A Randomized Trial of an Advanced Pneumatic Compression Device vs. Usual Care for Head and Neck Lymphedema
Phase: NA
Conditions: Lymphedema, Lymphedema of Face, Lymphedema, Secondary, Lymphedema Due to Radiation, Lymphedema; Surgical
Sponsor: Tactile Medical

 
 
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A Randomized Trial of an Advanced Pneumatic Compression 
Device vs. Usual Care for Head and Neck Lymphedema 
 
 
 
 
Protocol Number: 8030 
NCT Number: NCT04797390 
 
 
December 8, 2021 
Protocol Version 2.0 
 
 
 

 
 
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Investigator Signature 
 
 
 
Protocol Title: A Randomized Trial of an Advanced Pneumatic Compression Device vs. Usual 
Care for Head and Neck Lymphedema 
 
 
Protocol Number: 8030 
 
 
I confirm that I have read this protocol.  I will comply with the protocol and the principles of 
Good Clinical Practices (GCPs), institutional research policies and procedures, and other 
appropriate regulatory requirements. 
 
 
 
_______________________________ 
Site Principal Investigator Name (Print) 
 
 
_______________________________ 
 
 __________________ 
Site Principal Investigator Signature   
 
 Date 
 
 
 

 
 
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SYNOPSIS 
Study Title 
A Randomized Trial of an Advanced Pneumatic Compression Device vs. Usual 
Care for Head and Neck Lymphedema 
Protocol Date 
December 8, 2021 
Protocol Version 
2.0 
Protocol Number 
8030 
Name of Sponsor 
Tactile Medical™  
Study Design 
This study is an open label, multi-site, randomized trial comparing the use of an 
advanced pneumatic compression device (APCD) to Usual Care.  
Treatment Groups 
Eligible patients will be randomized to receive one of the following treatments:   
Ø APCD: Daily self-administered treatment with the Flexitouch® Plus system 
(FT) 
Ø Usual Care: Complete Decongestive Therapy (CDT) directed by a 
lymphedema therapist and any additional adjunctive measures as prescribed by 
the lymphedema therapist  
Study Objective 
To compare the effectiveness of an APCD to Usual Care in the management of 
lymphedema and fibrosis (LEF) in head and neck cancer (HNC) survivors.  
Primary Aims 
Aim 1: 
To compare the short-term and long-term effectiveness of self-administered APCD 
therapy versus Usual Care in HNC survivors with treatment naive LEF on anatomical 
measures of internal and external LEF. Baseline measures will be obtained at the start 
of therapy. Short-term effectiveness will be evaluated at 2 months and long-term 
effectiveness will be evaluated at 4 and 6 months. Hypothesis: the APCD therapy will 
be associated with greater short-term and long-term reduction in anatomical measures 
of LEF. 
Aim 2:  
To compare the short-term and long-term effectiveness of self-administered APCD 
therapy versus Usual Care in HNC survivors with treatment naive LEF on patient 
reported biopsychosocial outcome measures impacted by LEF. Outcome measures will 
include: 1) symptom burden, 2) symptom burden and functional impairment, 3) quality 
of life (QOL), 4) work and activity, 5) perceived self-management capacity, 6) body 
image, and 7) diet modifications. Baseline measures will be obtained at the start of 
therapy. Short-term effectiveness will be evaluated at 2 months and long-term 
effectiveness will be evaluated at 4 and 6 months. Hypothesis: the APCD therapy will 
be associated with greater short-term and long-term improvement in patient reported 
biopsychosocial outcomes. 
Primary Endpoints 
To compare the short (2 months) and long-term (4 & 6 months) effectiveness of self-
administered APCD therapy to Usual Care in HNC survivors with treatment naïve 
LEF.  
Anatomical Measures: 
1. Internal lymphedema 
o Assessment of upper aerodigestive tract (UADT) via endoscopy with 
direct or indirect visualization (Modified Patterson Scale) 
o Computed Tomography (CT) Imaging (CT Lymphedema and 
Fibrosis Assessment Tool [CT-LEFAT]) 
2. External lymphedema 

 
 
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o Assessment using Head and Neck Cancer Related Lymphedema and 
Fibrosis Grading (HN-LEFG) criteria 
o Digital Photography (30 section grid) 
Patient Reported Biopsychosocial Measures: 
1. Symptom Burden: Lymphedema Symptom Intensity and Distress Survey – 
Head and Neck (LSIDS-H&N v2.0)  
2. Symptom Burden and Functional Impairment: Vanderbilt Head and Neck 
Symptom Survey plus General Symptom Survey (VHNSS plus GSS) 
3. QOL: 5-item Linear Analog Self-Assessment   
4. Work and Activity: Work Productivity and Activity Impairment Questionnaire 
(WPAIQ) 
5. Perceived self-management compacity: Perceived Medical Condition Self-
Management Scale (PMCSMS) 
6. Body image: Body Image Quality of Life Inventory (BIQLI) 
7. Diet modifications: Automated Self-Administered 24-Hour Dietary 
Assessment Tool (ASA24®) 
Treatment 
Duration 
The duration of study will include the screening period, randomization, and therapeutic 
intervention. From the time patients sign consent until they initiate treatment is less 
than 1 month. The intervention phase will last 6 months. 
Inclusion/Exclusion 
Criteria 
 
Inclusion Criteria: 
1. Age ≥ 18 years 
2. Pathologically confirmed cancer of the head and neck (larynx, pharynx, 
oral cavity, paranasal sinuses, major salivary glands, and HNC of 
unknown primary) 
3. Completed curative intent cancer therapy with no evidence of active 
cancer at time of study enrollment  
4. A diagnosis of either internal or external head and neck lymphedema 
5. At least one core lymphedema associated symptom of ≥ 4 out of 10 at the 
time of study screening  
6. Must be able and willing to participate in all aspects of the study and 
provide informed consent prior to study participation 
7. Must be able to speak and understand English 
Exclusion Criteria: 
1. Previous APCD or Usual Care treatment for HNC LEF 
2. Acute facial infection (e.g., facial or parotid gland abscess) 
3. Known carotid sinus hypersensitivity syndrome 
4. Symptomatic carotid artery disease, as manifested by a recent (within 30 
days prior to consent) transient ischemic attack, ischemic stroke, or 
amaurosis fugax (monocular visual ischemic symptoms or blindness) 
5. Internal jugular venous thrombosis (within 3 months prior to consent) 
6. Patient is pregnant or trying to become pregnant 
Number Planned 
250 randomized patients 

 
 
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Table of Contents 
1.0 
Contact Information .............................................................................................................. 8 
1.1 
Sponsor .......................................................................................................................... 8 
1.2 
Study Principal Investigators ........................................................................................ 8 
1.3 
Clinical Investigator Information .................................................................................. 8 
2.0 
Abbreviations ........................................................................................................................ 9 
3.0 
Introduction ........................................................................................................................ 10 
3.1 
Importance of Problem ................................................................................................ 10 
3.2 
Conceptual Framework ............................................................................................... 11 
3.2.1 
Usual Care ............................................................................................................... 11 
3.2.1.1 
Barriers to Usual Care .......................................................................................... 12 
3.2.2 
Advanced Pneumatic Compression Devices ........................................................... 14 
3.2.2.1 
Flexitouch Plus system (FT) ................................................................................ 15 
3.2.2.2 
FT for treatment of HNC associated LEF ............................................................ 15 
3.2.2.3 
Strengths of Current APCD Research .................................................................. 17 
3.2.2.4 
Weaknesses of Current APCD Research ............................................................. 17 
3.2.3 
Summary of Usual Care and APCD ........................................................................ 17 
4.0 
Study Objectives ................................................................................................................. 17 
5.0 
Study Design ....................................................................................................................... 17 
5.1 
Primary Aims .............................................................................................................. 18 
5.2 
Primary Endpoints ....................................................................................................... 19 
5.2.1 
Anatomical Measures .............................................................................................. 19 
5.2.2 
Patient Reported Biopsychosocial Measures ........................................................... 19 
5.3 
Outcome Measures ...................................................................................................... 19 
5.4 
Subject Selection ......................................................................................................... 20 
5.4.1 
Inclusion Criteria ..................................................................................................... 20 
5.4.2 
Exclusion Criteria .................................................................................................... 21 
5.5 
Point of Enrollment and Randomization ..................................................................... 21 
6.0 
Study Visits ......................................................................................................................... 21 
6.1 
Screening Visit ............................................................................................................ 21 
6.2 
Baseline Visit .............................................................................................................. 23 
6.3 
Therapy Initiation ........................................................................................................ 23 
6.3.1 
Usual Care ............................................................................................................... 23 

 
 
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6.3.2 
APCD ....................................................................................................................... 23 
6.4 
2, 4, & 6 Week Contacts ............................................................................................. 24 
6.5 
2 Month Visit .............................................................................................................. 24 
6.6 
10, 12, & 14 Week Contacts ....................................................................................... 24 
6.7 
4 Month Visit .............................................................................................................. 24 
6.8 
18, 20, & 22 Week Contacts ....................................................................................... 25 
6.9 
6 Month Visit .............................................................................................................. 25 
7.0 
Study Schedule of Activities .............................................................................................. 25 
8.0 
Study Assessments ............................................................................................................. 27 
8.1 
Informed Consent ........................................................................................................ 27 
8.2 
Lymphedema Core Symptom Survey ......................................................................... 27 
8.3 
Demographics & Medical History .............................................................................. 27 
8.4 
Height and Weight ...................................................................................................... 27 
8.5 
Pregnancy Test ............................................................................................................ 27 
8.6 
Examination of the head, neck, and shoulders using the HN-LEFG Criteria ............. 27 
8.7 
Examination of the UADT via endoscopy using the Modified Patterson Scale ......... 28 
8.8 
Digital Photographs ..................................................................................................... 29 
8.9 
CT of the Neck ............................................................................................................ 29 
8.10 
Patient reported biopsychosocial measures ................................................................. 30 
8.10.1 LSIDS – H&N ......................................................................................................... 30 
8.10.2 VHNSS plus GSS .................................................................................................... 30 
8.10.3 5-item Linear Analog Self-Assessment ................................................................... 31 
8.10.4 WPAIQ .................................................................................................................... 31 
8.10.5 PMCSMS ................................................................................................................. 31 
8.10.6 BIQLI ....................................................................................................................... 31 
8.10.7 ASA24 ..................................................................................................................... 31 
8.11 
Adherence assessment. ................................................................................................ 31 
8.12 
Adverse event assessment ........................................................................................... 34 
8.13 
Subject Exit Interview (optional) ................................................................................ 35 
9.0 
Subject Discontinuation or Withdrawal ............................................................................. 35 
10.0 Accountability .................................................................................................................... 35 
11.0 Risk Analysis ...................................................................................................................... 36 
11.1 
Anticipated Side Effects of Pneumatic Compression ................................................. 36 
11.2 
Anticipated Side Effects of Usual Care ....................................................................... 36 

 
 
