITION 
The end of the study is defined relative to completion of the 3-month follow-up assessment shown in the 
Schedule of Activities (SoA), Section 1.3. 
 
4.2 
RCT OF NDURE VERSUS USUAL CARE 
4.2.1 OVERALL DESIGN 
We will conduct a single-site, non-blinded, parallel-group, RCT of NDURE versus usual care for the 
management of delays and racial disparities starting PORT in adults with surgically-managed, locally 
advanced HNSCC. The study is designed to test the following hypotheses: 1) NDURE will result in a 
lower rate of delayed PORT relative to usual care (primary objective) and 2) NDURE will result in a 
smaller difference in PORT delay between AA and whites relative to usual care (secondary objective). 
The statistical plan for this between-group design analyzes the superiority of NDURE relative to usual 
care, although our power analysis is calculated with α = 0.1 and 1 – β = 0.8 based on the desire to 
emphasize power over type I error at this early stage of development (single-site pilot RCT) to ensure 
follow-up on promising interventions. 
 
Upon enrollment and completion of the baseline assessments, patients will be randomized 1:1 to NDURE 
or usual care using a permuted block randomization method, with randomly selected block sizes of 2 or 4. 
Randomization, which will occur at the individual patient level, will be stratified with a 1:1 allocation 
ratio with strata defined by race (white, AA) and location of radiation facility (MUSC, non-MUSC) 
because of the known association of these variables with PORT delay6,33. Furthermore, to facilitate 
evaluation of PORT delay rates in racial subgroups, we will oversample AAs for a final sample size of 50 
white and 25 AA patients in each arm (see details in Section 9.4.6, Sub-Group Analyses). Given the 
impossibility of delivering the NDURE intervention in a non-blinded fashion, allocation concealment will 
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randomization list. The study coordinator will implement the randomization. Randomization errors will 
be handled as per the modified intention-to-treat (ITT) population for the efficacy analysis. 
 
NDURE is a theory-based, multi-level PN intervention consisting of three  sessions of manualized PN 
with multiple intervention components that target system- (care coordination), interpersonal- (social 
support), and individual- (HBM; perceived susceptibility, severity, barriers, self-efficacy) level health 
behavior theoretical constructs to reduce barriers to care, increase HNSCC care delivery, and improve 
clinical outcomes (timely, equitable PORT). NDURE will be delivered from surgical consultation to 
PORT initiation (~3 months). The three NDURE navigation sessions, which are expected to take 30-60 
minutes each, will coincide with the presurgical consult, hospital discharge, and 1st postoperative clinic 
visit, time points chosen to facilitate case identification and coordination across key care transitions. 
 
In the RCT, NDURE will be compared with usual care. Usual care consists of clinic-based, provider-led 
discussion about the referrals needed to start PORT. Usual care was selected as the appropriate 
comparison group because it is the current standard for the population under study. Limitations of 
comparing NDURE to usual care (instead of active control) include the potential that improvements seen 
with NDURE (relative to usual care) are due to nonspecific effects. However, we are collecting data about 
the potential behavioral mechanisms underlying NDURE, which helps to limit the concern about non-
specific effects of the NDURE intervention. In addition, given the pilot nature of this study, the goal is to 
achieve superior outcomes for patients over and above standard of care; therefore, usual care is a 
reasonable and appropriate comparison condition34. In the future, as we continue to assess and establish 
the efficacy of NDURE in larger trials, we will explore the ‘active ingredients’ relative to active control to 
better isolate the mechanisms underlying its efficacy. 
 
Because of the pilot nature of the study, refining the NDURE intervention is critical to ensure that 
NDURE is optimally developed and delivered prior to future definitive efficacy testing. As such, we will 
conduct qualitative, semi-structured interviews on n=25 (20% of the subjects enrolled in NDURE [n=15] 
and n=10 providers) to assess perceived barriers and facilitators to NDURE delivery, qualitatively assess 
mechanisms of change, and optimize NDURE for future research. 
 
4.2.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
We considered alternative study designs such as a single-arm pilot study with comparison to local and 
national historical control data. However, we consider the RCT a superior approach to a single-arm trial 
comparing to historical control35 because the RCT will allow us to demonstrate and precisely measure the 
control group, thereby avoiding sample error and case-mix differences between the single-arm and 
historical control36. As a result, the RCT design will provide us with more precise estimates of the effect 
size and sample size of the NDURE intervention relative to usual care in preparation for the definitive 
phase III RCT37. Although methodological challenges (e.g. contamination)38, will exist from running a 
single-site RCT (because providers will have patients in both NDURE and usual care concurrently), our 
group has experience successfully conducting single-site pilot RCTs39,40. Other groups testing PN have 
similarly reported successful study completion and avoidance of significant contamination when studying 
PN in the single-arm setting10. 
 
We also considered alternative comparison groups, including a form of active control against which to 
compare NDURE. Usual care is a more appropriate comparison group than active control because usual 
care represents the current standard for the management of this clinical scenario in population under 
study. Limitations of comparing NDURE to usual care (instead of active control) include the potential 
that improvements seen with NDURE (relative to usual care) are due to nonspecific effects instead of key 
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evaluate the preliminary behavioral mechanism of action of NDURE. As such, the data that we will 
analyze regarding underlying behavioral mechanisms will help to limit the concern about non-specific 
effects of the NDURE intervention. In addition, given the pilot nature of this trial, our goal is to achieve 
superior outcomes for patients over and above standard of care; therefore, usual care is a reasonable and 
appropriate comparison condition34. In the future, as we continue to assess and establish the efficacy of 
NDURE in larger trials, we will explore the ‘active ingredients’ relative to active control to better isolate 
the mechanisms underlying its efficacy. 
 
4.2.3 JUSTIFICATION FOR INTERVENTION 
4.2.3.1 JUSTIFICATION FOR THE MODE OF DELIVERY 
PN is a patient-centered intervention that addresses barriers to cancer care, thereby improving the delivery 
of timely, equitable cancer screening, decreasing racial differences in post-screening diagnostic 
resolution, and decreasing care fragmentation10,25-27. Although technology-enhanced interventions are 
increasingly common to facilitate care coordination, PN at its heart is still a patient-centered intervention 
and is delivered in person via face to face interactions. Face to face interactions can unduly burden 
patients and result in decreased intervention adherence. In addition, face to face interactions are being 
minimized to promote patient and healthcare worker safety during the COVID-19 pandemic. 
 
The preferred method for delivering NDURE is face to face. However, due to changes in healthcare 
delivery necessitated by COVID-19 pandemic, it is permissible for the NDURE navigator to use a 
telemedicine videoconferencing platform for NDURE sessions 1 or 3 (study visit 2 or 4). The number, 
frequency, and timing of intervention contacts (see details in Section 4.2.3.2, Justification for Number, 
Frequency, and Timing of Intervention Contacts) were carefully chosen to minimize potential 
concerns that may arise from face to face interactions. In addition, supplemental contact beyond the three 
prescribed sessions will occur with a frequency and modality (e.g. text message, email, etc.) dictated by 
patient and navigator need. 
 
4.2.3.2 JUSTIFICATION FOR NUMBER, FREQUENCY, AND TIMING OF 
INTERVENTION CONTACTS 
The three NDURE sessions, which are expected to take 30-60 minutes each, will coincide with the 
presurgical consult, hospital discharge, and 1st postoperative clinic visit. These time points were chosen to 
facilitate case identification (preoperatively; Visit 2) and coordination across key care transitions from 
inpatient to outpatient status at the time of hospital discharge (inpatient; Visit 3) and from surgical to 
radiation and medical oncology specialties (post-discharge; Visit 4). These timepoints also promote the 
feasibility of NDURE delivery as nearly 100% of patients attend these three visits (despite travel 
distance-related barriers41) since patients 1) cannot have surgery without their presurgical consult; 2) are 
hospitalized postoperatively; and 3) return for the 1st postoperative visit for drain/tube removal. The 
number of intervention contacts is justified by the need to focus the intervention to key transitions of care 
as described above. 
 
