A Pilot Study to Evaluate the Feasibility and Potential Effectiveness of the Flexitouch System Head and Neck Treatment
Phase: NA
Conditions: Head and Neck Neoplasms, Head and Neck Cancer, Head and Neck Lymphedema
Sponsor: Tactile Medical

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Tactile Medical™
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A Pilot Study to Evaluate the Feasibility and Potential
Effectiveness of the Flexitouch® System Head and Neck
Treatment
Protocol# 4030
September 26, 2017
Protocol Version 2.0
Sheila H. Ridner, PhD, RN, Vanderbilt University School of Nursing (Principal Investigator)
Barbara Murphy, MD, Co-I (Oncologist)
Mary S. Dietrich, PhD, Co-I (Biostatistics)

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Investigator Signature
Protocol Title: A Pilot Study to Evaluate the Feasibility and Potential Effectiveness of the
Flexitouch® System Head and Neck Treatment
Protocol Number: 4030
Version: 2.0; 26 September 2017
I confirm that I have read this protocol. I will comply with the protocol and the principles of
Good Clinical Practices (GCP), the International Conference on Harmonization Guidelines,
Therapeutic Goods Act, institutional research policies and procedures and other appropriate
regulatory requirements.
Site Principal Investigator Name (Print)
Site Principal Investigator Signature
Date

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Tactile Medical™
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SYNOPSIS
Title of Study
A Pilot Study to Evaluate the Feasibility and Potential Effectiveness of the
Flexitouch® System Head and Neck Treatment
Protocol Date
26 September 2017
Protocol Version
2.0
Name of Sponsor
Tactile Medical™
Investigational Product
Flexitouch® System Head and Neck System
Primary Aim
To determine the feasibility of use of the Flexitouch® Head and Neck
System, specifically a) to evaluate implementation fidelity (adherence)
and barriers to implementation fidelity, b) to establish safety, and c) to
assess satisfaction.
Secondary Aim
To determine the preliminary efficacy of the Flexitouch® Head and Neck
System compared to a wait-list control for the following outcomes: a)
reduction in swelling/inflammation, b) function (cervical, jaw, and shoulder
range of motion), c) symptoms, and d) quality of life changes.
Primary Endpoint
The primary endpoint will occur when subjects complete the 8th week of
interventional treatment and provide: a) evaluation of implementation fidelity
(adherence) and barriers to implementation fidelity, b) review of adverse events,
and c) report satisfaction.
Secondary Endpoint
The secondary endpoint will occur at the same time as the primary endpoint.
Secondary outcomes include: a) reduction in swelling/inflammation, b) function
(cervical, jaw and shoulder range of motion), c) symptoms, and d) quality of life.
METHODOLOGY
Study Design
This study is an open label, multi-site, stratified randomized, wait list control,
pilot study.
Treatments
Standard home care may include: self-MLD, exercise, skin care, and wearing
an appropriate compression garment, if applicable.
Interventional treatment: twice daily treatment with Flexitouch®
pneumatic compression device and home care regimen, which may 
include self-MLD exercise, skin care, and wearing an appropriate
compression garment, if applicable.
Treatment Duration
The interventional study duration is 8 weeks. The subjects randomized to the
investigational group will be seen at baseline and weeks 1, 4 and 8. Subjects
randomized to the wait-list group will be seen at baseline and weeks, 1, 4 and 
8 while receiving standard of care (SOC) treatment (wait-list control group).
SUBJECT POPULATION
Number Planned
40 subjects randomized with replacement of up to 10 early withdrawals.