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11.3 
Reportable Events ....................................................................................................... 36 
12.0 Provisions to Protect the Privacy of Study Participants/Information Security Plan ........... 36 
13.0 Deviation from Study Plan ................................................................................................. 36 
14.0 Quality Assurance Procedures ............................................................................................ 37 
14.1 
Site Qualification ......................................................................................................... 37 
14.2 
Site Initiation ............................................................................................................... 37 
14.3 
Fidelity Monitoring ..................................................................................................... 37 
14.4 
Monitoring ................................................................................................................... 37 
14.5 
Data Collection Procedures ......................................................................................... 38 
14.6 
Data Safety Monitoring ............................................................................................... 38 
14.7 
Reports and Records .................................................................................................... 38 
15.0 Change to Investigational Plan ........................................................................................... 39 
16.0 Statistical Methods ............................................................................................................. 40 
16.1 
Sample Size Determination ......................................................................................... 40 
16.2 
Randomization ............................................................................................................ 40 
16.3 
Statistical Analysis ...................................................................................................... 40 
17.0 Publication Plan .................................................................................................................. 41 
18.0 References .......................................................................................................................... 42 
19.0 Appendices ......................................................................................................................... 46 
Appendix A: Standard Digital Photography Procedure ................................................................ 47 
 
 
 

 
 
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1.0 
Contact Information 
1.1 
Sponsor   
Tactile Medical 
 
3701 Wayzata Blvd, Suite 300 
Minneapolis, MN 55416 USA 
 
 
1.2 
Study Principal Investigators 
Barbara A Murphy, MD  
Vanderbilt University Medical Center 
777 Preston Research Building 
Nashville, TN 37212 
 
 
 
Sheila H Ridner, PhD, RN, FAAN   
Vanderbilt University School of Nursing  
524 Godchaux Hall 
461 21st Ave. S. Nashville, TN 37072 
 
 
1.3 
Clinical Investigator Information 
The sponsor will maintain a document with contact information for all investigators 
participating in the study. The information maintained will include full name, 
addresses, telephone, and, if available, email addresses for the Site Principal 
Investigators, and Institutional Review Board (IRB) chairperson.  
 
 

 
 
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Abbreviations 
Abbreviation 
Term 
APCD 
Advanced Pneumatic Compression Device 
ASA24 
Automated Self-Administered 24-Hour Dietary Assessment Tool 
BIQLI 
Body Image Quality of Life Inventory 
CDT 
Complete Decongestive Therapy 
CFR 
Code of Federal Regulations 
CMS 
Centers for Medicare & Medicaid Services 
CT 
Computed Tomography 
CTA 
Clinical Trial Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT-LEFAT 
Computed Tomography Lymphedema and Fibrosis Assessment Tool 
eCRF 
electronic Case Report Form 
ePRO 
electronic Patient Reported Outcomes 
FT 
Flexitouch Plus system 
GCPs 
Good Clinical Practices 
HN-LEFG 
Head and Neck Cancer Related Lymphedema and Fibrosis Grading 
HNC 
Head and Neck Cancer 
HPV 
Human Papilloma Virus 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
LEF  
Lymphedema and Fibrosis 
LSIDS-H&N 
Lymphedema Symptom Intensity and Distress Survey – Head and 
Neck 
NIRFLI 
Near-Infrared Fluorescence Lymphatic Imaging 
PI 
Principal Investigator 
PMCSMS 
Perceived Medical Condition Self-Management Scale 
PRO 
Patient Reported Outcome 
QOL 
Quality of Life 
RCT 
Randomized Controlled Trial 
Sub-I 
Sub-Investigator 
UADT 
Upper Aerodigestive Tract 
VHNSS plus 
GSS 
Vanderbilt Head and Neck Symptom Survey plus General Symptom 
Survey 
VUMC 
Vanderbilt University Medical Center 
WPAIQ 
Work Productivity and Activity Impairment Questionnaire 
  
 

 
 
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3.0 
Introduction 
3.1 
Importance of Problem 
Approximately 53,260 Americans will develop head and neck cancer (HNC) in 
2020 and an estimated 10,750 patients will die of these cancers.1 For patients with 
locally advanced disease, aggressive multi-modality therapy has been shown to 
improve local control and survival but at the expense of significant acute and late 
treatment effects.2 There has also been an increase in human papilloma virus (HPV) 
associated and oropharyngeal cancers and oral cavity cancers.3-6 As a result of 
improved treatment outcomes and changing epidemiology, there has been an 
increase in the number of HNC survivors, many destined to live for protracted 
periods of time with the side effects from cancer and its therapy.7-10 A common but 
under recognized late effect of HNC treatment is secondary lymphedema and 
fibrosis (LEF).7   
LEF occurs when either lymphatic structures or surrounding soft tissues are 
damaged or blocked. LEF manifests as soft tissue swelling and fibrosis.11  The 
sequalae vary based on the site of tissue involvement.  HNC associated LEF may 
involve external structures (e.g., face, neck and shoulders, and internal structures 
(e.g., larynx and pharynx).7,12  Involvement of external sites may lead to 
alternations in skin color or texture, pain and discomfort, stiffness and decreased 
range of motion in the neck and shoulders, and body image issues.13,14 Involvement 
of internal structures including the pharynx and larynx results in functional deficits 
such as altered speech and shortness of breath due to airway obstruction.14,15 Of 
note, LEF is a common cause of acute and long term dysphagia resulting in dietary 
adaptations, long term feeding tube dependence, and increased risk for aspiration 
pneumonia. Without early identification and timely therapy, soft tissues affected by 
lymphedema can become increasingly fibrotic and contracted. This can result in 
profound function loss with disability. For example, patients with fibrosis and 
contractures of the neck (e.g., neck fibrosis) may have chronic pain, pronounced 
postural abnormalities, and severe function loss due to decreased range of motion 
(ROM) in the neck (e.g., inability to drive or dress). Trismus secondary to fibrosis 
of the muscle of mastication results in limiting oral intake, inability to maintain oral 
care, speech abnormalities, and difficulty with intubation.14,16 Our data indicate that 
increasing LEF severity is associated with increasing symptom burden, functional 
impairments, and decreased QOL.14 In a prospective longitudinal study describing 
the incidence, biological mechanisms, and impact of LEF in HNC patients, one 
hundred percent of patients followed for 18-months post-cancer treatment 
experienced LEF at some point along the time course of their disease, treatment, or 
recovery.17 Furthermore, the severity was in the moderate to severe range in the 
majority of patients.  Evidence supports the hypothesis that early identification of 
LEF followed by aggressive lymphedema therapy may improve patient outcomes 
in lymphedema patient populations.18,19  
 
 

 
 
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3.2 
Conceptual Framework 
In non-pathological conditions, the blood capillaries and lymphatic system provide 
for fluid exchange at the blood capillary-interstitial-lymphatic-interface.20,21 
Filtration pressures at the arterial side of a capillary force fluid and protein into the 
interstitium. Although re-absorption pressures pull some of the fluid back into the 
capillary at the venous side, the  majority of filtered fluid and protein are removed 
by the lymphatics.20-23 The face and neck contains an extensive network of 
lymphatic channels and over 300 lymph nodes (1/3 of lymph nodes within the 
body).20-23 Cancer, surgery, and radiation may disrupt lymphatic structures, 
blocking lymph flow and resulting in soft tissue edema.25-27 This stagnant edema 
results in an inflammatory response. If edema is not reduced in a timely manner, 
chronic inflammation leads to non-reducible fibrofatty scarring. This in term 
further damages lymphatics creating a self-perpetuating cycle of soft tissue 
damage. Both usual care CDT and Advanced Pneumatic Compression Devices 
(APCD) move lymphatic fluid from the extracellular spaces thereby decreasing 
edema and the associated inflammation. By interrupting the cycle, they can not 
only halt the progression of soft tissue damage, but they can also impact the 
symptoms and functional impairment associated with LEF. 
 
Figure 1. Conceptual Framework for Impact of FT on LEF and Associated 
Outcomes 
3.2.1 Usual Care 
The cornerstone of lymphedema management is usual care two-phase 
complete decongestive therapy (CDT). Phase 1 is most commonly 
performed by a physical or occupational therapist with specialized training 
and certification in lymphedema management.28 Phase 2 is long term self-
care.28,29 Initial Therapy (Phase 1 Care): This phase includes: consultation 
with a lymphedema therapist, patient education, therapist administered 
manual lymph drainage, compression garments or bandages where 
indicated, skin care techniques, and a program of exercises and postural 
recommendations. The goal is to reduce visible or palpable LEF and 
control associated symptoms. The duration of the initial therapy varies with 
LEF severity and therapeutic response. Though 5 therapy sessions per week 
are recommended, a 2017 study of 107 lymphedema therapists reported a 
mean of 3.71 therapy sessions per week being most common.30 Self-Care 

 
 
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(Phase 2 Care): During the self-care phase, patients must conduct a life-
long program of disease management that mimics the program undertaken 
by the lymphedema therapist as delineated above with compression and 
lymphatic massage as integral components. Unlike other chronic diseases 
there are no routine or annual follow-ups to monitor the patient after Phase 
1 care. Patients are expected to contact their primary care provider should 
LEF exacerbations or infections arise during Phase 2 care. They would then 
be referred back for Phase 1 CDT. 
Treatment algorithms for HNC associated lymphedema are based on 
clinical experience and data from other anatomical sites of lymphedema. A 
systematic review evaluating treatment modalities for HNC lymphedema 
published in 2019 identified 26 studies including: usual care CDT (n=10), 
alternative or complementary studies (n=7), non-liposuction surgical 
techniques (n=6), and liposuction (n=3). No studies addressed APCDs and 
none assessed internal lymphedema or fibrosis as outcomes.31 The most 
informative data was generated through a retrospective review conducted at 
MD Anderson in which 733 out of 1200 lymphedema patients were 
evaluable for treatment response.32 Patients were divided into two cohorts: 
1) those who underwent CDT at the MD Anderson Cancer Center (n=86; 
12%) or 2) those who received instruction for self-administered home CDT 
(n=647; 88%). Patients in the second cohort either “could not or declined” 
therapist administered Phase 1 CDT.31 External lymphedema was assessed 
by composite surface tape measurements. For patients in cohort 1, the 
frequency and duration of therapy sessions varied from between 2-5 
sessions per week over 2-4 weeks. Patients exhibited a 60% response rate 
(no p values given) for external lymphedema, suggesting that CDT was 
effective for some, but not all patients. Patients in cohort 1 demonstrated 
greater improvement at follow-up (p=0.014) compared to those in cohort 2 
who conducted self-care only.  
3.2.1.1 Barriers to Usual Care 
Barriers to Initial Therapy (Phase 1):1) High Cost of Therapy: 
Lymphedema therapy is provided in a one-on-one fashion as it 
requires extensive manual interventions such as lymphatic massage 
and commonly lasts 90 minutes.33 One therapy session at 
Vanderbilt-Ingram Cancer Center costs $344 (not including 
supplies). Thus, weekly costs range from $688 to $1,032 and total 
costs over 8-weeks exceed $8,000.  2) Lack of Insurance Coverage 
for Therapy: A cross-sectional study of 103 HNC patients found 
8% did not have insurance coverage.14 For those with insurance, 
lymphedema therapy may not be covered. Costly copayments and 
claim denials are common. Data also indicate that most third-party 
payers may fail to cover the recommended number of sessions 
needed to achieve maximum reduction of swelling and symptom 
relief in this population. 3) Lack of Access to General 
Lymphedema Therapy Services: Lymphedema management 