4.2.4 END-OF-STUDY DEFINITION 
The end-of-study is defined in relation to the 3-month follow-up (see Section 1.3, Schedule of Activities 
[SoA]). This end-of-study definition will permit sufficient follow-up to capture the primary endpoint, 
delays starting PORT (>6 weeks after surgery). A secondary endpoint, time-to-initiation of PORT (TTP), 
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As such, it is possible that at the conclusion of the SoA, a patient may not yet have initiated PORT (which 
would imply starting PORT more than 12 weeks after surgery). Based on national historical data, <9% of 
patients have such an extreme delay initiating PORT that they start more than 12 weeks after surgery6. 
Relative to the loss of marginal missing data that will require censoring for the TTP endpoint (which is 
secondary in nature), we believe that the cons of extending the end-of-study definition longer than what 
we have proposed in terms of the adverse impact on trial feasibility, grant funding timeline, and 
administrative loom large (as outweigh the pros). As such, we consider our end-of-trial definition 
justified. 
 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
Patient and disease characteristics 
1. Age > 18 years at the time of screening 
2. Self-identified white or AA race 
3. Histologically or pathologically confirmed invasive SCC (or histologic variant) of the oral cavity, 
oropharynx (p16 positive, negative, or unknown), hypopharynx, larynx, unknown primary, 
paranasal sinuses, or nasal cavity. 
a. In situations in which the patient fulfills all other inclusion criteria but the biopsy shows 
SCC in-situ or moderate/severe dysplasia (without definitive evidence of invasive SCC), 
but the patient is scheduled to undergo curative intent surgery by the treating oncologic 
surgeon due to clinical suspicion of invasive SCC, the diagnosis of SCC-in situ or 
moderate/severe dysplasia is sufficient to full the pathologic diagnosis enrollment 
criterion. 
4. American Joint Committee on Cancer (AJCC) clinical stage grouping III-IV (8th edition) for 
patients with SCC of the oral cavity, p16-negative oropharynx, hypopharynx, larynx, paranasal 
sinuses, and nasal cavity; or AJCC clinical stage grouping III-IV (7th edition) for patients with 
p16-positive SCC of the oropharynx or unknown primary. 
a. At screening, AJCC clinical stage grouping should be determined based on a combination 
of physical exam, diagnostic evaluation with cross sectional imaging of the neck 
(computerized tomography (CT) and/or magnetic resonance imaging (MRI)) and/or 18-F-
fluoro-deoxyglucose positron emission tomography (FDG PET) CT within 30 days 
b. In situations in which the patient fulfills all other inclusion criteria but the biopsy shows 
SCC in-situ or moderate/severe dysplasia (without definitive evidence of invasive SCC), 
but would otherwise have an appropriate clinical stage grouping as defined in criterion 5, 
the diagnosis of SCC-in situ or moderate/severe dysplasia is sufficient to full the staging 
enrollment criterion. 
5. No prior exposure to radiation therapy, with or without concurrent chemotherapy, for treatment of 
HNSCC in the definitive or adjuvant therapy settings 
 
Surgery and adjuvant therapy eligibility 
6. Plan for curative intent surgery at MUSC 
a. At screening, plan for curative intent surgical resection of the HNSCC at MUSC must be 
deemed likely by the treating surgeon and/or multidisciplinary tumor board, which must 
include a fellowship-trained head and neck oncologic surgeon 
7. Plan for PORT (at MUSC or non-MUSC) with or without concurrent chemotherapy following 
curative intent surgery 
a. At screening, plan for adjuvant therapy following curative intent surgical resection of the 
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tumor board, which must include a fellowship-trained head and neck oncologic surgeon, 
based on the clinical expectation of at least one of the following adverse features on final 
pathologic evaluation: extranodal extension (ENE), pT3 or pT4 primary, N1 or greater 
nodal disease, nodal disease in levels IV or V, perineural invasion (PNI), or 
lymphovascular invasion (LVI) 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Self-identified Hispanic ethnicity 
2. Presence of cognitive impairment that precludes participation 
3. Synchronous untreated malignancy 
a. Patients with known untreated indolent malignancies (defined as non-melanoma skin cancer) 
at the time of diagnosis or that develop during the study period would not exclude a patient 
from the study 
4. Failure to undergo curative intent surgery at MUSC 
5. Lack of indication for PORT (with or without concurrent chemotherapy) per National 
Comprehensive Cancer Network (NCCN) Guidelines based on the presence of at least one of the 
following adverse features on final pathologic evaluation: ENE, positive margin, pT3 or pT4 
primary, N1 or greater nodal disease, nodal disease in levels IV or V, PNI, or LVI 
 
Individuals across the lifespan will be included with the following exception: children (i.e., individuals 
under age 18) will be excluded. Children are not eligible to participate in the study for the following 
scientific reasons: 1) HNSCC is a rare pediatric malignancy; and 2) the care delivery experiences of 
children with HNSCC are likely very different from those of adults. The age distribution included in the 
study (all ages > 18) will allow us to evaluate the feasibility and acceptability of NDURE in individuals 
of across the lifespan. 
 
Patients of non-white, non-AA racial groups (e.g. Asian American, Native American) will be excluded 
from the clinical trial of NDURE. Our decision to focus only on white and AA patients (and exclude other 
racial groups) is justified by the following considerations: 1) In terms of timely PORT, the racial 
disparities are largest among white compared with AA HNSCC patients (nationally and at MUSC); 2) 
The barriers causing racial differences in time to PORT among AAs and other racial groups may be 
different, necessitating a different patient navigation intervention; 3) Other non-white, non-AA racial 
groups make up only 1% of HNSCC patients treated at MUSC. As a result, finding a sufficient number of 
patients who are non-AA racial minorities to participate in the RCT of NDURE would be challenging. 
Patients who self-identify as being of Hispanic ethnicity will be excluded from the clinical trial of 
NDURE. Although Hispanic ethnicity is a risk factor for delayed PORT, we justify our exclusion of 
Hispanic patients from the clinical trial for the following reasons: 1) The barriers causing racial 
differences in time to PORT among AAs and Hispanics are likely different (e.g. language); 2) Hispanic 
HNSCC patients account for only 3% of patients at MUSC. As a result, finding a sufficient number of 
Hispanic patients to participate in the clinical trial of NDURE would be challenging. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
N/A 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in this study but are not 
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criteria for participation in this trial (screen failure) because of meeting one or more exclusion criteria will 
not be rescreened. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment for the NDURE 2.0 trial will occur using a clinic-based approach from the MUSC Head and 
Neck Tumor Center, a high-volume academic HNSCC program at the NCI-designated Hollings Cancer 
Center. Research staff will use cancer center registry data, discussion with the HNSCC clinical team, and 
the electronic medical record (EMR) to identify patients who meet study inclusion criteria. Research staff 
will then review clinic rosters to identify eligible patients who are scheduled for an appointment in the 
Head and Neck Tumor Center. Study recruitment will be facilitated through the use of tested, structured 
protocols. Chanita Hughes-Halbert, PhD has evidenced-based strategies that have been successfully 
employed to recruit AA cancer patients to therapeutic trials. We will also use structured protocols from 
the principal investigator (Evan Graboyes, MD) and co-mentor Katherine Sterba, PhD, MPH. These 
protocols have been successfully employed and refined for clinic-based recruitment of patients with 
HNSCC to participate in behavioral research during treatment periods. Recruitment is expected to be 
enhanced by the active clinical practice of the PI. The study participants may include patients of the PI’s, 
but will not be exclusively patients of the PI. For potential participants where the PI is not the attending 
physician and the potential participant has not consented to participate in research per EPIC, the attending 
physician for the patient will introduce the study to the potential participant. Other than the notification of 
the study by the attending physician for potential trial participants, the research team will not ask other 
clinicians to be involved in recruitment. All of the recruitment will be handled by the study coordinator 
and team. 
 
For the feasibility study, we propose to accrue 15 patients (white, n=10 and AA, n=5) to the study over 4 
months. Based on data from MUSC/HCC for 2018, it is expected that 125 patients/year will be eligible 
for the study, of whom 22% are expected to be AA and 78% are expected to be white. During the 4-
month accrual period, we would expect to screen 41 patients, of whom 9 would be AA and 32 would be 
white. Based on the PI and study team’s prior experience recruiting and enrolling for similar studies 
embedded into clinical care, we anticipate that 60% of eligible patients will accrue to this study. Based on 
this 60% expected accrual rate, over the course of 4 months, we would expect to accrue our target of n=5 
AA patients (and over-accrue white patients, n=20). Thus, by conservative estimates with over-sampling 
of AA, our accrual target for the AA subgroup (n=5) and overall (n=15) appear highly feasible. 
 
For the RCT comparing NDURE to usual care, we note that our accrual rate target of 60%, by which we 
establish the feasibility of recruitment for this RCT, will have been tested in the pilot single-arm 
feasibility study. Refinements to the recruitment strategies and study timeline, as described below, will 
occur as needed to ensure that we achieve our accrual targets described below. We propose to accrue 75 
patients to each arm (white, n=50 and AA, n=25) to the study over 36 months. Based on data from 
MUSC/HCC for 2018, it is expected that 125 patients/year will be eligible for the study, of whom 28 
(22%) are expected to be AA and 97 (78%) are expected to be white. During the 36-month accrual period, 
we would expect to screen 375 patients, of whom 83 would be AA and 292 would be white. Based on the 
PI and study team’s prior experience recruiting and enrolling for similar studies embedded into clinical 
care and the feasibility data gathered from the single-arm pilot of NDURE, we anticipate that 60% of 
eligible patients will accrue to this study. Based on this 60% accrual rate, over the course of 36 months, 
we would expect to accrue 225 patients (50 AAs and 175 white). Thus, by conservative estimates with 
appropriate over-sampling of AAs, our overall accrual target (n=150) and for the AA racial subgroup 
(n=50) appear highly feasible. If continued optimization of enrollment and recruitment strategies fails to 
yield an accrual rate of 60%, we will extend the duration of the study accrual beyond the planned 36 
months by an additional 6 months (and remain within the grant funding period). If we extend the study 
timeline for accrual by 6 months to 42 months instead of 36 months (and thus screen 437 patients  [96 

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AAs] instead of 375 [83 AAs]), we would only need an accrual rate of 52% among AAs to achieve our 
racial subgroup distribution of n=50 (and an accrual rate of 29% among white HNSCC patients). For all 
of the above reasons (PI and team experience, feasibility testing, refinement of recruitment protocols, and 
extension of recruitment period), we are highly confident that we can accrue our overall and racial 
subgroup targets for the RCT. 
 