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Tactile Medical™
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Major
Inclusion/Exclusion
Criteria
Inclusion Criteria :
x
Age  18 years
x
A previous diagnosis of histologically defined head and neck cancer
x
A diagnosis of head and neck lymphedema
x
Must be able and willing to participate in all aspects of the study and
provide informed consent prior to study participation
x
Completed cancer treatment with no evidence of active cancer; all post-
surgical swelling must be resolved.
x
The head and neck garments must fit appropriately. For patients with a
tracheostomy, the fit will be assessed to ensure that the garments do not
interfere with their tracheostomy.
x
The subject must have experienced at least one of the following:
o Completion of phase 1 lymphedema care in the past 8 weeks
o The inability to participate/complete phase 1 care due to:
 lack of available therapist/clinic
 lack of insurance coverage/funding to support cost of care.
Exclusion Criteria :
x
Uncontrolled hyperthyroidism or parathyroidism (for which endocrinologist
recommends against neck compression)
x
Carotid sinus hypersensitivity syndrome
x
Symptomatic carotid artery disease, as manifested by a recent transient
ischemic attack (within 30 days), ischemic stroke, or amaurosis fugax
(monocular visual ischemic symptoms or blindness)
x
Symptomatic bradycardia in the absence of a pacemaker
x
Internal jugular venous thrombosis, acute or within 3 months
x
Increased intracranial pressure or other contraindications to internal or
external jugular venous compression
x
Acute radiation dermatitis, unhealed surgical scar, unhealed or open
wound(s), surgical flap less than 6-8 week post-operative
x
Facial or head and neck dermal metastasis
x
Acute facial infection (e.g., facial or parotid gland abscess)
x
Any condition in which increased venous and lymphatic return is
undesirable
x
History of pulmonary edema or decompensated congestive heart failure
with in six (6) week of enrollment.
x
Subject is pregnant or trying to become pregnant
ASSESSMENTS
Feasibility /Safety
 
Adherence and barriers monitoring
Adverse Event Monitoring (CTCAE)
Satisfaction-Subject Self-report
Physical Examination

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Efficacy
Visits will take place at Vanderbilt University School of Nursing, Vanderbilt
Medical Center, or other facility approved location. Any additional sites will
see patients in a location as determined by their research environment. Home
visits may take place if unexpected circumstances arise that compromise data
collection taking place in a timely manner. The following assessments will be
completed at predefined times throughout the study.
x
Digital Photos
x
Endoscopy / Revised Patterson Scale
x
Cytokine testing
x
Neck Disability Index
x
Voice Handicap Index
x
Range of Motion Measures
o Cervical ROM
o Jaw ROM
o Shoulder ROM
x
Vanderbilt Head and Neck Symptom Survey
x
Lymphedema Symptom Intensity and Distress Survey
x
Linear Analog Self-Assessment Quality of Life

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TABLE OF CONTENTS
1.1
Contact Information .................................................................................................8
1.2 Sponsor Contact Information............................................................................8
1.3 Study Principal Investigator Information..........................................................8
2.0
Abbreviations...........................................................................................................8
3.1
Introduction..............................................................................................................9
3.2 Background and Rationale................................................................................9
3.3 Device Description .........................................................................................10
4.1
Study Objectives ....................................................................................................10
4.2 Objective.........................................................................................................10
4.3 Primary Aim ...................................................................................................10
4.4 Secondary Aim ...............................................................................................10
5.1
Study Design..........................................................................................................10
5.2 Study Endpoints..............................................................................................11
5.2.1
Primary Endpoint...........................................................................11
5.2.2
Secondary Endpoint.......................................................................11
5.3 Subject Selection ............................................................................................11
5.3.1
Inclusion Criteria............................................................................12
5.3.2
Exclusion Criteria ..........................................................................12
5.3.3
Subject Withdrawal or Early Termination .....................................13
5.4 Dosing.............................................................................................................13
5.5 Study Timetable..............................................................................................14
6.1
Study Visit Summaries...........................................................................................14
6.2 Screening Visit................................................................................................14
6.3 Baseline Visit.................................................................................................14
6.4 Follow-up Visits .............................................................................................15
6.5 Final Visit .......................................................................................................15
7.1
Study Procedures....................................................................................................15
7.2 Data Collection...............................................................................................15
7.2.1
Vital Signs/Height and Weight ......................................................15
7.2.2
Laboratory Testing.........................................................................15
7.2.3
Feasibility.......................................................................................16
7.2.4
Swelling/Inflammation...................................................................16
7.2.4.1 Endoscopy with Modified Patterson Scale.........................16
7.2.4.2 Cytokines ...........................................................................16
7.2.4.3 Digital Photography...........................................................16
7.2.5
Function .........................................................................................16
7.2.5.1 Neck Disability Index ........................................................16
7.2.5.2 Voice Handicap Index........................................................17
7.2.5.3 Cervical and Shoulder ROM..............................................17
7.2.5.4 Jaw ROM ...........................................................................17
7.2.6
Symptoms.......................................................................................17
7.2.6.1 Vanderbilt Head and Neck Symptom Survey (plus General
Symptom Survey 2.0..........................................................17
7.2.6.2 Lymphedema Symptom Intensity and Distress Survey .....17
7.2.7
Quality of Life................................................................................17
7.3 Study Device Application...............................................................................17