 
 
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services, especially for HNC survivors, are often difficult to 
obtain.34-35 There are limited numbers of certified lymphedema 
therapists. Most are located in urban areas. Data revealed that 37% 
of patients resided in rural areas without lymphedema services.14 4) 
Lack of Certified Lymphedema Therapists: Lymphedema 
therapists require additional training to adequately treat patients 
with HNC associated LEF. Few have this training. Wait-lists range 
from weeks to months.28 5) Time Burden to Patients and 
Caregivers: Following a rigorous and time-consuming HNC 
therapy, patients and families feel compelled to concentrate time 
and effort on return to work and other important activities that 
were suspended during treatment. Lymphedema therapy is often 
seen as a nonessential activity. 6) Transportation Difficulties: 
Patients with HNC LEF often depend on others to bring them to 
treatment. 7) Profitability: Basic lymphedema certification requires 
several weeks of training beyond what is provided in graduate 
rehabilitation therapy education.28 This training can cost thousands 
of dollars in direct and indirect (loss of income) costs.  
Management of head and neck lymphedema requires additional 
time-consuming courses which results in added expense. Centers 
for Medicare & Medicaid Services (CMS) requires lymphedema 
therapy be conducted one-on-one.33,36 This is in distinction to 
orthopedic therapy where one therapist treats two to three non-
Medicare patients simultaneously.36 Thus, the earning potential of 
a lymphedema therapist is limited when compared to the provision 
of other therapies. The high cost of training and reduced earning 
potential has limited the number of practitioners and directed 
lymphedema services to tertiary care centers where reimbursement 
is higher and a loss-leading service is better tolerated.37 Taken 
together, an alternative approach to usual Phase 1 care such, as 
self-administered home-based APCD treatment, warrants 
investigation to address these barriers that contribute to Phase-1 
treatment failure.  
Barriers to Self-Care (Phase 2): Lymphedema therapists set 
therapeutic goals and stop Phase 1 therapy once those goals are 
met. Previous studies have indicated that approximately 50% of 
patients did not conduct Phase 2 self-care activities for their LEF 
after initial lymphedema therapy due to the following barriers. 1) 
Lack of Guidelines or Protocols: Standardized LEF self-
management protocols have yet to be developed and tested for 
feasibility, safety and efficacy in the HNC population.14 2) Lack of 
Monitoring: LEF is an evolving process that may regress, 
redevelop, or progress to fibrosis over time during Phase 2 self-
care.11,14,16 However, there are no protocols for monitoring patients 
after lymphedema therapy is completed to identify and address 
changing therapeutic needs secondary to progressing LEF. 3) 

 
 
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Limited Knowledge, Lack of Training on Skills and Techniques 
for Self-Care: Many HNC survivors with LEF state despite 
education from therapists, there remained lack of required 
knowledge and skills and they were unable to replicate techniques 
needed for self-management; thus, they felt self-care did not work 
and required re-education.7 4) Lack of Motivation: A previous 
study found patents did not conduct Phase 2 self-care activities due 
to lack of personal motivation and/or social motivation 
(social/family support).7 5) Low Self-Efficacy: Previous research 
has highlighted that low self-efficacy (efficacy of self-care) was a 
predominant issue among HNC survivors with LEF.7 6) Difficulty 
Integrating into Daily Routine: After completion of Phase-1 
lymphedema therapy, patients desire to return to their previous life 
and to work full time. They specify that it is difficult to integrate 
self-care into established daily, busy routine. 7) Symptom Burden: 
LEF therapy would optimally be initiated early post-cancer-
treatment as patients continue to experience high levels and 
severity of symptoms that may impact adherence including fatigue, 
neurocognitive deficits, anxiety, and depression. These barriers 
often lead to failed self-care and poor patient outcomes.  
3.2.2 Advanced Pneumatic Compression Devices 
Two types of pneumatic compression devices (billing codes E0651 and 
E0652) are used in the treatment of limb lymphedema. Both have multiple 
outflow ports on the compressor that release pressurized air from the 
outflow ports lead to corresponding segments on the appliance/garment. 
The segments inflate and deflate based upon the specified pressures and 
cycle times. A segmented device without calibrated gradient pressure 
(E0651) is one in which either the same pressure is present in each segment 
or there is a predetermined pressure gradient in successive segments.  An 
advanced segmented device with calibrated gradient pressure (E0652) is 
characterized by manual control on at least three outflow ports that can 
deliver an individually determined pressure to each corresponding 
appliance segment. The only known compression device FDA cleared for 
treatment of head and neck LEF is the advanced Flexitouch Plus system 
(Tactile Medical), classified as E0652. It is differentiated from all other 
pumps because it has flat, curved chambers and peristaltic pressure flow. 
This device more closely replicates human massage techniques than do 
other compression devices as it produces gentle, dynamic “stretch and 
release” mechanism of action to stimulate lymphatic function similar to 
manual lymphatic drainage massage rather than a “squeeze and hold” 
mechanism of action which tends to simply displace interstitial fluid as do 
other pumps. 
 
 

 
 
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3.2.2.1 Flexitouch Plus system (FT) 
The Flexitouch Plus system (Tactile Medical, Minneapolis, MN, 
USA) is an APCD clinically proven to stimulate the lymphatic 
system and is cleared for market in the USA (K170216, HCPCS 
code E0652). The device helps direct and move excess fluid from 
an impaired lymphatic region to healthy regions, where fluid can 
be absorbed and processed naturally by the body.  
FT garment chambers inflate sequentially with each chamber 
inflating before the adjacent distal chamber deflates. This creates a 
dynamic wave that directs fluid into the lymphatic capillaries while 
maintaining distal pressure to prevent distal backflow. 
The Flexitouch Plus system consists of two primary components, 
the controller unit and garments. The controller unit is a 
programmable pneumatic compressor with four connector outlets. 
Each connector has eight outflow ports that garment hoses plug 
into. Air passes through the hoses, delivering treatment through the 
sequential inflation and deflation of up to 14 air chambers covering 
the head, neck, and chest. The air chambered garments are made of 
soft, pliable fabric. They are designed to fit the contours of the 
body by wrapping around the affected area(s) and attaching with 
hook and loop fasteners.  
3.2.2.2 FT for treatment of HNC associated LEF 
Use of APCDs to treat head and neck LEF began in 2017.41 Three 
preliminary studies and 1 pilot randomized controlled trial (RCT) 
have been published that address the use of the FT in head and 
neck LEF.34,41,42  
The initial study, (n=44), demonstrated potential efficacy and 
feasibility in a single observed session of 32-45 minutes. 
Reduction in swelling ascertained by composite surface tape 
measurements (p=<0.001) was noted, 63% reporting feeling better 
after treatment, and 93% stated they would likely use the device at 
home if available.41 No adverse events were noted. A second 
study, (N=10) examined response to both a single observed 
treatment and once (n=5) or twice (n=5) daily 30-minute sessions 
at home for two weeks.42 Near-infrared fluorescence lymphatic 
imaging (NIRFLI) conducted immediately after each observed 
treatment revealed improved lymphatic uptake and drainage as 
compared to pre-treatment in all patients, indicative of effective 
treatment. Using a 20% change as indication of reduction of 
dermal backflow, NIRFLI conducted after two weeks of home 
treatment showed disappearance or reduction of backflow in 75% 
of patients whose initial images revealed backflow. Composite 
tape measurements of the head and neck were made prior to each 
NIRFLI measurement. Slight reductions in composite scores, 

 
 
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according to the authors, “tracked with reductions in backflow”. 
Improvement occurred in patients who had once or twice daily 
treatment, suggesting that once a day treatment is possibly 
adequate. A subsequent retrospective study, (n=205), addressed 
patients using the device at home for a minimum of 30 minutes per 
day as part of Phase 2 self-care. Average use of the device was 
about 4 weeks.34 Adherence to and satisfaction with the therapy 
were striking as 71% of patients reported daily use and 87% were 
satisfied. This study provided the first firm indication of potential 
symptom relief when using the device. Responses to a standard 5 
item survey administered by Tactile Medical to all patients using a 
FT, established that 90% reported feeling generally better after 
using the device and all symptom and function items improved 
(p=<0.00001). 
A pilot RCT (N=49), was conducted at Vanderbilt University 
School of Nursing and Southern Illinois University with Dr. Sheila 
Ridner as PI, and Drs. Barbara Murphy and Sandra Ettema as Co-
I’s.43 Eligible patients were cancer-free after completed HNC 
therapy and had persistent LEF after Phase 1 CDT. Patients who 
were unable to access CDT were considered eligible for the study. 
Patients were randomized to wait-list LEF self-management (usual 
care) or LEF self-management plus the use of the APCD twice per 
day. Safety (CTCAE V4.0) and feasibility were primary endpoints; 
secondary endpoints included efficacy measured by objective 
examination and patient reported outcomes (PRO’s) (symptoms, 
QOL, function), adherence barriers and satisfaction.  Anatomic 
measures included: a clinician-report measure of external 
lymphedema, inspection of the UADT for evaluation of the soft 
tissues and spaces in the pharynx and larynx, a cervical range of 
motion device, measurement of interincisal distance, and blood 
specimens. Assessments were conducted at baseline and weeks 4 
and 8. Forty-nine patients were enrolled (wait-list n=25; 
intervention n=24).  Forty-three completed the study. No device 
related SAEs were reported. Most used the APCD once per day, 
instead of the prescribed twice per day, citing time related factors 
as barriers to use. APCD use was associated with significant 
improvement in perceived ability to control lymphedema (p=.003) 
and reduction in visible external swelling (front view p<.001, right 
view p=.004, left p=.005) as evidenced by scored digital 
photography. Use of the APCD was associated with reduced soft 
tissue symptoms (e.g. heaviness, tightness, p=0.0008), and 
neurological symptoms (tingling, pins and needles, p=0.047) as 
captured by the LSIDS-H&N v.2 and improved swallowing solids 
and improved mucous control as captured using the Vanderbilt 
Head and Neck Symptom Survey. All wait-list controls opted to 

 
 