Because we plan to enroll consecutive patients for this clinic-based intervention, one potential concern 
relates to systematic, non-random differences between patients who participate in NDURE and patients 
who decline to participate. Enthusiastic, health-motivated patients may enroll while marginalized, 
burdened patients who distrust the medical system may preferentially decline. Alternatively, patients with 
few/no perceived barriers may disproportionately decline the intervention due to perceived lack of need 
while burdened patients participate because of the perceived need. Whichever, if any, situation occurs, 
our approach ensure that we will still be well positioned because we will collect information about which 
patients enroll/decline and their reasons for enrolling/declining to help refine NDURE for future 
dissemination. 
 
Three strategies will be used to ensure retention of enrolled patients in the study. First, supportive and 
frequent interactions between the participant and navigator are expected to occur throughout NDURE, 
which should help mitigate against retention problems (for those in the NDURE arm). Second, we have 
accounted for the burden of surveys/questionnaires while patients are on treatment to ensure that the 
expected time commitment from surveys is reasonable and that the study interactions will be scheduled at 
a convenient time for patients (usually while at MUSC for clinical care already). Finally, remuneration 
will also occur on a schedule that is weighted towards providing the majority of the compensation at the 
end of the study time period. 
 
As a result of the aforementioned three strategies, retention of subjects is expected to be highly feasible. 
The scheduled timepoints of navigator-participant interaction (initial surgical consultation, prior to 
hospital discharge, first clinic visit after hospital discharge) were chosen because these are situations in 
which the likelihood of contact is ~100%. Although challenges with retention for cancer studies due to 
mortality (overall and disease-specific) and treatment toxicity are potentially problematic, we do not think 
that they will limit retention in this feasibility study of NDURE. The rate of on-treatment mortality 
(during surgery or adjuvant therapy) is quite low (<5%) and the study follow-up does not extend past the 
completion of therapy. Thus, lack of retention due to mortality is not expected to be significant. 
Treatment toxicity is potentially a problem, as patients may not want to answer surveys while undergoing 
treatment or choose to withdraw due to competing treatment demands. We do not expect this to be a 
problem, however, because NDURE will be integrated into routine clinical care and thus should not 
create an excess time burden for patients. In fact, it is likely that participation in the intervention, which is 
expected to improve care coordination and decrease barriers to care, will make this potential source of 
dropout less likely than other intervention trials. Using NDURE to address individualized barriers to 
timely HNSCC treatment is a significant strength and innovation of the study and will likely also improve 
retention relative to historical rates. 
 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
6.1.1.1 NDURE 

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NDURE is a theory-based, multi-level PN intervention consisting of three sessions of manualized PN 
with multiple intervention components that target system- (care coordination), interpersonal- (social 
support), and individual- (HBM; perceived susceptibility, severity, barriers, self-efficacy) level health 
behavior theoretical constructs to reduce barriers to care, increase HNSCC care delivery, and improve 
clinical outcomes (timely, equitable PORT). The NDURE intervention components and targeted 
theoretical constructs are outlined in Table 2. NDURE will be delivered from surgical consultation to 
PORT initiation (~3 months). The three NDURE navigation sessions, which are expected to take 30-60 
minutes each, will coincide with the presurgical consult, hospital discharge, and 1st postoperative clinic 
visit, time points chosen to facilitate case identification and coordination across key care transitions. The 
preferred method for delivering NDURE is face to face. However, due to changes in healthcare delivery 
necessitated by COVID-19 pandemic, it is permissible for the NDURE navigator to use a telemedicine 
videoconferencing platform for NDURE sessions 1 or 3 (study visit 2 or 4). Contact beyond the three 
prescribed sessions will occur with a frequency and modality (e.g. text message, email, etc.) dictated by 
patient and navigator need. During the first session, the navigator will 1) elicit barriers and facilitators to 
timely PORT from the patient, caregiver, and provider, 2) develop the personalized barrier reduction plan 
(BRP), review it with the patient, caregiver, and provider, and 3) implement the BRP. At the two 
subsequent sessions, the navigator will review and update the BRP in an iterative, dynamic fashion, 
identifying new barriers and systematically tracking resolution of prior barriers until the start of PORT. 
The Navigator Manual  
  
Table 2. NDURE Intervention Components 
Component           Description 
Theoretical Target 
Clinical Tool 
NDURE 
Navigation 
Sessions 
Three manualized sessions in which the navigator 
develops and enacts a personalized BRP. While 
performing the BRP, the navigator will facilitate care 
coordination, 
link 
patients 
to 
resources 
and 
instrumentally assist with barrier mediation, educate 
patients on the risk and health consequences of PORT 
delay, 
and 
provide 
verbal 
reinforcement 
and 
demonstration to enhance patients’ self-confidence to 
achieve timely PORT 
-Care coordination 
-Instrumental support 
-Informational support 
-Perceived susceptibility 
-Perceived severity 
-Perceived barriers 
-Perceived self-efficacy 
NDURE 
Navigator 
Manual 
-Contact information for HNSCC providers in SC 
-Taxonomy of barriers to timely PORT 
-Resource library matched to key barriers 
-Care coordination 
-Perceived barriers 
-Support 
NDURE Patient 
Guide 
-Personalized contact information for HNSCC team 
-Resources to address barriers in BRP 
-Personalized PORT Timeline 
-At-risk population and tailored risk of PORT delay 
-Health consequences of delayed PORT 
-Personalized BRP 
-Care coordination 
-Instrumental support 
-Informational support 
-Perceived susceptibility 
-Perceived severity 
-Perceived barriers 
System Changes 
Documentation 
Structured EMR flowchart to document barriers and 
BRP that is accessible to HNSCC care team 
Care coordination 
Conferences 
Multi-D weekly review of PORT timeline adherence  
Care coordination 
Patient Tracking 
Real-time EMR tracking of care delivery processes 
Informational support 
Reporting 
Monthly PORT delay run charts at Tumor Board 
Informational support 
BRP: Barrier reduction plan, EMR: electronic medical record, HNSCC: Head and neck squamous cell 
carcinoma, PORT: Postoperative radiation therapy, SC: South Carolina 

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provides a structured resource to guide intervention delivery and enhance reproducibility. The Patient 
Guide is 1) literacy-level appropriate, 2) personalized for each patient’s care pathway and BRP, 3) 
updated longitudinally as the patient progresses along the cancer continuum, and 4) available to patients 
in print and/or electronically via the patient portal in the EMR. 
 
Culture, the set of shared and socially transmitted beliefs and values regarding the nature of time, social 
relationships, and supernatural entities that are passed between generations and shared among members of 
ethnic and racial groups42 is a critical determinant of cancer prevention, control, and treatment behaviors 
as well as cancer-related psychological and behavioral outcomes43. As a result, NDURE navigation 
sessions and intervention components will be delivered in a culturally appropriate manner. We will also 
use validated measures of key cultural variables to understand the role that culture plays in the delivery, 
acceptability, and clinical impact of NDURE. 
 
6.1.1.2 USUAL CARE 
Usual care consists of clinic-based, provider-led discussion about the referrals needed to start PORT. 
Usual care is not formally theory-based. The targeted clinical endpoint is timely, Guideline-adherent 
adjuvant therapy. 
 
6.1.2 ADMINISTRATION AND/OR DOSING 
6.1.2.1 NDURE 
NDURE will be delivered in one-on-one, face-to-face sessions between the navigator and the participant 
in a clinic- or hospital-based setting. The NDURE intervention consists of three navigation sessions 
(Study Visits 2-4), which are expected to take 30-60 minutes each. The NDURE sessions (Study Visits 2-
4) will coincide with the presurgical consult, hospital discharge, and 1st postoperative clinic visit (see 
Section 1.3, Schedule of Activities). These time points were chosen to facilitate case identification and 
coordination across key care transitions. Contact beyond the three prescribed sessions will occur with a 
frequency and modality (e.g. text message, email, etc.) dictated by patient and navigator need. The 
NDURE intervention will delivered in the following settings: the MUSC Head and Neck Tumor Center 
and MUSC hospital. A single dedicated navigator with no competing clinical or administrative 
responsibilities outside of this trial will deliver the NDURE intervention. Full dose of the NDURE 
intervention will consist of completing all three navigation sessions. Because the administration schedule 
and dose of usual care is highly variable, the NDURE intervention will not be dose-matched to usual care 
on intensity, duration, and/or frequency. Participants in the trial are permitted to interact with other 
participants after randomization, regardless of treatment allocation. Such encounters may occur in waiting 
rooms before or after clinic appointments given the single-site design of the trial. 
 