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use the device and, without prompting, patients stated they 
perceived the device to be more effective than the Phase 1 CDT.  
3.2.2.3 Strengths of Current APCD Research 
Physiologic measurement of lymphatic flow provides 
documentation of the mechanism of action and effectiveness. 34,41-
43 Reduction of external swelling was noted in two of the studies 
using composite tape measurements and in one study documented 
reduction of dermal backflow and external swelling occurred 
simultaneously.34,41,42 There is support that patients are satisfied 
with the device, will use it at home, and perceive treatment with 
the device improves symptom and function.34,43 No Serious 
Adverse Events have been reported. Data supports a “dose” of 
daily one-time use of the device as effective.43  
3.2.2.4 Weaknesses of Current APCD Research 
Research regarding APCD use in the treatment LEF in this 
population is limited (N=4). The total number of patients studied is 
308, and data from 205 (60%) of those came from a retrospective 
chart review.34 No RCTs have compared APCDs to usual care, 
thus it is unknown whether or not this home-self-care method is a 
viable option for initial therapy of HN LEF. Outcome measures 
varied across studies making it difficult to compare results. 
3.2.3 Summary of Usual Care and APCD 
There are few studies addressing Usual Care or APCD therapy in the HNC 
population. Treatment algorithms for HNC associated lymphedema are 
based on clinical experience and data from treatment of other anatomical 
sites of lymphedema. Additional research regarding potential first-line 
therapies for this patient population is indicated. 
4.0 
Study Objectives 
Our long-term goal is to improve outcomes for individuals suffering from LEF. The overall 
objective for this study is to conduct a randomized clinical trial comparing the effectiveness 
of APCD and Usual Care for the management of LEF.  
5.0 
Study Design 
This study is an open label, multi-site two-group stratified, prospective, randomized 
clinical trial that will compare Usual Care which entails CDT administered by a 
lymphedema therapist to decongestive therapy using an APCD. All patients will be 
consented and then screened to confirm the presence of either internal or external LEF and 
at least one of the core lymphedema associated symptoms identified in our preliminary 
research.43 Patients must meet all eligibility criteria to be considered for study. Once 
eligibility is confirmed, patients will be randomized. Patients randomized to Usual Care 
will be referred to a local lymphedema therapist per institution standard practice. 
If patients are randomized to APCD therapy, the site will arrange an appointment for the 
patient with a Tactile Representative to initiate therapy. Patients in both arms will undergo 

 
 
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all baseline measures within 7 days prior to the first therapy appointment (exception: CT 
scan and internal exam may be done up to 28 days prior to initiation of therapy). Measures 
will be repeated at 2, 4, and 6 months. Study staff will contact patients every 2 weeks to 
document ongoing lymphedema therapy related activities, barriers to care, and adverse 
events. After the subject has completed their 6-month visit, they will be exited from the 
study. Subjects who received Usual Care will be offered a referral to receive an APCD 
through normal commercial means. Subjects who received an APCD will return their 
controller and will be offered a referral to receive an APCD through normal commercial 
means.  
 
Figure 2. Study Design 
5.1 
Primary Aims 
1) To compare the short-term and long-term effectiveness of self-administered 
APCD therapy versus Usual Care in HNC survivors with treatment naive 
LEF on anatomical measures of internal and external LEF. Baseline 
measures will be obtained at the start of therapy. Short-term effectiveness 
will be evaluated at 2 months, and long-term effectiveness will be evaluated 
at 4 and 6 months. Hypothesis: the APCD therapy will be associated with 
greater short-term and long-term reduction in anatomical measures of LEF. 
2) To compare the short-term and long-term effectiveness of self-administered 
APCD therapy versus Usual Care in HNC survivors with treatment naive 
LEF on patient reported biopsychosocial outcome measures impacted by 
LEF. Outcome measures will include: 1) symptom burden, 2) symptom 
burden and functional impairment, 3) QOL, 4) work and activity, 5) 
perceived self-management capacity, 6) body image, and 7) diet 
modifications. Baseline measures will be obtained at the start of therapy. 
Short-term effectiveness will be evaluated at 2 months and long-term 
effectiveness will be evaluated at 4 and 6 months. Hypothesis: the APCD 
therapy will be associated with greater short-term and long-term 
improvement in patient reported outcomes. 

 
 
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5.2 
Primary Endpoints 
To compare the short and long-term effectiveness of self-administered APCD 
therapy to Usual Care in HNC survivors with treatment naïve LEF. 
5.2.1 Anatomical Measures 
1. Internal lymphedema 
o Assessment of UADT via endoscopy with direct or indirect 
visualization (Modified Patterson Scale) 
o CT Imaging (CT-LEFAT) 
2. External lymphedema 
o Assessment using the HN-LEFG criteria 
o Digital Photographs (30 section grid) 
5.2.2 Patient Reported Biopsychosocial Measures 
1. Symptom Burden: LSIDS-H&N v2.0 
2. Physical Function: VHNSS plus GSS 
3. QOL: 5-item Linear Analog Self-Assessment   
4. Work and Activity: WPAIQ 
5. Perceived self-management compacity: PMCSMS 
6. Body image: BIQLI 
7. Diet modifications: ASA24 
5.3 
Outcome Measures 
Endpoints will be based on outcome measures as described in Tables 1 and 2.  
Table 1. Anatomical Outcome Measures 
Endpoint 
Outcome Measure 
Internal 
Lymphedema 
• Compare Modified Patterson Scale measurements 
between APCD and Usual Care subjects at baseline, 
2, 4, and 6 months 
• Compare CT-LEFAT Imaging measurements 
between APCD and Usual Care subjects at baseline, 
2, and 6 months 
External 
Lymphedema 
• Compare HN-LEFG measurements between APCD 
and Usual Care subjects at baseline, 2, 4, and 6 
months 
• Compare Digital Photograph measurements (30 
section grid) between APCD and Usual Care subjects 
at baseline, 2, 4, and 6 months 
 
 
 

 
 
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Table 2. Patient Reported Biopsychosocial Outcome Measures 
Endpoint 
Outcome Measure 
Symptom Burden 
• Compare LSIDS-H&N scores between APCD and 
Usual Care subjects at baseline, 2, 4, and 6 months 
Symptom Burden and 
Functional 
Impairment 
• Compare VHNSS plus GSS scores between APCD 
and Usual Care subjects at baseline, 2, 4, and 6 
months 
QOL 
• Compare QOL scores between APCD and Usual Care 
subjects at baseline, 2, 4, and 6 months 
Work and Activity 
• Compare WPAIQ scores between APCD and Usual 
Care subjects at baseline, 2, 4, and 6 months 
Perceived self-
management 
compacity 
• Compare PMCSMS scores between APCD and Usual 
Care subjects at baseline, 2, 4, and 6 months 
Body image 
• Compare BIQLI scores between APCD and Usual 
Care subjects at baseline, 2, 4, and 6 months 
Diet modifications 
• Compare ASA24 data between APCD and Usual 
Care subjects at baseline, 2, 4, and 6 months 
5.4 
Subject Selection 
The target population includes HNC survivors with treatment naïve LEF who meet 
the criteria listed below and have provided informed consent.  
5.4.1 Inclusion Criteria 
1. Age ≥ 18 years 
2. Pathologically confirmed cancer of the head and neck (larynx, 
pharynx, oral cavity, paranasal sinuses, major salivary glands, and 
HNC of unknown primary) 
3. Completed curative intent cancer therapy with no evidence of 
active cancer at time of study enrollment  
4. A diagnosis of either internal or external head and neck 
lymphedema 
5. At least one core lymphedema associated symptom of ≥ 4 out of 10 
at the time of study screening  
6. Must be able and willing to participate in all aspects of the study 
and provide informed consent prior to study participation 
7. Must be able to speak and understand English 
 
 

 
 
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5.4.2 Exclusion Criteria 
1. Previous APCD or Usual Care treatment for HNC LEF 
2. Acute facial infection (e.g., facial or parotid gland abscess) 
3. Known carotid sinus hypersensitivity syndrome 
4. Symptomatic carotid artery disease, as manifested by a recent 
(within 30 days of informed consent) transient ischemic attack, 
ischemic stroke, or amaurosis fugax (monocular visual ischemic 
symptoms or blindness) 
5. Internal jugular venous thrombosis (within 3 months of informed 
consent) 
6. Patient is pregnant or trying to become pregnant 
5.5 
Point of Enrollment and Randomization 
Randomization codes will be generated by the study statistician in a permuted 
block design. The block size will be balanced within each block and will maintain a 
1:1 ratio between treatment groups. Randomization within each site will proceed in 
10-unit blocks with a randomly generated sequence defined a priori.  
Subjects will be considered enrolled in the study once the informed consent form 
(ICF) is signed, all inclusion/exclusion criteria are met, and the Randomization 
electronic case report form (eCRF) is completed in iMedNet, the study database. 
Once the Randomization eCRF is saved, the randomization assignment will 
populate on the eCRF.  
Any patient who is approached for participation in the study (including those that 
decline participation) should be recorded in the iMedNet database.  
Consented subjects that do not meet inclusion/exclusion criteria will be considered 
screen failures and all collected data will be entered into the study database.  If 
consented subjects are found to not meet eligibility criteria, all data up to that point 
should be entered into the study database and a Study Exit form shall be completed.  
If a subject does not meet all the eligibility criteria and is randomized in error, or 
incorrectly started on treatment, the Investigator should inform Tactile Medical 
immediately. 
6.0 
Study Visits 
Electronic case report forms (eCRFs) and database queries will be used for data collection 
and query resolution. The Investigator will ensure the accuracy, completeness, and 
timeliness of the data recorded and responses to data queries according to the Clinical Trial 
Agreement (CTA).  
6.1 
Screening Visit  
If a patient appears eligible to participate based on medical history, he or she will 
be contacted or approached to assess interest. If the patient is interested in learning 
more, an ICF will be provided to them (in person, electronically, or via mail) and 
the subject will be given adequate time to review and ask questions. If the subject 

 
 
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decides to participate and provides documented informed consent, the following 
screening assessments will be performed and may occur on different days. 
• Administer the lymphedema core symptom survey  
o Note – subject must have a score of ≥4 on at least one question to be 
eligible for the study 
• Collection of demographic data 
• Review of medical history to ensure the subject is an appropriate candidate for 
APCD or Usual Care treatment 
• Height and weight 
• Administer a urine pregnancy test for all female subjects of child-bearing 
potential 
• Assess for external or internal LEF – subjects must have positive exam findings 
for external or internal lymphedema  
o External assessment 
§ Examination of the face, neck, and shoulders using the HN-LEFG 
Criteria– if subject has at least mild external lymphedema involving 
at least one anatomical site, they are considered positive for 
lymphedema and it is not necessary to perform the internal 
assessment at the screening visit 
o Internal assessment 
§ Examination of the UADT via endoscopy using the Modified 
Patterson Scale – if subject has at least mild internal lymphedema 
involving at least one anatomical site or space, they are considered 
positive for lymphedema  
§ CT of the neck – if subject is not positive for lymphedema via 
external or internal exam via endoscopy, a standard of care CT 
that is within the previous 28 days may be reviewed by the Study 
Investigators for evidence of internal lymphedema. If CT is positive 
for lymphedema, they may be included in the trial. 
• Collect head and neck measurements 
• Confirmation of eligibility & randomization 
If the subject continues to meet criteria, the site investigator will confirm the subject 
is clinically appropriate for APCD or Usual Care treatment and they will be 
randomized via entry of the randomization eCRF in iMedNet. If the subject is assigned 
to Usual Care, the site investigator will sign an order for referral to a lymphedema 
therapist. If the subject is assigned to APCD therapy, the site investigator will initiate 
an order for a FT through a Tactile Medical Product Specialist.  
Study personnel will monitor the scheduling process and arrange for the Baseline Visit 
procedures to occur within 7 days prior to the initiation of Usual Care or APCD 
treatment (exception for CT and UADT evaluation, which may occur up to 28 days 
prior).   
 