6.1.2.2 USUAL CARE 
UC consists of discussions about the indications, risks/benefits/alternative, Guidelines, timing, and 
logistical details of adjuvant therapy. These discussions will be administered according to practice 
patterns of the involved providers. As such, usual care is expected to be variable in the number, 
frequency, intensity, and duration of visits and discussions dedicated to planning adjuvant therapy, 
depending upon the patient, provider, caregiver, tumor board, and clinical scenario. Usual care will be 
delivered in the following settings: the MUSC Head and Neck Tumor Center and MUSC hospital. No 
dedicated interventionist will deliver usual care; instead a combination of physicians (attendings and 
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medical, radiation oncology) at MUSC or an outside facility will all contribute to these discussions. 
Administration of usual care will consist of direct face-to-face communication and other methods (e.g. 
telephone call, e-mail correspondence). The face-to-face conversations can occur during a structured 
clinical setting (e.g. clinic visit) or more informal, non-appointment-based manner (e.g. inpatient rounds).  
Given the variability in expected delivery of usual care, there is no number of sessions that constitute 
“full-dose”. Because the administration schedule and dose of usual care is highly variable, usual care will 
not be dose-matched to NDURE on intensity, duration, and/or frequency. However, the three clinical 
encounters at which NDURE will be delivered are clinical in nature and thus will likely correlate highly 
with usual care. Participants in the trial are permitted to interact with other participants after 
randomization, regardless of treatment allocation. Such encounters may occur in waiting rooms before or 
after clinic appointments given the single-site design of the trial. 
 
6.2 
FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
Because the objectives of the protocol depend upon consistent administration of the NDURE intervention, 
the fidelity of delivery will be monitored closely. The specific duties necessary to ensure optimal 
administration of NDURE are detailed in the NDURE Navigator Standard Operating Procedure (SOP). 
The navigator, supervised by Dr. Graboyes, will keep a tracking log with encounters (number, modality 
of each session), time (direct with patient, indirect to complete BRP), barriers (number, type), and BRP 
activity (action, outcome)44. NDURE sessions will be audio-recorded and randomly selected sessions 
(20%) will be reviewed by Dr. Graboyes to ensure fidelity. Bi-monthly case conferences with the 
navigator, Dr. Graboyes, and Dr. Hughes-Halbert will further ensure continued high-quality PN. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Bias will be minimized through stratified sampling and a stratified randomized permuted block design. 
We will use a stratified sampling approach to achieve a fixed sample size for AA patients (n=25 in each 
arm) to ensure that we 1) achieve racial balance between the NDURE and UC arms, and 2) oversample 
AA relative to their frequency in the study population. Oversampling AAs is key for the study design 
because of the prognostic significance of AA race with delayed PORT initiation6,33.  We will then use a 
stratified randomization scheme, with randomization at the individual patient level using a 1:1 allocation 
ratio. Strata will be defined by location of radiation facility (MUSC, non-MUSC) because of the known 
association of this variable with PORT delay6,33.  As such, our design balances by key potential 
confounders across trial arms. Patients will be randomized 1:1 to NDURE or usual care using a permuted 
block randomization method, with randomly selected block sizes of 2 or 4. Given the impossibility of 
delivering the NDURE intervention in a non-blinded fashion, allocation concealment will be non-blinded. 
The study statistician (Hong Li, PhD) will generate and implement the randomization schema and 
randomization list. The study coordinator will implement the randomization. Randomization errors will 
be handled as per the modified ITT population for the efficacy analysis (see Section 9.3, Population for 
Analyses). 
 
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
Participants’ adherence with study procedures will be tracked by attendance at intervention visits.  All 
study visits are mandatory to remain an active participant. Adherence to attendance at Visits 2-4 will be 
ascertained from the NDURE visit note authored by the navigator that is available in the EMR. 
Adherence to attendance at Visits 1 and 5 will be ascertained from the REDCap data collection form. 
Adherence to attendance at visits 1-5 will be documented in the electronic Case Report Form (eCRF). 
 
6.5 
CONCOMITANT THERAPY 

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6.5.1 RESCUE THERAPY 
N/A 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION 
OF 
STUDY 
INTERVENTION/EXPERIMENTAL 
MANIPULATION 
At subject, PI, or study team member request. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. The 
investigators will seek to minimize participant discontinuation/withdrawal from the study (see Section 
7.3, Lost to Follow-Up) except for safety reasons. 
 
The investigator may discontinue a participant from the study for the following reasons: 
 
Significant study intervention non-compliance 
 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
 
Any event or medical condition or situation occurs such that continued collection of follow-up  
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study 
 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. Specific situations in which this is expected 
to occur through the course of the study are: 
1) Patient is expected to have surgery and then decides to pursue a nonsurgical treatment 
(thus not undergoing curative-intent surgery at MUSC) 
2) Patient is expected to have surgery at MUSC and then decides to pursue treatment 
elsewhere (thus not undergoing curative-intent surgery at MUSC) 
3) PORT is expected based on the clinical TNM classification, but analysis of the pathology 
specimen after surgery demonstrates no indication for PORT (with or without concurrent 
chemotherapy) per NCCN Guidelines based on the absence of all of the following 
adverse features: ENE, positive margin, pT3 or pT4 primary, N1 or greater nodal disease, 
nodal disease in levels IV or V, PNI, or LVI 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the eCRF. 
Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced. Subjects who sign the informed consent form, and are randomized and 
receive the study intervention, and subsequently withdraw, will not be replaced. Subjects sign the 
informed consent form, are randomized and receive at least some of the study intervention and are 
subsequently found to meet one of the exclusion criteria 1-3 described above, will be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for two scheduled visits and 
study staff are unable to contact the participant after at least 3 attempts.  
 
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 
The site will attempt to contact the participant, reschedule the missed visit within 2 weeks, 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts will be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENT 
Feasibility 
NDURE Accrual Rate is defined as the proportion of eligible patients who enroll in NDURE 
 
NDURE Completion Rate is defined as the proportion of enrolled patients who complete the baseline 
assessment, at least two NDURE intervention sessions, and the final follow-up assessment 
 
Navigation Session Completion Rate is the proportion of NDURE navigation sessions completed by each 
individual 
 
Navigator Caseload is the number of simultaneous cases (on-trial participants) being navigated by the 
NDURE navigator 
 
Navigator Time Allocation (Direct) is the time (in minutes), that the NDURE navigator spends directly 
interacting with the patient to identify and address barriers to timely, equitable PORT 
 
Navigator Time Allocation (Indirect) is the time (in minutes), that the navigator spends generating and 
enacting each Barrier Reduction Plan that is not directly interacting with the patient 
 
Questionnaire Completion Rate is the proportion of pre- and post-treatment questionnaires completed by 
enrolled patients  
 
Acceptability 
Satisfaction with the Interpersonal Relationship with the Navigator Scale Score is defined as the total 
score of this 9-item measure of the satisfaction of the interpersonal relationship with the patient navigator. 
This reliable and validated measure30,31 has been widely used in prior studies of PN. The total score of the 
measure ranges from 9 (minimum) to 45 (maximum); higher scores represent a better outcome (greater 
satisfaction with the interpersonal relationship with the navigator). 
 
Satisfaction with Logistical Aspects of Navigation Scale Score is defined as the total score of the 26-item 
measure of the satisfaction of the logistical aspects of PN. This reliable and validated measure32  has been 
widely used in prior studies of PN. The total score of the measure ranges from 0 (minimum) to 78 
(maximum); higher scores represent a better outcome (greater satisfaction with the logistical aspects of 
navigation). 
 
Clinical Outcomes 
PORT Delay is defined as the initiation of PORT more than 6 weeks (42 calendar days) from the date of 
the definitive surgical resection. In situations in which the surgical management of the primary tumor and 

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the neck are staged (i.e. occur on two different calendar days), the date of the definitive surgery for the 
primary tumor will be used. In situations in which an additional surgical resection is required (e.g. re-
resection of positive margins to clear residual disease), the date of the earlier (i.e. attempted definitive) 
surgical procedure will be used to determine the date of definitive surgical resection. 
 
Time-to-PORT (TTP) is defined as the time, in days, between the date of definitive surgical resection to 
the initiation of PORT. All of the criteria used to adjudicate the date of the definitive surgical procedure 
described for the primary outcome measure will be applied to this measure. 
 
Barriers to Care 
Rate of barrier resolution is defined as the proportion of confirmed barriers (as determined by the 
navigator log) that are resolved during the NDURE intervention. 
 
Unresolved barriers are the number of confirmed barriers (as determined by the navigator log) that are not 
resolved during the NDURE intervention. 
 
Cancer Care Delivery Processes 
Pre-Surgical Radiation Consultation is defined as the attendance by the patient at a consultation with a 
radiation oncologist (at MUSC or elsewhere) prior to surgery to discuss RT in the definitive or adjuvant 
setting 
 
Pre-Radiation Therapy Dental Extractions is defined as the extraction of teeth prior to discharge from the 
index hospitalization for the definitive surgical procedure. Patients who are edentulous are not evaluable 
for this measure. 
 
Surgery to Pathology Report </= 7 days is defined as the production of the pathology report from the 
definitive surgical procedure within the EMR within 7 calendar days of the definitive surgical procedure. 
Addenda to the pathology report at the request of the HNSCC team (e.g. tumor p16 status) are not 
counted in this measure. 
 
Surgery to PORT Referral </= 10 days is defined as the placement of a referral for PORT, at MUSC or 
elsewhere, within 10 calendar days of the definitive surgical procedure. 
 