 

 
 
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6.2 
Baseline Visit 
The following baseline assessments will be performed and may occur on different 
days but within either 7 days prior to therapy initiation or 6 weeks (+5 days) from 
the date of the Screening Visit (whichever occurs first) unless otherwise noted: 
• Examination of the head, neck, and shoulders using the HN-LEFG Criteria 
• Digital photographs 
• Patient reported biopsychosocial measures. 
• Examination of the UADT via endoscopy using the Modified Patterson Scale 
o Note – if this screening examination was performed within 28 days of 
therapy initiation, it does not need to be repeated at baseline 
• CT of the neck  
o Note – scans performed as part of standard surveillance that are within 
the previous 28 days of therapy initiation may be used in lieu of obtaining 
a separate scan 
If the visit is conducted at 6 weeks in place of therapy initiation, this date will be 
considered “day 0” for the purposes of calculating the follow-up schedule.  
6.3 
Therapy Initiation 
6.3.1 Usual Care 
Patients randomized to Usual Care will be referred for lymphedema 
therapy per standard procedures at their site and the Site Principal 
Investigator (PI) or Sub-Investigator (Sub-I) will sign the order for the 
referral. Patients will be encouraged not to share with the lymphedema 
therapist that they are participating in a research study.  
It is anticipated that there will be variability in Usual Care. This includes 
variability in the accessibility to lymphedema care, assessment tools and 
techniques, treatment recommendations, implementation, patient 
adherence, enactment, and follow-up.  
No attempt will be made to influence or modify the treatment plan 
generated by the lymphedema therapist unless: 
• there is a concern about the patient’s health or safety or; 
• the lymphedema therapist refers a Usual Care subject for a 
Flexitouch. If a Flexitouch referral is made, the prescription should 
not be signed/processed until the subject has completed the study. 
6.3.2 APCD 
Patients randomized to the APCD will be referred to a Tactile Medical 
Product Specialist and the Site PI or Sub-I will sign the order for the 
APCD.   
A Tactile Medical Product Specialist will schedule a visit with the subject 
to fit the device and provide training. At this visit, measurements of the 
subject’s head, neck, and chest may be collected to confirm garment size 
selection, including ensuring fit does not interfere for those patients with 

 
 
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tracheostomies. Should the Product Specialist not be able find a garment 
that will fit the patient, the patient will continue study participation with a 
referral to Usual Care.  
Patients will be trained on donning and doffing the head and neck garments 
and operating the controller and will demonstrate proficiency at doing this 
independently. The APCD prescription will be a daily H1 treatment at 
normal pressure. If the subject is having difficulty tolerating the device 
pressure, they may work with Tactile Medical to modify settings as needed. 
These modifications will be documented.  
6.4 
2, 4, & 6 Week Contacts 
Subjects will be contacted at 2, 4, and 6 weeks post therapy initiation (±5 days) and 
the following assessments will be performed in person, via telephone, or video 
conference: 
• Adherence assessment 
• Adverse event assessment 
6.5 
2 Month Visit 
The following assessments will be performed 2 months (±7 days) from therapy 
initiation unless otherwise noted: 
• Examination of the head, neck, and shoulders using the HN-LEFG Criteria 
• Examination of the UADT via endoscopy using the Modified Patterson Scale 
(±14 days) 
• Digital photographs 
• CT of the neck (±14 days) 
• Patient reported biopsychosocial measures 
• Adherence assessment 
• Adverse event assessment  
6.6 
10, 12, & 14 Week Contacts 
Subjects will be contacted at 10, 12, and 14 weeks post therapy initiation (±5 days) 
and the following assessments will be performed in person, via telephone, or video 
conference: 
• Adherence assessment 
• Adverse event assessment 
6.7 
4 Month Visit 
The following assessments will be performed 4 months (±7 days) from therapy 
initiation unless otherwise noted: 
• Examination of the head, neck, and shoulders using the HN-LEFG Criteria 
• Examination of the UADT via endoscopy using the Modified Patterson Scale 
(±14 days) 
• Digital photographs 
• Patient reported biopsychosocial measures 

 
 
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• Adherence assessment 
• Adverse event assessment 
6.8 
18, 20, & 22 Week Contacts 
Subjects will be contacted at 18, 20, and 22 weeks post therapy initiation (±5 days) 
and the following assessments will be performed in person, via telephone, or video 
conference: 
• Adherence assessment 
• Adverse event assessment 
6.9 
6 Month Visit 
The following assessments will be performed 6 months (±7 days) from therapy 
initiation unless otherwise noted: 
• Examination of the head, neck, and shoulders using the HN-LEFG Criteria 
• Examination of the UADT via endoscopy using the Modified Patterson Scale 
(±14 days) 
• Digital photographs 
• CT of the neck (±14 days) 
• Patient reported biopsychosocial measures 
• Adherence assessment 
• Adverse event assessment 
• Study exit interview (optional) 
After the subject has completed their 6-month visit, they will be exited from the 
study. Subjects who received Usual Care will be offered a referral to receive an 
APCD through normal commercial means. Subjects who received an APCD will 
return their controller and will be offered a referral to receive an APCD through 
normal commercial means.  
7.0 
Study Schedule of Activities  
The study schedule of activities is shown below (Table 3). 

 
 
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Table 3. Schedule of Activities 
Assessments 
Screening 
Baseline 
Therapy 
Initiation 
2, 4 & 6 Week 
Contact 
2 Month Visit 
10, 12, & 14 
Week Contact 
4 Month Visit 
18, 20 & 22 
Week Contact 
6 Month Visit 
 
NA 
-7 to 0 
Days◊◊ 
Day 0 
±5 
Days 
±7 
Days 
±5 
Days 
±7 
Days 
±5 
Days 
±7 Days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Lymphedema Core 
Symptom Survey 
X 
 
 
 
 
 
 
 
 
Demographics & 
Medical History 
X 
 
 
 
 
 
 
 
 
Height* & Weight 
X 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
Exam using HN-
LEFG 
X 
X 
 
 
X 
 
X 
 
X 
Exam of UADT 
via endoscopy 
using Modified 
Patterson Scale 
X† 
X‡ 
 
 
X§ 
 
X 
 
X§ 
Randomization 
X 
 
 
 
 
 
 
 
 
Digital 
Photographs 
 
X 
 
 
X 
 
X 
 
X 
CT of the Neck 
 
X‡ 
 
 
X§ 
 
 
 
X§ 
LSIDS – H&N 
 
X 
 
 
X 
 
X 
 
X 
VHNSS plus GSS 
 
X 
 
 
X 
 
X 
 
X 
5-item Linear 
Analog Self-
Assessment 
 
X 
 
 
X 
 
X 
 
X 
WPAIQ 
 
X 
 
 
X 
 
X 
 
X 
PMCSMS 
 
X 
 
 
X 
 
X 
 
X 
BIQLI 
 
X 
 
 
X 
 
X 
 
X 
ASA24 
 
X 
 
 
X 
 
X 
 
X 
Usual Care/APCD 
Initiation 
 
 
X 
 
 
 
 
 
 
Adherence 
Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
Study Exit 
Interview 
(optional) 
 
 
 
 
 
 
 
 
X 
*Height collected at Screening visit only; historical records may be used for height  
†If exam using HN-LEFG shows at least mild external lymphedema involving at least one anatomical site, they are considered 
positive for lymphedema, and it is not necessary to perform the Exam of UADT via endoscopy 
‡Visit window is within 28 days prior to therapy initiation 
§Visit window is ±14 days 
◊◊Or 6 weeks (+5 days) post Screening Date whichever comes first.  If the visit is conducted at 6 weeks in place of therapy 
initiation, this date will be considered “day 0” for the purposes of calculating the follow-up schedule.  
 

 
 
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8.0 
Study Assessments 
8.1 
Informed Consent  
A sponsor and IRB-approved ICF must be signed by each subject before study 
participation.   
Each subject (or a legally authorized representative) must give written consent, in 
accordance with local requirements, after the nature of the study has been fully 
explained and questions answered. The consent form must be signed prior to any 
study-related procedures, and the process of informed consent must be documented 
in the medical record.  
8.2 
Lymphedema Core Symptom Survey 
The Lymphedema Core Symptom Survey is a brief screening questionnaire which 
includes core symptoms associated with lymphedema that are deemed clinically 
meaningful. Subjects must rank at least one core symptom ≥4 to be eligible for this 
study. 
8.3 
Demographics & Medical History 
Demographics will be collected including the date of birth, ethnicity, race, and sex.  
Significant medical history and treatment data will be obtained through chart 
review and patient interview.   
8.4 
Height and Weight 
Height and weight will be collected at the screening visit. If the clinic does not 
have access to a stadiometer to measure height, a historical value from the subject’s 
medical record may be used. 
8.5 
Pregnancy Test 
Women of childbearing potential will be tested for pregnancy according to site 
specific procedures. If the pregnancy test is positive, the subject will not be 
enrolled in the study. 
8.6 
Examination of the head, neck, and shoulders using the HN-LEFG Criteria 
Trained study staff will perform an examination of face, neck, and shoulders and 
grading will be performed based on the HN-LEFG criteria.47 This tool assesses the 
type and grade of soft tissue abnormalities at different anatomical sites. The 
anatomical sites include: 
• Left/right peri-orbital region 
• Left/right cheek 
• Submental 
• Left/right neck 
• Left/right supraclavicular fossa 
• Additional sites noted, as specified by the examiner 
 
 

 
 
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Each anatomical site is assessed and if soft tissue abnormality is noted, it is 
assigned a type and grade using the following criteria: 
Type 
Description & Grades 
A 
No visible tissue swelling; Palpable thickening and/or tightness of 
dermis 
B 
Visible soft tissue swelling; involved tissues are soft to touch; 
tissue swelling is reducible and fluctuates in severity 
Grade: 
• Mild – visible soft tissue swelling on close inspection 
• Moderate – easily visible swelling that significantly alters 
normal tissue contours 
• Severe – extreme or massive swelling 
C 
Visible soft tissue swelling; involved tissues are firm to 
touch; tissue swelling is non-reducible and persistent 
Grade: 
• Mild – visible soft tissue swelling on close inspection 
• Moderate – easily visible swelling that significantly alters 
normal tissue contours 
• Severe – extreme or massive swelling 
D 
Firm skin with increased density and decreased 
compliance in the absence of swelling 
Grade: 
• Mild – palpable firmness of soft tissues 
• Moderate – soft tissues are extremely hard and have a woody 
texture 
• Severe – fibrosis associated with contracture 
8.7 
Examination of the UADT via endoscopy using the Modified Patterson Scale 
The original Patterson Scale was developed to assess edema/swelling in the 
pharynx and larynx for patients treated with radiation. The scale included 11 
structures and 2 spaces and had good intrarater reliability (weighted kappa, 0.84) 
and moderate interrater reliability (weighted kappa, 0.54).44 Four grades are used to 
evaluate the internal edema level, in the pharynx and larynx, from normal (no 
edema) to severe edema.13 Previously reported findings have been reported 
showing internal lymphedema captured by the Patterson Scale correlated with 
patient reported swallowing difficulty as well as objective findings of swallowing 
dysfunction on modified barium swallow.45  
A Modified Patterson Scale will be used in this trial. This modified scale now 
includes 16 structures and 2 spaces. An examination of the UADT via endoscopy 
will performed by a trained clinician and the following anatomical sites will be 
assessed for lymphedema/edema using this Modified Patterson Scale: 
 