RT Referral to Consult  </=  10 days is defined as the evaluation of the patient at a postoperative 
consultation with a radiation oncologist within 10 calendar days of the referral being placed (or 
postoperative appointment being scheduled in cases in which care has been established and the return 
visit is no longer a consultation). The consultation may occur in the clinic or the hospital depending upon 
clinical circumstances. 
 
RT Consult to Initiation </= 21 days is defined as the initiation of PORT within 21 calendar days of the 
patient being evaluated by a radiation oncologist for PORT. 
 
Health Behavior Constructs 
Care Transition Measure-15 (CTM-15) score is reported as a score out of 100 and calculated as the mean 
score (the summed score from each question divided by the total number of questions) with a linear 
transformation to 100. The CTM-15 is a validated, psychometrically sound 15-item, unidimensional 
measure of care transitions across the healthcare system that is consistent with the concept of patient-
centeredness and useful from an organization perspective for the purpose of performance measurement 
and quality improvement45. Items are rated on a 4-point Likert scale from ‘Strongly Disagree’ (1) to 
‘Strongly Agree’ (4). Higher scores reflect more care integration and better care transitions. 
 

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Change from baseline in Interpersonal Support Evaluation List-12 (ISEL-12) score is defined as the 
change in total ISEL-12 scores from baseline. The ISEL-12 is a validated, 12-item assessment of three 
subscales (appraisal, belonging, and tangible)46 that has been used to assess support in prior PN studies47. 
Items are rated on a 4-point Likert scale from ‘Definitely False’ (1) to ‘Definitely True’ (4). The score is 
calculated by summing scores across all items (with reverse coding for items 1, 2, 7, 8, 11, 12). Scores 
range from 12-48. Higher scores indicate more support. 
 
Change from baseline in Perceived Susceptibility Questionnaire score is defined as the change in the 
score for each of the two subscales relative to baseline.  The Perceived Susceptibility Questionnaire is a 
validated 3-item perceived susceptibility subscale for mammography screening48 that has been modified 
to assess perceived susceptibility for delays starting PORT after HNSCC surgery. It consists of two 
subscales. The first subscale consists of two questions, one assessing absolute perceived susceptibility to 
delays starting PORT and the other assessing relative perceived susceptibility to delays starting PORT. 
Items are rated on a 5-point Likert scale from ‘Strongly Disagree’ (1) to ‘Strongly Agree’ (5). The score 
of the subscale is calculated by summing scores across all items. Total scores for the subscale range from 
2-10. Higher scores indicate greater perceived susceptibility to delays starting PORT. The second 
subscale is a single item assessing the cognitive evaluation of absolute perceived susceptibility to PORT 
delay. The item is measured as a continuous measure from 0 (no chance of delay) to 100 (guaranteed 
delay). Scores on this subscale range from 0-100 with higher scores indicating a greater perceived 
susceptibility to PORT delays. 
 
Change from baseline in Illness Perception Questionnaire-Revised (IPQ-R) Consequences Subscale 
(HNSCC Modification) score is defined as the change in IPQ-R Consequences Subscale Score from 
baseline. The IPQ-R is a validated assessment of a patient’s self-representation of the health 
consequences of their illness that consists of 8 separate subscales49. The IPQ-R Consequences Subscale is 
easily modifiable to asses disease-specific perceived severity50.The HNSCC Modification of the IPQ-R 
Consequences Subscale consists of 6 questions. Items are rated using a 5-point Likert scale from 
‘Strongly Disagree’ (1) to ‘Strongly Agree’ (5). The score is calculated by summing across all items (with 
reverse coding for item 3). Scores range from 5 to 30. Higher scores indicate a greater degree of perceived 
severity of the illness. 
 
Change from baseline in Perceived Barriers Questionnaire is a self-report measure of the 
presence/absence of pre-specified barriers to cancer care (yes/no). The questionnaire has been used 
extensively to assess perceived barriers in prior PN studies11,44,51,52. 
 
Change from baseline in Communication & Attitudinal Self-Efficacy Scale (CASE)-Cancer score is 
defined as the change in CASE-Cancer Score from baseline. The CASE-Cancer is a validated, 
psychometrically sound 12-item scale that addresses three domains of self-efficacy in cancer care 
(understanding and participating in care, maintaining a positive attitude, and seeking and obtaining 
information)53. The CASE-Cancer scale has been used extensively in PN studies to measure perceived 
self-efficacy10,44,52. Responses are on a 4-point Likert scale from ‘Strongly disagree’ (1) to ‘Strongly 
Agree’ (4). Higher scores indicate greater levels of self-efficacy in cancer care. 
 
Navigator Barrier Log will measure 1) the number of barriers identified in the BRP during NDURE; and 
2) the type of barrier in our modified version of existing PN logs11,44,51 
 
 
Covariates 
Behavioral Risk Factor Surveillance Survey (BRFSS) Demographics. The BRFSS is the nation’s premier 
health-related survey that collects data about health-related risk behaviors from US residents. The 
demographic section from the BRFSS will be used (in-person) to ascertain participant sex, age, race, 

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marital status, insurance, educational attainment, living situation, zipcode, phones for personal use, 
employment, and annual household income54. 
 
BRFSS Tobacco Use and Alcohol Consumption. The tobacco use and alcohol consumption sections of 
the BRFSS will be used (in-person) to characterize total cigarette exposure, current cigarette use, quit 
attempts, days of alcohol consumption, average drinks/day, frequency of > 5 drinks, and maximum 
number of drinks. 
 
Clinical and Oncologic Characteristics. Clinical characteristics will include comorbid medical conditions 
(as defined by the ACE-2755, which ranks the severity of each of a patient’s comorbidities from 0-3 and 
gives an overall comorbidity score based on the patient’s highest comorbidity score for any individual 
type of ailment, with 3 indicating severe comorbidity) and cancer history. Oncologic characteristics will 
include HNSCC tumor subsite, HNSCC tumor histology, p16/human papillomavirus (HPV) tumor status, 
American Joint Committee on Cancer TNM Class and overall stage grouping, type of ablative surgery, 
type of reconstruction, treatment dates, facility of planned adjuvant therapy, and adjuvant treatment type 
planned (adjuvant radiation or chemoradiation). 
 
Cultural Factor Survey Scores is reported as the total score for each of the three individual subscales. The 
Cultural Factor Survey is a validated, psychometrically sound questionnaire consists of three subscales 
assessing temporal orientation (5 items), collectivism (6 items), and religiosity (9 items)56. Prior PN 
studies have used these scales to measure cultural factors57. Items are scored on a 4-point Likert scale 
from ‘Strongly Disagree’ (1) to ‘Strongly Agree’ (4). Scores on each sub-scale range from 5-20 (temporal 
orientation), 6-24 (collectivism), and 9-36 (religiosity). Higher scores on each subscale indicate greater 
amounts of each of the measured construct. 
 
PORT Nomogram is a validated risk-prediction tool to estimate a personalized pre-treatment risk of 
PORT delay58. 
 
8.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.2.1 DEFINITION OF ADVERSE EVENTS 
This trial is considered to carry a low risk to subjects (i.e. has a “no more than minimal risk” designation). 
As such, this protocol defines an adverse event (AE) as any undesirable sign, symptom, medical, 
psychological, social, or emotional reaction that is definitely, probably, or possibly related to the study 
intervention.  
 
8.2.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) will be considered any undesirable sign, symptom, or medical condition 
which is fatal, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent or 
significant disability/incapacity, constitutes a congenital anomaly or birth defect, is medically significant 
and which the investigator regards as serious based on appropriate medical judgment. An important 
medical event is any AE that may not result in death, be life-threatening, or require hospitalization but 
may be considered an SAE when, based upon appropriate medical judgment, it may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions 
of SAEs. 
 
8.2.3 CLASSIFICATION OF AN ADVERSE EVENT 

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8.2.3.1 SEVERITY OF EVENT 
The following guidelines will be used to describe AE severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating.  
Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.2.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All AEs will have their relationship to study procedures, including the intervention, assessed by the PI 
based on temporal relationship and his clinical judgment. The degree of certainty about causality will be 
graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study procedures administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study procedures should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study procedures, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal.  
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of study procedures). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
 
8.2.3.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Recording/reporting of AEs will begin after the subject signs informed consent and end after the subject 
completes the intervention and follow up period as defined in the protocol. 
 
8.2.3.4 ADVERSE EVENT REPORTING 
All AEs, as defined above, will be collected and reported. Data collection will occur via electronic 
spreadsheet. The information will be saved in REDCap and managed by the study team. In consultation 
with the PI, a trained member of the study team will be responsible for conducting an evaluation of a SAE 
and shall report the results of such evaluation to the NIH and the reviewing Institutional Review Board 
(IRB) as soon as possible and in accordance with the reviewing IRB policy 
 
8.2.3.5 SERIOUS ADVERSE EVENT REPORTING 

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In consultation with the PI, a trained member of the study team will be responsible for conducting an 
evaluation of a SAE and shall report the results of such evaluation to the NIH and the reviewing IRB as 
soon as possible and in accordance with the reviewing IRB policy. 
 
8.2.3.6 REPORTING EVENTS TO PARTICIPANT 
N/A 
8.2.3.7 EVENTS OF SPECIAL INTEREST 
N/A 
8.2.3.8 REPORTING OF PREGNANCY 
N/A 
 
8.3 
UNANTICIPATED PROBLEMS 
8.3.1 DEFINITION OF UNANTICIPATED PROBLEMS 
This protocol uses the definition of Unanticipated Problems (UP) as defined by the Office for Human 
Research Protections (OHRP). OHRP considers unanticipated problems involving risks to participants or 
others to include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.3.2 UNANTICIPATED PROBLEMS REPORTING 
The investigator will report UPs to the reviewing IRB and to the lead PI. The UP report will include the 
following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
A detailed description of the event, incident, experience, or outcome  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
• 
Ups will be reported to the IRB and to the NCI in accordance with policy regarding timeliness of 
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All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the OHRP in 
accordance with policy regarding timeliness 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
 
Primary Endpoint: 
PORT Delay 
We hypothesize that, compared with patients who receive usual care, patients who receive NDURE 
will have a decreased rate of PORT delay (initiation of PORT > 6 weeks after surgery). Alternatively, 
our null hypothesis is that there will be no difference in the rate of PORT delay between NDURE and 
usual care. 
 
The preliminary efficacy analysis will be calculated for the primary endpoint over the 6 week time 
period from the date of definitive surgical resection of the primary tumor. 
 
 
 
Secondary Endpoints: 
PORT Delay 
We hypothesize that, compared with usual care, NDURE will result in a smaller difference in the rate 
of PORT delay (initiation of PORT > 6 weeks after surgery) between AA and white patients. 
Alternatively, our null hypothesis is that there will be no difference in the rate of PORT delay 
between AA and white patients between NDURE and usual care. 
 
The preliminary efficacy analysis will be calculated for the primary endpoint over the 6 week time 
period from the date of definitive surgical resection of the primary tumor. 
 
TTP 
We hypothesize that, compared with patients who receive usual care, patients who receive NDURE 
will have a shorter median TTP (time, in days, between the date of definitive surgical resection to the 
initiation of PORT). Alternatively, our null hypothesis is that there will be no difference in median 
TTP between NDURE and usual care. 
 
TTP 
We hypothesize that, compared with usual care, NDURE will result in a smaller difference in the 
median TTP between AA and white patients. Alternatively, our null hypothesis is that there will be no 
difference in the median TTP between AA and white patients between NDURE and usual care. 
 
NDURE Accrual 
We hypothesize that at least 60% of eligible subjects for the NDURE study will accrue to the study. 
Alternatively, our null hypothesis is that less than 60% of eligible subjects for the NDURE study will 
accrue to the study 
 
The preliminary feasibility analysis will be calculated for the secondary endpoint using the first 25 
patients eligible to accrue to the study, which is expected to occur over 4 months. 
 
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We hypothesize that at least 85% of subjects who enroll in the NDURE study (at least 13 of 15 
subjects) will complete all 3 NDURE sessions. Alternatively, our null hypothesis is that less than 13 
of the 15 subjects who enroll in the NDURE study will complete all 3 NDURE sessions 
 
The preliminary feasibility analysis will be calculated for the secondary endpoint using the first 15 
patients who accrue to the study, which is expected to occur over 6 months. 
 
9.2 
SAMPLE SIZE DETERMINATION 
9.2.1 NDURE FEASIBILITY STUDY 
Power and sample size calculations were performed using the University of Iowa Binomial Distribution 
applet. The sample size justification for this single-arm study is based on the primary feasibility endpoints 
of NDURE accrual and completion. In the RCT of NDURE, we plan to enroll 60% of eligible patients. 
We expect similar accrual in this feasibility study. Therefore, we hypothesize that at least 60% of eligible 
subjects for the NDURE study will accrue to the study. Alternatively, our null hypothesis is that less than 
60% of eligible subjects for the NDURE study will accrue to the study. Accruing to NDURE will be 
considered feasible if at least 15 of 25 eligible subjects enroll.  Our sample size for the feasibility study 
was selected to provide a small probability of having an observed accrual rate of at least 60% when the 
true accrual probability is actually less than 60%. For example, if the true accrual probability for our 
proposed design is 45% (35%), the probability of enrolling 15 or more of 25 eligible subjects is only 10% 
(1%). Additionally, we hypothesize that at least 85% of subjects who enroll in the NDURE study will 
complete all 3 NDURE sessions. Alternatively, our null hypothesis is that less than 85% of subjects who 
enroll in the NDURE study will complete all 3 NDURE sessions That is to say, NDURE will be 
considered feasible if at least 13 of the 15 subjects enrolled complete all three NDURE sessions. 
Accordingly, our sample size for the single-arm study was selected to provide a small probability of 
having an observed completion rate of at least 85% when the true completion probability of the 
intervention is actually less than 85%. For example, if the true completion probability for our proposed 
design is 70% (60%), the probability that 13 or more of the 15 enrolled patients complete all three 
NDURE sessions is 13% (3%). Therefore, the probability of falsely declaring NDURE feasible is 
reasonably controlled based on this sample size. 
 
9.2.2 RCT OF NDURE VERSUS USUAL CARE 
Power and sample size calculations were performed using PASS v08.0.13, “Inequality Tests for Two 
Independent Proportions.” The primary endpoint for this pilot RCT is the rate of PORT delay, defined as 
starting PORT > 6 weeks after surgery. Our primary objective is to compare PORT delay rates between 
the NDURE and usual care arms. We hypothesize that, compared with patients who receive usual care, 
patients who receive NDURE will have a decreased rate of PORT delay (initiation of PORT > 6 weeks 
after surgery). Alternatively, our null hypothesis is that there will be no difference in the rate of PORT 
delay between NDURE and usual care. We assume the rate of PORT delay in the usual care arm will be 
45%33 and target an absolute reduction in PORT delay of 20% (rate of PORT delay in the NDURE arm = 
25%)24. This effect size is clinically significant and realistic given results in similar (non-randomized) 
interventions24. Seventy-five patients in each arm yields 83% power to detect a 20% reduction in PORT 
delay (45% versus 25%) based on a two-sided Mantel-Haenszel test of two independent proportions 
assuming a two-sided α = 0.1. Our choice of the Mantel-Haenszel test to compare proportions is based on 
the trial’s stratified design. Our selection of α = 0.1 and 1 – β = 0.8 is based on the desire to emphasize 
power over type I error at this early stage of development (single-site pilot RCT) to ensure follow-up on 
promising interventions. We therefore consider our RCT to be appropriately and rigorously designed to 
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efficacy analysis in the modified ITT population (see Section 9.3, Population for Analyses), we plan to 
enroll 170 patients. Our sample size is inflated by 17% based on historical data. This inflation account for 
the predictable subset of patients would be enrolled in the study, be randomized to NDURE or Usual 
Care, receive a portion of the intervention (NDURE Visit 1) and then subsequently develop a study 
exclusion criterion, namely: 1) failure to undergo curative intent surgery at MUSC (exclusion criteria #4); 
2) lack of indication for PORT (with or without chemotherapy) per NCCN Guidelines (exclusion criteria 
#5). As such, patients who meet study inclusion criteria but subsequently develop exclusion criteria #4 or 
#5 during the course of the study will be replaced since the primary endpoint is anchored to findings that 
occur after analysis of the pathologic specimen obtained during surgery. 
 
Every effort will be made to minimize missing data and lost-to-follow-up participants. Participants will 
complete assessments at baseline and post intervention using an iPad-based REDCap collection method. 
The program coordinator will attempt to contact patients at least three times using a variety of methods of 
communication (e.g. text message, phone call, email, mail, etc) to complete outcome measures. This 
method resulted in 100% instrument completion in prior studies conducted by our team. Patients in the 
ITT population for whom the primary endpoint is not evaluable due to loss to follow-up will be 
considered NDURE failures, and their time to PORT will be treated as exceeding 6 weeks for the 
purposes of analysis (a very conservative approach for this single-arm, pilot RCT). 
 
We note that our accrual rate target of 60%, by which we establish the feasibility of recruitment for this 
RCT, will have been tested in the feasibility study as described. Refinements to the recruitment strategies 
and study timeline will occur as needed to ensure that we achieve our accrual targets described below. We 
propose to accrue 75 patients to each arm (white, n=50 and African American, n=25) to the study over 36 
months. Based on data from MUSC/HCC for 2018, it is expected that 125 patients/year will be eligible 
for the study, of whom 28 (22%) are expected to be African American and 97 (78%) are expected to be 
white. During the 36-month accrual period, we would expect to screen 375 patients, of whom 83 would 
be African American and 292 would be white. Based on the PI and study team’s prior experience 
recruiting and enrolling for similar studies embedded into clinical care and the feasibility data gathered 
from the single-arm pilot of NDURE, we anticipate that 60% of eligible patients will accrue to this study. 
Based on this 60% accrual rate, over the course of 36 months, we would expect to accrue 225 patients (50 
African Americans and 175 white). Thus, by conservative estimates with appropriate over-sampling of 
African Americans, our overall accrual target (n=150) and for the African American racial subgroup 
(n=50) appear highly feasible. If continued optimization of enrollment and recruitment strategies fails to 
yield an accrual rate of 60%, we will extend the duration of the study accrual beyond the planned 36 
months by an additional 6 months (and remain within the grant funding period). If we extend the study 
timeline for accrual by 6 months to 42 months instead of 36 months (and thus screen 437 patients  [96 
African Americans] instead of 375 [83 African Americans]), we would only need an accrual rate of 52% 
among African Americans to achieve our racial subgroup distribution of n=50 (and an accrual rate of 29% 
among white HNSCC patients). For all of the above reasons (PI and team experience, prior feasibility 
testing, refinement of recruitment protocols, and extension of recruitment period), we are highly confident 
that we can accrue our overall and racial subgroup targets for the RCT. 
 