 

 
 
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• Lip 
• Oral tongue (Anterior 2/3) 
• Uvula 
• Buccal Mucosa 
• Floor of the Mouth 
• Soft Palate 
• Base of Tongue 
• Posterior Pharyngeal Wall 
• Epiglottis 
• Pharyngoepiglottic Folds 
• Aryepiglottic Folds 
• Interaryenoid Space 
• Arytenoids 
• False Vocal Folds 
• True Vocal Folds 
• Anterior Commissure 
• Valleculae Space 
• Pyriform Sinus Space 
If lymphedema/edema is present, severity will be graded as mild, moderate, or 
severe.  
8.8 
Digital Photographs 
Using well-established procedures that have been successful in both single and 
multi-site studies, research team members will photograph patient’s right and left 
profiles and front from the shoulders to top of head.43 Patients will be seated 
against a plain background and have clear visibility to their head, neck, and 
shoulders (see Appendix A for additional detail).  
Digital photos will be uploaded to iMedNet and centrally scored by a blinded 
assessor. Each photo will be divided into 30 quadrants and the presence or absence 
of swelling will be assessed.  
8.9 
CT of the Neck 
CT of the neck, with and without contrast, will be collected at Baseline and the 2 
and 6-month follow-up visits. A baseline standard of care scan may be used if it is 
within 28 days prior to the initiation of therapy. Standard of care scans may be used 
for the 2 and 6-month follow-up visits if they are within 14 days of the target visit 
date. All scans will be submitted to the CT Core Lab for analysis per the 
instructions found in the CRF Completion Guidelines.  
CT images are used as part of standard of care to evaluate response to oral cavity 
and oropharyngeal cancer treatment in the study sites. The scans collected for this 
trial will be reviewed and scored centrally by a blinded radiologist, using the CT-
LEFAT46. This CT scoring system was developed to score LEF status post HNC. 
This tool grades fat stranding at the level of the superior thyroid cartilage in the 
following five locations:  

 
 
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• Midline anterior subcutaneous fat, anterior to platysma 
• Anterior cervical space fat, anterior to SCM – right 
• Anterior cervical space fat, anterior to SCM – left 
• Posterior cervical space fat, anterior to SCM – right 
• Posterior cervical space fat, anterior to SCM – left 
In addition, this tool measures midline prevertebral soft tissue (PVST) thickness 
(mm) at the mid C3 level, epiglottis thickness (mm), and grades submental fat 
stranding.  
8.10 Patient reported biopsychosocial measures 
Subjects will complete the biopsychosocial measures at their baseline, 2, 4, and 6- 
month follow-up visits. When the subject’s visit-window opens, they will receive 
an email with a link to the following questionnaires that will allow them to enter 
their responses directly into the iMedNet electronic database via the electronic 
Patient Reported Outcomes (ePRO) function: 
• LSIDS – H&N v2.0 
• VHNSS plus GSS 
• 5-item Linear Analog Self-Assessment 
• WPAIQ 
• PMCSMS 
• BIQLI 
Subjects may also complete these questionnaires at the clinic using the ePRO 
function. If requested by the subject, study staff may read the questionnaires aloud 
and document the subject’s response and/or clarify the meaning of questions. Input 
from study staff, friends, or family on how to answer questions is strongly 
discouraged.  
Study personnel are responsible for reviewing the questionnaires to ensure they are 
completed within the study visit window and complete.  
Subjects will also complete the ASA24 by logging into a secure web-based system 
with their own user account and entering their food and liquid consumption for the 
previous 24 hours. The first time this is administered at the Baseline Visit, study 
staff should facilitate entry. The subject may request assistance in completed this at 
subsequent visits. 
8.10.1 LSIDS – H&N 
This 31 item tool captures LEF-related symptom burden in HNC patients.  
It includes 7 symptom clusters. Internal consistency values of scores 
generated from the HNC symptom clusters range from 0.83 to 0.95 
confirming the cluster compositions. The LSIDS-H&N v2.0 (manuscript 
in-press) takes 5-7 minutes to complete.43,48 
8.10.2 VHNSS plus GSS 
The VHNSS v.2.0 consists of 50-items within 13 domains including 
nutrition, swallowing, xerostomia, mucositis, excess mucus, speech, 

 
 
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hearing, taste change, smell, dental health, mucosal sensitivity, range of 
motion, and pain.43,49 Items are scored on a numeric scale rating the 
severity of the symptom from 0 (none) to 10 (severe). VHNSS v2.0 plus 
GSS includes 12 additional items directed at the systemic effects of 
therapy. Studies have reported good internal consistency for the total scale 
(alpha=0.94) and five subscales (i.e., swallow, nutrition, mucous/dry 
mouth, pain, voice) (alphas=0.77-0.93), and adequate convergent and 
divergent validity. The VHNSS v2.0 plus GSS takes approximately 10 
minutes to complete. 
8.10.3 5-item Linear Analog Self-Assessment 
The scale assesses physical, emotional, spiritual, intellectual, and over-all 
well-being, on a 0-10 scale. It has been used successfully in cancer 
populations.50 It takes approximately less than 1 minute to complete. 
8.10.4 WPAIQ 
This commonly used, valid and reliable, 9-item questionnaire evaluates lost 
hours of productivity seven days prior to administration and can be targeted 
to evaluate lost productivity due a specific medical condition (e.g., 
lymphedema). When compared to the SF-36, it has been found to correlate 
with general health scores (r=0.52), and physical role (r=0.52).51,52 The 
WPAIQ takes less than 5 minutes to complete. 
8.10.5 PMCSMS 
The PMCSMS is a generic (template) instrument that can be specific to any 
medical condition. The scale was initially used in individuals with diabetes 
(N=398) and Cronbach’s alpha was .84 and has since been validated 
against a shorter version of the instrument that did not perform as well.53,54 
The PMCSMS takes less than 5 minutes to complete. 
8.10.6 BIQLI 
This validated, self-report measure captures body image (19 items, 
Cronbach’s α =.95).55 The BIQLI takes 10 minutes to complete. 
8.10.7 ASA24 
Detailed information about dietary intake and nutritional values can be 
obtained using this NCI tool. 56 It can be completed using smart phones, 
tablets, laptops, and desktops. Patients will enter their information and the 
program will calculate nutrition results. LEF has been associated with 
dysphagia and dietary adaptations.  This will allow us to determine whether 
improvement in swallow function can result in improvement in dietary 
intake. The ASA24 takes approximately 30 minutes to complete. 
8.11 Adherence assessment. 
Study staff will assess subject adherence and barriers to their lymphedema 
treatment by asking the questions below. If the subject does report issues or barriers 
to APCD use or Usual Care, study personnel should not attempt to provide 

 
 
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additional support or guidance on how to address these issues. Instead, the subject 
should be encouraged to contact their Tactile Medical Product Specialist (APCD 
Group) or Lymphedema Therapist (Usual Care Group) or.  
If study personnel have questions or concerns about a subject’s ongoing 
lymphedema care, they will be directed to contact their Site PI or a Study PI. Study 
personnel should avoid influencing physician or patient behavior.  
APCD Group 
1) In the past week, how many days did you use your Flexitouch? 
2) In the past week, did you experience any barriers that prevented you from using 
your Flexitouch? If yes, ask subject to specify barriers impacting their use of the 
Flexitouch (select all that apply). 
• Did not know how to perform 
• Does not feel treatment works 
• Does not have the motivation to perform 
• Does not have the time 
• Treatment is uncomfortable 
3) Since your last visit, did you have any other treatment for your Lymphedema? If 
yes, ask subject to specify type of treatment and number of days within the past 
week the treatment has been used / administered (select all that apply). 
• MLD 
a) Self-only massage 
b) Healthcare professional – If so, how many tx since last visit? 
• Compression 
• Myofascial release 
• Other, specify (attach field notes, etc.) 
Usual Care Group 
1) Have you been instructed to perform self-administered massage or manual lymph 
drainage to manage your lymphedema? If yes, continue below. 
a) How many days did you perform self-administered massage or manual 
lymph drainage in the past week? 
b) In the past week, did you experience any barriers that prevented you from 
performing self-administered massage? If yes, ask subject to specify and 
select all that apply. 
• Did not know how to perform 
• Does not feel treatment works 
• Does not have the motivation to perform 
• Does not have the time 
• Treatment is uncomfortable 
2) Have you been instructed to wear a compression garment to manage your 
lymphedema? If yes, continue below. 
a) How many days did you wear a compression garment the past week? 

 
 
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b) In the past week, did you experience any barriers that prevented you from 
wearing your compression garment? If yes, ask subject to specify and select 
all that apply. 
• Did not know how to perform 
• Does not feel treatment works 
• Does not have the motivation to perform 
• Does not have the time 
• Treatment is uncomfortable 
3) Have you been instructed to wear bandaging to manage your lymphedema? If 
yes, continue below. 
a) How many days did you wear bandaging in the past week? 
b) In the past week, did you experience any barriers that prevented you from 
wearing bandages? If yes, ask subject to specify and select all that apply. 
• Did not know how to perform 
• Does not feel treatment works 
• Does not have the motivation to perform 
• Does not have the time 
• Treatment is uncomfortable 
4) Have you been instructed to use skin care techniques to manage your 
lymphedema? If yes, continue below. 
a) How many days did you use skin care techniques in the past week? 
b) In the past week, did you experience any barriers that prevented you from 
using skin care techniques? If yes, ask subject to specify and select all that 
apply. 
• Did not know how to perform 
• Does not feel treatment works 
• Does not have the motivation to perform 
• Does not have the time 
• Treatment is uncomfortable 
5) Have you been instructed to perform exercises to manage your lymphedema? If 
yes, continue below. 
a) How many days did you perform these exercises in the past week? 
b) In the past week, did you experience any barriers that prevented you 
from performing these exercises? If yes, ask subject to specify and 
select all that apply. 
• Did not know how to perform 
• Does not feel treatment works 
• Does not have the motivation to perform 
• Does not have the time 
• Treatment is uncomfortable 
6) Have you been instructed to perform breathing exercises to manage your 
lymphedema? If yes, continue below. 
a) How many days did you perform these breathing exercises in the past week? 