9.3 
POPULATIONS FOR ANALYSES 
For the efficacy analysis, we will utilize a modified ITT population. Participants will be part of the 
modified ITT population as defined by the following criteria: 
1. Randomized to NDURE or Usual Care 
2. Receipt of curative intent surgery at MUSC 
3. Indication for PORT (with or without concurrent chemotherapy) per NCCN Guidelines based on 
the presence of at least one of the following adverse features on final pathologic evaluation: ENE, 
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non-oropharyngeal SCC or AJCC 7th edition for p16+ve oropharyngeal SCC), nodal disease in 
levels IV or V, PNI or LVI 
 
The modified ITT analytic population addresses the fact that eligibility, registration, randomization, and 
delivery of a portion of the intervention (NDURE or Usual Care) occur prior to definitive treatment of the 
HNSCC. However, the primary study objective (and endpoint) are defined and evaluable only for patients 
who undergo surgery for HNSCC and have an indication for adjuvant therapy (which can only be 
definitively known following surgical resection). Therefore, we expect that a predictable subset of 
patients will be enrolled in the study, based on meeting all inclusion, be randomized to NDURE or Usual 
Care, receive a portion of the intervention (NDURE Visit 1) and then subsequently develop a study 
exclusion criterion based on interval information that becomes available later in the clinical course that 
cannot be known at the time of study enrollment and registration, namely: 
 
failure to undergo curative intent surgery at MUSC (exclusion criteria #4) 
 
lack of indication for PORT (with or without chemotherapy) per NCCN Guidelines (exclusion 
criteria #5) 
As such, patients who meet study inclusion criteria but subsequently develop exclusion criteria #4 or #5 
during the course of the study will be replaced since the primary endpoint is anchored to findings that 
occur after analysis of the pathologic specimen obtained during surgery. Patients in the modified ITT 
population for whom the primary endpoint is not evaluable due to loss to follow-up will be considered 
navigation failures, and their time to PORT will be treated as exceeding 6 weeks for the purposes of 
analysis. 
 
We will also perform an efficacy analysis on the per-protocol analytic dataset, a subset of the modified 
ITT population who completed all 3 NDURE study sessions. These patients are judged to have complied 
with the protocol sufficiently to ensure that these data would be likely to represent the effects of the 
NDURE intervention according to the underlying scientific model. 
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
We will construct graphical displays and calculate descriptive statistics (e.g. frequencies and percent for 
categorical variables, and mean, median, standard deviation, and range for continuous variables). 
Covariates will be specified below. For inferential tests, we will use a p-value of 0.05, two-sided, and 
95% confidence intervals (CIs) to assess statistical significance (Type I error). Covariates will be pre-
specified as described below. Normality of the data will be assessed before underlying statistical 
procedures will be performed. We will evaluate variable transformations as needed to satisfy assumptions 
and consider transformations of variables to induce approximate normality and stabilize variance as 
needed. Nonparametric tests will be applied when appropriate. 
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT 
9.4.2.1 NDURE FEASIBILITY STUDY 
For the primary endpoint (NDURE Accrual Rate), we will calculate the proportion and frequency of 
eligible patients who accrue (overall, white, and African American). Given its pilot nature, the study is 
not designed to evaluate racial differences in accrual, although reasons for study decline will be collected, 
analyzed for each racial subgroup, and used to refine recruitment. 
 
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For the primary endpoint (delays starting PORT as defined in Section 8.1, Endpoint and Other Non-
Safety Assessments), we will calculate the percentage of patients who start PORT > 6 weeks after 
surgery and corresponding 95% confidence interval (CI) for both arms and for white and AA subgroups 
within each arm in the efficacy analysis population. The rate of PORT delay will be compared between 
arms using a Mantel-Haenszel test of two proportions, with strata defined by race and location of 
radiation facility. 
Every effort will be made to minimize missing data and lost-to-follow-up participants. Participants will 
complete assessments at baseline and post intervention using an iPad-based REDCap collection method. 
The program coordinator will attempt to contact patients at least three times using a variety of methods of 
communication (e.g. text message, phone call, email, mail, etc) to complete outcome measures. This 
method resulted in 100% instrument completion in prior studies conducted by our team. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINTS 
9.4.3.1 NDURE FEASIBILITY STUDY 
NDURE completion rate will be analyzed as 1) the percentage of enrolled patients who attend all three 
NDURE sessions and 2) the proportion of three NDURE sessions that are completed. For navigator 
caseload, we will consider the frequency of simultaneous cases navigated. Navigator time allocation for 
direct and indirect time, as well as patient-report measures of satisfaction with navigation will be 
summarized as described above for continuous data. Study questionnaire completion rate will be 
calculated as the proportion of pre- and post-intervention questionnaires (n=5 each) completed. 
Qualitative data will be analyzed using established team codebooks and focus on the content, format, 
delivery, and timing of NDURE. Qualitative analysis of semi-structured interviews with patients and 
providers following the pilot will be analyzed using established codebooks from the study team for 
evaluating the feasibility and acceptability of clinic-based HNSCC interventions with a focus on the 
content, format, delivery, and timing of NDURE. 
 
9.4.3.2 RCT OF NDURE VERSUS USUAL CARE 
We will analyze the secondary endpoint of TTP as a continuous variable and estimate median time to 
PORT for each arm and for racial subgroups within each arm using Kaplan-Meier curves with 
Greenwood variance estimation to construct the corresponding 95% CIs. Hazard ratio comparing the two 
arms will be estimated using Cox proportional hazards regression controlling for the stratification 
variables. TTP will be compared between intervention arms using a stratified log-rank test on the 
modified ITT efficacy analysis population. 
 
For the secondary endpoints of barrier reduction and unresolved barriers, we will calculate the proportion 
of unresolved barriers and the frequency of unresolved barriers (respectively) at the end of NDURE, 
consistent with prior PN studies51. We will use logistic regression to assess the relationship between 
unresolved barriers and the rate of PORT delay (primary endpoint), controlling for covariates listed in 
Section 8.1. 
 
For other secondary endpoints, data will be summarized using frequency and percent for categorical 
variables and using mean, median, standard deviation, IQR and range for continuous variables. We will 
construct 95% CIs to provide a measure of uncertainty in estimated proportions and means. Comparisons 
between trial arms of other secondary endpoints will be performed using t-tests and chi-square tests, or 
Wilcoxon rank sum and Fisher’s exact tests as appropriate. Pre- and post-intervention values of variables 
measuring the theoretical constructs underlying NDURE (i.e. care coordination, self-efficacy in cancer 
care, support, and knowledge) will be compared using Wilcoxon sign rank tests. Comparisons between 
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will be analyzed on the modified ITT efficacy analysis population. Missing data will be handled as 
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9.4.4 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline characteristics (e.g., demographics, oncologic details, behavioral characteristics) for the NDURE 
and Usual Care arms will be compared and descriptive statistics calculated. Baseline differences between 
the two groups, stratified by race and location of radiation facility, will be compared using t-tests and chi-
square tests, or Wilcoxon rank sum and Fisher’s exact tests as appropriate. 
 
9.4.5 PLANNED INTERIM ANALYSES  
N/A 
 
9.4.6 SUB-GROUP ANALYSES 
Planned sub-group analyses of the primary endpoint will occur based on age and sex to evaluate the 
impact of inclusion across the lifespan and sex as biologic variables. Historical data have not established 
an association between either age or sex with the primary endpoint6. Given the importance of race to the 
study objectives, analysis of the primary endpoint by race is evaluated as a secondary objective instead of 
planned subset analysis. Additional planned subset analyses will evaluate the impact of the NDURE 
intervention on the primary endpoint based on insurance status and fragmentation of care between the 
surgical facility and radiation facility, both of which have been described as risk factors for delayed 
PORT6. As such, both of these variables have the potential to confound the effect of the intervention were 
they to be imbalanced in a future RCT. As such, evaluating their impact on the primary endpoint in this 
study would allow for rational stratification in planned future RCTs. 
 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will not be listed by measure and time point. 
 