 
 
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b) In the past week, did you experience any barriers that prevented you from 
performing these breathing exercises? If yes, ask subject to specify and select 
all that apply. 
• Did not know how to perform 
• Does not feel treatment works 
• Does not have the motivation to perform 
• Does not have the time 
• Treatment is uncomfortable 
7) Have you been instructed to perform any other treatments/activities to manage 
your lymphedema? If yes, continue below. 
a) Please describe this treatment/activity. 
b) How many days did you perform this treatment/activity in the past week? 
c) In the past week, did you experience any barriers that prevented you from 
performing this treatment/activity? If yes, ask subject to specify and select all 
that apply. 
• Did not know how to perform 
• Does not feel treatment works 
• Does not have the motivation to perform 
• Does not have the time 
• Treatment is uncomfortable 
Information collected will not be shared with the treating physician unless such 
information is deemed important for patient care and safety.  
In addition, the APCD records device usage, including number of sessions and 
minutes of therapy delivered.  
Clinic records of Phase 1 CDT will be collected and reviewed, and the details of 
the treatment(s) will be captured in the study database.  
8.12 Adverse event assessment 
Adverse event assessment will occur after randomization and continue throughout 
the study. Reportable events, as defined below, will be recorded on an Adverse 
Event eCRF and classified and graded using Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0. This study will collect severe (Grade 3-5) adverse 
events that are possibly, probably, or definitely related to participation in the trial 
and the administration of the intervention (APCD or Usual Care).  
An adverse event is defined as any complication whose clinical significance is 
greater than anticipated, or which occurs with a frequency greater than that which is 
usually seen for this type of intervention (APCD or Usual Care).  
An adverse event will be classified as serious if the outcome: 
1) Results in death; 
2) is life-threatening (places subject at immediate risk of death from the 
experience as it occurred);  
3) hospitalization (initial or prolonged) if admission to hospital was warranted as 
a result of the adverse event); 

 
 
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4) results in disability or permanent damage (substantial disruption of one’s 
ability to carry out normal life functions); 
5) results in congenital anomaly or birth defect; or 
6) required intervention to prevent permanent impairment or damage. 
Investigators must report all serious adverse events to Tactile Medical within 10 
working days of becoming aware of the event. Serious events will be reported in 
writing to the appropriate IRB in accordance with IRB policy.  
8.13 Subject Exit Interview (optional) 
Subjects will be invited (via the informed consent process) to participate in an 
optional exit interview. Participation in this interview is optional and subjects must 
provide additional consent to be contacted.  If the subject declines participation in 
the exit interview they will not be excluded from the trial and will not be contacted.   
Subjects agreeing to participate will be contacted by Vanderbilt University Medical 
Center (VUMC) staff and will be asked to share their lymphedema care experience. 
This interview will be done remotely (by telephone or video conference) and will 
last 10-15 minutes.  
Participation in this interview is optional; if subject wishes to participate, they must 
provide consent for the release of their contact information to VUMC.  
9.0 
Subject Discontinuation or Withdrawal 
Subjects may choose to discontinue the use of the APCD or Usual Care therapy. 
Discontinuation of the APCD or Usual Care therapy will not constitute a reason for the 
subject to be withdrawn from the study. The subject will be encouraged to continue in the 
study and complete all planned and future assessments. Should the subject choose to 
terminate their participation in the study, they will be treated according to the standard of 
care that applies at the point of withdrawal.  
The Site PI may choose to withdraw a subject from the study if:  
• It is deemed medically necessary 
• Subject non-adherence with study procedures as defined by failure to participate 
in study related outcome measures 
• Subject is no longer able to provide informed consent (i.e., subject voluntarily 
withdraws) 
• Recurrence of HNC 
10.0 Accountability  
The FT will be provided at no cost to the site and subject. For subjects randomized to the 
APCD group, the FT system (controller & garments) will be provided to the subject by the 
Tactile Medical Product Specialist/Trainer at their Treatment Initiation Visit. When the 
subject completes the study, they will return the controller to the study site, where the study 
site will arrange for the return to Tactile Medical. The study subjects may keep their FT 
garments and are not to return them to the site.  
 
 

 
 
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11.0 Risk Analysis  
Study subjects will be informed of any significant new findings that develop during the 
course of this study that may affect their willingness to continue participation. 
11.1 Anticipated Side Effects of Pneumatic Compression  
Pneumatic compression is a minimal risk therapy with minimal known 
complications or side effects. The expected side effects that are experienced are 
often due to the natural history of the primary disease or failure to achieve adequate 
response to the treatment. Side effects may include a local skin reaction to the device 
materials, increased swelling at other sites, or pain and discomfort. The subject will 
be made aware of known complications and adverse events at time of consent and 
monitored closely throughout the study.  
11.2 Anticipated Side Effects of Usual Care 
Risks of Usual Care are not well understood. As with APCD, the expected side 
effects that are experienced are often due to the natural history of the primary disease 
or failure to achieve an adequate response to CDT.  
Standard Compression Garments: It is possible, though unlikely, that some patients 
could experience skin irritation due to an allergic response to garment material, 
increased swelling at other sites, or pain and discomfort. It is also likely that an ill-
fitting garment could lead to itching, redness, pain, increased swelling, or numbness. 
Other expected likely risks are often a failure to respond to the standard compression 
intervention and not related to the compression itself.  
11.3 Reportable Events 
Reportable events are defined as any unanticipated or severe complications that are 
possibly or probably related to Usual Care or APCD. Adverse events will be graded 
using CTCAE v5.0. and a severe event will be defined as Grades 3-5.   
12.0 Provisions to Protect the Privacy of Study Participants/Information Security Plan 
The most likely risk posed to participants would be a breach of confidentiality if someone 
other than the research team obtained access to the data.  
There are security measures in place to prevent a breach of confidentiality from happening 
including password protected electronic database and the use of subject codes to de-
identify data). 
Precautions will be taken to make sure that only authorized individuals will be accessing 
subject research records.  The collection of sensitive information about subjects is limited 
to the amount necessary to achieve the aims of the research registry, so that no unneeded 
sensitive information is being collected.   
13.0 Deviation from Study Plan  
All deviations from the protocol will be documented on a Protocol Deviation eCRF and 
reported to the IRB as required by IRB policies and / or the terms of the IRB approval.  
 
 

 
 
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14.0 Quality Assurance Procedures  
This study will be conducted in accordance with GCPs, Code of Federal Regulations 
(CFR), institutional research policies and procedures, and other appropriate regulatory 
requirements to ensure subject safety and quality of clinical procedures related to the 
conduct of the clinical trial. As required by United States Food and Drug Administration 
(FDA) 21 CFR 56 and the Declaration of Helsinki, the protocol, amendments, and ICF will 
be reviewed and approved, according to 21 CFR §50 and §56, by each center’s IRB.  
14.1 Site Qualification  
Tactile Medical personnel will conduct a Qualification Visit onsite or by telephone 
to verify the resources, staffing, and subject pool are adequate to ensure successful 
enrollment and study completion. 
14.2 Site Initiation  
A Site Initiation Visit will be conducted to ensure all required regulatory 
documents are accurate and complete, and site personnel has been adequately 
trained on the protocol. An activation letter will be sent to the Site PI once the site 
is approved to enroll subjects. 
14.3 Fidelity Monitoring 
Annual visits, from the time of site initiation, conducted in person or via 
videoconference, will be made by Dr. Ridner or a trained designated alternate to 
observe all measurements, data collection, and site-specific intervention, and 
communication methods/techniques with the device manufacturer. This will 
include direct observation of subjects during all data collection procedures except 
CT and UADT scoping procedures.  Just-in-time training for any deficits noted 
during the visit will be provided and documented.  
14.4 Monitoring  
Clinical sites will be monitored for compliance with the clinical protocol, 
investigator agreement, and applicable regulations. Regular contact will be 
maintained to ensure: 
• Subject safety; 
• Clinical site staff are well informed of regulations and sponsor 
requirements; 
• The clinical protocol is followed; 
• Data is gathered in a complete and timely manner; 
• Problems with data or data collection are addressed appropriately and in a 
timely manner;  
• Adverse events are properly reported in a timely manner; and 
The Site PI and Institution agree to permit all trial related monitoring, audits, IRB 
review, and regulatory inspection(s); providing direct access to source data and 
documents, as appropriate. Monitoring and source verification will be performed 
by Tactile Medical personnel and/or designee. Source verification includes 

 
 
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reviewing subject source documentation and eCRFs for accuracy, completeness, 
and compliance with GCP.  
14.5 Data Collection Procedures 
Data will be collected using iMedNet, a CFR Title 21 Part 11 compliant electronic 
data capture (EDC) tool. Sites will be expected to enter data directly into iMedNet 
instead of using hard copy source documents. However, in the rare incidence when 
hard copy source documents are used, the site will upload a scanned image of the 
source document to the applicable eCRF and it will be 100% source document 
verified by the sponsor.  
14.6 Data Safety Monitoring  
The Site PI will be responsible for subject safety. Additionally, a periodic review of 
safety data may be completed by an independent monitoring committee (IMC), 
whose members will not be associated with the research project.  
14.7 Reports and Records   
Records to be maintained by the Site PI in a designated study file include: 
• Investigational plan and all amendments; 
• Signed Investigator Agreement/Research Contract; 
• IRB approval letter, including a copy of the approved consent forms, 
progress reports, and adverse event reports; 
• IRB roster or Assurance number, if applicable; 
• All correspondence relating to the conduct of this study between the site 
and sponsor, IRB, and study monitor; 
• Curriculum Vitae and professional license (if applicable) for all 
investigators; 
• Site personnel signature and documentation regarding the investigator’s 
delegation of responsibility; 
• Site visit log; 
• Protocol related training records for all applicable study personnel; 
• Device accountability log; 
• Screening log; and 
• Reports (shown below). 
The Site PI is required to prepare and submit to Tactile Medical, or its designees, 
complete, accurate, and timely reports on this investigation as required by 
regulations (Table 4).  
 
 

 
 
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Table 4. Required Reports 
15.0 
 
Reports 
Submit To 
Timeframe 
SAE  
Sponsor and 
Reviewing IRB 
Sponsor: Within 10 working 
days of becoming aware of the 
event; 
IRB: In accordance with 
IRB procedure. 
Withdrawal of IRB 
Approval 
Sponsor 
Within 5 working 
days 
IRB determination that 
study is classified as 
Significant Risk (SR) 
Sponsor 
Immediately upon notification 
from the IRB 
Progress Report 
Reviewing IRB 
Annually, at a 
minimum 
Final Clinical Study 
Report 
Sponsor and 
Reviewing IRB 
Within 3 months 
following the completion 
or termination of the 
Investigator’s part 
The following records must be maintained for each subject enrolled: 
• Original, signed and dated ICF (electronic or hard copy), as well as 
documentation of the process of consent; 
• Completed eCRFs, database queries, and source document worksheets, as 
applicable; and 
• Complete medical records including procedure reports, lab reports, etc., as 
applicable 
Subject study records, correspondence files, all supporting study documentation, 
and reports must remain on file at the site for a minimum of ten years after the 
conclusion of this study. All site investigators must contact Tactile Medical 
personnel prior to destroying or archiving off-site any records and reports 
pertaining to this study to ensure that they no longer need to be retained on-site. 
Additionally, Tactile Medical personnel must be contacted if the site investigator 
plans to leave the investigational site to ensure that arrangements for a new 
investigator or records transfer are made prior to the investigator’s departure. 
15.0 Change to Investigational Plan  
Should changes in the study plan or protocol become necessary during the course of the 
clinical research study, proposed changes will be appropriately reviewed and approved by 
Tactile Medical and the Study PIs, and IRB approval will be obtained before any changes 
are implemented.  
 
 

 
 
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16.0 Statistical Methods   
16.1 Sample Size Determination 
Preliminary data from a previous study, which was administered in patients whose 
LEF was refractory to usual care, was used to perform the power calculations for 
this study.  Because the previous study selected for patients who had already failed 
usual care, at least for a time, it was expected that the effect sizes in that population 
were somewhat attenuated compared to what we will see in this study’s treatment 
naïve population.  Thus, we expect that the power calculated here is slightly 
conservative. 
 
 
 
 
 
  
The study will plan to enroll 250 patients to 
ensure sufficient power with a dropout rate of up to 20%. In the previous trial 
12.2% of the patients withdrew from the study. 
16.2 Randomization 
This is a multicenter study with up to 10 sites.  Each site will have a target 
enrollment of 50 patients.  Randomization within each site will proceed in 10-unit 
blocks with a randomly generated sequence defined a priori. If a site is unable to 
meet its recruitment target, a block will be removed from that site and assigned to 
one of the remaining four sites or an additional site that may be added at a later 
date.  
16.3 Statistical Analysis 
This study has a classical design with no early looks at aggregate data. At the 
conclusion of the study, data will be exported, checked for errors, and appropriately 
cleaned.  Graphical and numeric summaries of relevant patient demographics and 
baseline characteristics will be generated by site and in aggregate. Subscale scores 
will be calculated for each, or the responses designated as outcomes at each 
timepoint (baseline, 4 Month, 6 Month). The 4- and 6-Month measures will be 
analyzed separately with the 4 Month data being used to determine effectiveness of 
the intervention and the 6 Month data representing the durability of the effect. The 
data will be analyzed using a mixed effects generalized linear model with a random 
intercept for study site. Each model will be adjusted for relevant covariates 
including the baseline subscale score. Results will be deemed statistically 
significant if they attain a p-value<0.05 and will be reported as an effect size with 
its associated 95% confidence interval.  
All analyses will be conducted as both complete case analysis. Whenever missing 
data exceeds 10% of the data, the analysis will be repeated under multiple 

 
 
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imputation with an assumption that the data is missing at random. In the case that 
these analyses disagree, both results will be reported. 
17.0 Publication Plan 
The sponsor and the investigators are committed to the publication and widespread 
dissemination of the results of the study. This study represents a joint effort between 
sponsors and investigators, and as such, the parties agree that the recommendation of any 
party concerning manuscripts or text shall be taken into consideration in the preparation of 
final scientific documents for publication or presentation. 
All information concerning this study that has not been previously published is considered 
the confidential property solely of Tactile Medical. This information includes, but is not 
limited to, the protocol, workbooks, technical methodology, and resulting data. 
Investigators will maintain the intellectual property rights of assessment tools and 
methodologies developed prior to and outside of this protocol. All proposed publications 
and presentations by the sponsor and investigators or their personnel and associates 
resulting from or relating to the study must be submitted to Tactile Medical for review and 
written consent prior to submission for publication or presentation. To allow for the use of 
the information derived from this study and to ensure compliance with current USA 
Federal Regulations, the Investigator is obliged to provide Tactile Medical with complete 
test results and all data developed from this study. Regulatory audits and inspections of the 
information obtained during this study may be made available to others (including but not 
limited to government, institutional, corporate, regulatory, news media, or other 
organizations) at the sole discretion of Tactile Medical. 
If any such proposed publication or presentation contains patentable subject matter, which 
in the sponsor’s opinion warrants intellectual property protection, the sponsor may delay 
any publication or presentation for the purpose of pursing such protection. The first author 
will be the coordinating investigators, followed by the other investigators in order of 
patient recruitment (taking into account the number of analyzable follow-up patients and 
occurrence of protocol violations/deviations). The number of authors will be determined 
according to the rules of the addressed scientific journal. Sites may not publish or present 
their own single-center experience or multi-center results until the main study results have 
been published, or at least 1 year following study closure. 
 
 

 
 
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18.0 References 
1. 
American Cancer Society. Cancer Facts & Figures, 2020. 
https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-
figures/cancer-facts-figures-2020.html. Published 2020. Accessed September 29, 
2020. 
2. 
Murphy BA, Gilbert J, Ridner SH. Systemic and global toxicities of head and neck 
treatment. Expert Rev Anticancer Ther. 2007;7(7):1043-1053. 
3. 
Udeabor SE, Rana M, Wegener G, Gellrich NC, Eckardt AM. Squamous cell 
carcinoma of the oral cavity and the oropharynx in patients less than 40 years of 
age: a 20-year analysis. Head Neck Oncol. 2012;4:28. 
4. 
Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human 
papillomavirus-positive head and neck squamous cell carcinoma in a prospective 
clinical trial. Journal of the National Cancer Institute. 2008;100(4):261-269. 
5. 
Dayyani F, Etzel CJ, Liu M, Ho CH, Lippman SM, Tsao AS. Meta-analysis of the 
impact of human papillomavirus (HPV) on cancer risk and overall survival in head 
and neck squamous cell carcinomas (HNSCC). Head Neck Oncol. 2010;2:15. 
6. 
Sathish N, Wang X, Yuan Y. Human Papillomavirus (HPV)-associated Oral 
Cancers and Treatment Strategies. J Dent Res. 2014;93(7 Suppl):29S-36S. 
7. 
Deng J, Ridner S, Murphy B. Lymphedema in Patients With Head and Neck 
Cancer. Oncology Nursing Forum. 2011;38(1):E1-E10. 
8. 
Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon 
head and neck squamous cell carcinomas. Oral Oncol. 2014;50(6):565-574. 
9. 
Bernier J. Head and Neck Cancer: Multimodality Management. New York: 
Springer; 2011. 
10. 
Majchrzak E, Szybiak B, Wegner A, et al. Oral cavity and oropharyngeal 
squamous cell carcinoma in young adults: a review of the literature. Radiol Oncol. 
2014;48(1):1-10. 
11. 
Avraham T, Zampell JC, Yan A, et al. Th2 differentiation is necessary for soft 
tissue fibrosis and lymphatic dysfunction resulting from lymphedema. FASEB J. 
2013;27(3):1114-1126. 
12. 
Deng J, Ridner SH, Dietrich MS, et al. Prevalence of secondary lymphedema in 
patients with head and neck cancer. Journal of Pain and Symptom Management. 
2012;43(2):244-252. 
13. 
Smith BG, Lewin JS. Lymphedema management in head and neck cancer. Curr 
Opin Otolaryngol Head Neck Surg. 2010;18(3):153-158. 
14. 
Deng J, Murphy BA, Dietrich MS, et al. Impact of secondary lymphedema after 
head and neck cancer treatment on symptoms, functional status, and quality of life. 
Head Neck. 2013;35(7):1026-1035. 
15. 
Murphy BA, Gilbert J. Dysphagia in head and neck cancer patients treated with 
radiation: assessment, sequelae, and rehabilitation. Semin Radiat Oncol. 
2009;19(1):35-42. 
16. 
Stubblefield M, O'Dell M. Cancer Rehabilitation: Principles and Practice. New 
York: Demos Publishing, LLC; 2009. 
17. 
Ridner SH, Dietrich MS, Niermann K, Cmelak A, Mannion K, Murphy B. A 
Prospective Study of the Lymphedema and Fibrosis Continuum in Patients with 
Head and Neck Cancer. Lymphat Res Biol. 2016;14(4):198-205. 

 
 
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18. 
Stout Gergich NL, Pfalzer LA, McGarvey C, Springer B, Gerber LH, Soballe P. 
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Ridner SH, Dietrich MS, Cowher MS, et al. A Randomized Trial Evaluating 
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Desai SS, Shao M, Vascular Outcomes C. Superior Clinical, Quality of Life, 
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Pigott A, Nixon J, Fleming J, Porceddu S. Head and neck lymphedema 
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Aulino JM, Wulff-Burchfield EM, Dietrich MS, et al. Evaluation of CT Changes 
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Deng J, Ridner SH, Murphy BA, Dietrich MS. Preliminary development of a 
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19.0 Appendices 
Appendix A: Standard Digital Photography Procedure 
 

 
 
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Appendix A: Standard Digital Photography Procedure

 
 
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Standard Digital Photography Procedure 
 
1.0 
PURPOSE 
To ensure that the imaging for all photos taken for study assessments meet 
necessary quality requirements. 
2.0 
DEFINITIONS 
Photo Background:  Should be an even, neutral, non-reflecting, monochromatic 
surface.  The preferred background colors are white, grey and blue.  Having a fixed 
place in the clinic for photography will allow for standardization. 
Subject Position:  The subject will be asked to wear garments that expose their full 
head, neck and shoulders.  If necessary, a gown can be provided.  The subject 
should sit normally on a chair or stool and positioned at least one foot in front of 
the background.  The seating should not have any recline and the subject should 
have both feet on the floor and their hands placed on their knees. 
Frontal View:  This includes the upper limit of the subject’s head to just below 
their collar bone with the subject looking at the camera. 
Lateral View:  From the frontal view body positioning, with the subject’s whole 
body rotated 90° and align the nasal tip and chin.  Have the subject keep their head 
in its anatomical position with no lateral inclination, flexion, or extension. 
3.0 
PROCEDURE 
3.1 
Set-up: 
• Use the same cameral, lens, settings, magnifications, illumination, and 
positions at each visit. 
• The camera should be in the same position and distance at each visit (floor 
markings can be used to keep this uniform). 
• A tripod is recommended to fix the camera in position 
• Ensure proper background set-up prior to taking photos.  Ensure the chair or 
stool is placed at least one foot from the background. 
• Have the subject in a chair or stool and assume the proper position in the 
frontal view position to start.   
• Preferably the same photographer should take the pictures at each visit after 
reviewing the photos taken at the previous visit. 
3.2 
Image Capturing: 
• Ensure the subject is in the proper frontal view position and instruct the 
subject to look straight ahead and assume a neutral facial expression, holding 
their head in a natural head position and relaxed. 
• 
Take the frontal view photo and review the photo against the previous 
visit’s photos to ensure even placement of the head and neck.   
• 
Have the subject move into the lateral view position on the right side and 

 
 
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again instruct the subject to look straight ahead and assume a neutral face 
expression, holding their head in a natural head position and relaxed. 
• 
Take the right lateral view photo and review against the previous visits 
photos to ensure even placement of the head and neck. 
• 
Repeat again on the left side lateral view. 
3.3 
Uploading Images: 
• 
Save images for subject and visit and upload to iMedNet (refer to Case Report 
Form Completion Instructions for more detail on how to upload images).