9.4.8 EXPLORATORY ANALYSES 
N/A 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
We will obtain full written Informed consent from patients enrolling in the study. Informed consent will 
occur via face-face discussion between one of the study team members designated to perform informed 
consent and the potential study participant.  After describing the study and allowing the potential 
participants to ask any questions, we will schedule interviews with those who are eligible and interested 
in participating in the study. Participant will have time to read the informed consent form and HIPAA 
document on their own.  Consents will be written in simple, easy-to-understand language and obtained on 
the day of enrollment by the trained study coordinator. A study team member will answer any questions 
about the study and participants will be asked to sign the consent and HIPAA forms. All participants will 
sign informed consent forms before the interview.  All participants will receive a copy of their informed 
consent and HIPAA forms for their records. The informed consent process will take place in a private 
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study participant will provide informed consent. Subjects will be allowed up to one week to decide 
whether to participate in the study. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. 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, and regulatory 
authorities. If the study is prematurely terminated or suspended, the PI will promptly inform study 
participants, the IRB, and sponsor/funding agency and will provide the reason(s) for the termination or 
suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Insufficient compliance of study staff to the protocol (e.g. significant protocol violations) 
 
Data that are not sufficiently complete and/or evaluable 
 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the funding agency, sponsor, IRB, Food and Drug Administration (FDA), or other relevant 
regulatory or oversight bodies (OHRP, DSMB). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence within the research team. No personally identifiable 
information from the study will be released to any unauthorized third party without prior written 
approval of the sponsor/funding agency. To help protect participant confidentiality, we will assign a 
unique study ID number to each subject’s information in place of his/her name and will label data 
collection forms only with the ID number. All hard copy and electronic files will be stored appropriately 
using double-locked methods and password-protection. Only the study team member will have access 
to study records. Participant data will be collected and recorded on either a password-protected 
electronic data capture format (Research Electronic Data Capture; REDCap) or paper-based forms 
depending upon patient preference. For the paper collection data method, the data collection form will 
be labeled only with the participant's unique study ID number, and then stored within locked drawers in 
a locked office. The information on these paper forms will be transferred to a password-protected 
REDCap database such that all data will be stored in the password-protected REDCap Database. Only 
members of the study team will have access to the data. We have no plan to use laptops, jump drives, 
CDs/DVDs to transport data. 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, representatives 
of the IRB, regulatory agencies or representatives from companies or organizations supplying the 
product, 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 participants 
in this study. The clinical study site will permit access to such records. 
 

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The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor/funding agency 
requirements. 
 
It is NIH policy that the results and accomplishments of the activities that it funds should be made 
available to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms 
used to share data will include proper plans and safeguards for the protection of privacy, confidentiality, 
and security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not 
be traceable to a specific study participant). Plans for archiving and long-term preservation of the data 
will be implemented, as appropriate.  
 
To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), 
has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, 
clinical or other human subjects research funded wholly or in part by the federal 
government.  Recipients of NIH funding for human subjects research are required to protect identifiable 
research 
information 
from 
forced 
disclosure 
per 
the 
terms 
of 
the 
NIH 
Policy 
(see 
https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 75.303(a) and NIHGPS Chapter 
8.3, recipients conducting NIH-supported research covered by this Policy are required to establish and 
maintain effective internal controls (e.g., policies and procedures) that provide reasonable assurance 
that the award is managed in compliance with Federal statutes, regulations, and the terms and 
conditions of award. It is the NIH policy that investigators and others who have access to research 
records will not disclose identifying information except when the participant consents or in certain 
instances when federal, state, or local law or regulation requires disclosure. NIH expects investigators to 
inform research participants of the protections and the limits to protections provided by a Certificate 
issued by this Policy. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored with the study team. After the study is 
completed, the de-identified, archived data will be transmitted to and stored with the study team, for use 
by other researchers including those outside of the study. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Evan Graboyes, MD 
Medical University of South Carolina  
135 Rutledge Ave, MSC 550 
Charleston, SC 29425 
843-792-0719 
graboyes@musc.edu 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a PI. Aggregate reviews will occur by the PI for all AEs, 
UPs, protocol violations, audit results, early withdrawals, whether the study accrual pattern warrants 
continuation/action, and endpoint data. Aggregate reviews will occur monthly. 
 

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10.1.7 CLINICAL MONITORING 
N/A 
 
10.1.8 QUALITY ASSURANCE (QA) AND QUALITY CONTROL (QC) 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. 
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as well as 
a percentage of the completed consent documents.  This review will evaluate compliance with GCP, 
accuracy, and completeness.  Feedback will be provided to the study team to ensure proper consenting 
procedures are followed.  
 
Source documents and the electronic data --- Data will be initially captured on source documents (see 
Section 10.1.9, Data Handling and Record Keeping) and will ultimately be entered into the study 
database.  To ensure accuracy site staff will compare a representative sample of source data against the 
database, targeting key data points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking.  
 
Should independent monitoring become necessary, the PI will provide direct access to all trial related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection will be the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator will be responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. All source documents will be completed in a neat, legible manner to 
ensure accurate interpretation of data.  
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant consented/enrolled in the study.  Data recorded in the eCRF derived 
from source documents will be consistent with the data recorded on the source documents.  
 
Clinical data will be entered into REDCap. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
In accordance with Health and Human Services regulation at 45 CFR 46.115(b), we will retain IRB 
records for at least three years. At the end of three years, records will be boxed, labeled, and sent to 

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central storage for another three years. Research records will be retained for six years to allow evaluation 
and repetition by others of the results and to investigate an allegation of research misconduct. 
 
10.1.10 
PROTOCOL DEVIATIONS   
A protocol deviation is any variance from the protocol involving a subject or subjects that is not approved 
by the IRB prior to its initiation or implementation, and occurs when a member of the study team departs 
from the IRB-approved protocol in any way without the investigator first obtaining IRB approval (See 
MUSC IRB Policy HRPP 4.14). 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from 
this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results 
in peer-reviewed journals.  Data from this study may be requested from other researchers 2 years after the 
completion of the primary endpoint by contacting Evan Graboyes, MD.  Considerations for ensuring 
confidentiality of these shared data are described in Section 10.1.3. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical. Therefore, any actual 
conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect 
of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest 
will be required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial. The study leadership in conjunction with the NCI has established policies 
and procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
Table 3. Abbreviations and Special Terms 
AA 
AA 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
BRFSS 
Behavioral Risk Factor Surveillance Survey 
BRP 
Barrier Reduction Plan 

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CASE 
Communication & Attitudinal Self-Efficacy 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
eCRF 
Electronic Case Report Form 
CT 
Computed Tomography 
CTM-15 
Care Transition Method-15 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
EMR 
Electronic Medical Record 
ENE 
Extranodal Extension 
FDA 
Food and Drug Administration 
FDG 
Fluoro-deoxyglucose 
GCP 
Good Clinical Practice 
HBM 
Health Belief Model 
HCC 
Hollings Cancer Center 
HIPAA 
Health Insurance Portability and Accountability Act  
HNSCC 
Head and Neck Squamous Cell Carcinoma 
ICH 
International Council on Harmonisation  
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug 
IPQ-R 
Illness Perception Questionnaire-Revised 
IRB 
Institutional Review Board 
ISEL-12 
Interpersonal Support Evaluation List-12 
ITT 
Intention-To-Treat 
LVI 
Lymphovascular Invasion 
MOP 
Manual of Procedures 
MRI 
Magnetic Resonance Imaging 
MUSC 
Medical University of South Carolina 
NCI 
National Cancer Institute 
NCCN 
National Comprehensive Cancer Network 
NCT 
National Clinical Trial 
NDURE 
Navigation for Disparities and Untimely Radiation thErapy 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PN 
Patient Navigation 
PNI 
Perineural Invasion 
PORT 
Postoperative Radiation Therapy 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomized Controlled Trial 
REDCap Research Electronic Data Capture 
RT 
Radiation Therapy 
SCC 
Squamous Cell Carcinoma 
SAE 
Serious Adverse Event 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure 

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TTP 
Time-to-PORT 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Table 4. Protocol Amendment History 
Version 
Date 
Description of Change  
Brief Rationale 
1.1 
7/26/19 
-Removed 10th floor from location of 
ICF process 
-removed language about ability to 
provide informed consent and adhere 
to study regimen from inclusion 
criteria 
-changes requested by MUSC 
IRB 
2.0 
9/27/19 
-updated objectives to specify 
comparison of NDURE with UC 
-created more comprehensive and 
specific SoA 
-removed neoadjuvant therapy; 
added synchronous malignancy to 
exclusion criteria 
-removed MDASI-HN 
-added NIH confidentiality vocab 
-enhance clarity of objectives 
 
-more transparent SoA 
 
-improve clinical relevance of 
target population 
 
-improve clinical workflow 
-NIH compliance 
3.0 
12/16/19 
-replaced Elizabeth Hill with Hong 
Li on study team 
 
-updated SOA 
 
 
 
-added white or AA race to inclusion 
criteria 
 
-clarified stratified sampling and 
stratified randomization 
 
 
-rename barrier load survey 
 
-harmonized staging information in 
inclusion criteria with mod ITT 
population 
-Elizabeth Hill left MUSC/HCC 
 
 
-more precision; address 
accidental overlap between visit 
1 and 2 
 
-internally harmonize protocol 
 
 
-previously mis-reported as 
stratified randomization across 
two strata 
 
-clarity for study assessment 
 
-internally harmonize protocol 
4.0 
2/26/20 
-allowed use of telemedicine for 
NDURE sessions 1 or 3 
 
-added NDURE nomogram 
 
 
-clarified that comorbidity will be 
measured using ACE-27 
-COVID-19 
 
 
-assess pre-treatment risk of 
PORT delay 
 
-previously not specified 
 
 
 
 
 
 
 
 

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