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7.4 Study Schedule of Activities...........................................................................18
8.0
Study Device Accountability .................................................................................19
9.1
Risk Analysis and Adverse Events ........................................................................19
9.2 Risk Analysis..................................................................................................19
9.3 Anticipated Adverse Events............................................................................19
9.4 Adverse Event Reporting................................................................................19
10.0
Deviation from Study Plan.....................................................................................19
11.1
Data/Safety Monitoring & Quality Assurance Procedures ....................................20
11.2Site Qualifications ..........................................................................................20
11.3Data Collection Procedures.............................................................................20
11.4Clinical Site Monitoring.................................................................................21
11.5Reports and Records.......................................................................................21
11.6Changes to Study Plan....................................................................................22
12.1
Statistical Methods and Determination of Sample Size.........................................23
12.2Data Management...........................................................................................23
12.3Statistical Analysis Plan .................................................................................23
12.4Statistical Analysis..........................................................................................24
13.0
Compensation.........................................................................................................24
14.0
Publication Plan (if applicable)..............................................................................25
15.0
References..............................................................................................................25
16.1
Appendices.............................................................................................................26
A. Flexitouch® Users Guide and Neck Garment Measuring Guide
B. Informed Consent
C. Patient Screening Form
D. Self-Care Kit Instructions and Checklist
E. Feasibility Data Collection Forms
F. Swelling/Inflammation Data Collection Forms
G. Function Data Collection Instruments
H. Symptom and Quality of Life Data Collection Instruments
I. Accountability Logs
J. FDA Documents

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1.1
Contact Information
1.2
Sponsor Contact Information
Tactile Medical™
Sunday Hoy, Esq., Director of Clinical Resources and Research
1331 Tyler Street NE, Suite 200
Minneapolis, MN 55413
612-355-5121
shoy@tactilemedical.com
1.3
Study Principal Investigator Information
Sheila Hedden Ridner, PhD, RN, FAAN
Vanderbilt University School of Nursing
525 Godchaux Hall,
461 21st Ave. S.
Nashville, TN 37072
615-322-0831
Sheila.Ridner@Vanderbilt.edu
2.0
Abbreviations
AE
Adverse Event
BP
Blood Pressure
CDT
Complete decongestive therapy
CFR
Code of Federal Regulations
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DVT
Deep vein thrombosis
FT
Flexitouch®
GSS
General Symptom Survey
HIPAA
Health Insurance Portability and Accountability Act
HNC
Head and neck cancer
HNL
Head and neck lymphedema
ICF
Informed consent form
ICH
International Council for Harmonisation
IRB
Institutional review board
L-SIDS
Lymphedema Symptom Intensity and Distress Survey
MLD
Manual lymph drainage
NDI
Neck Disability Index
REDCap
Research Electronic Data Capture
ROM
Range of motion
SD
Standard Deviation
VHI
Voice Handicap Index
VHNSS
Vanderbilt Head and Neck Symptom Survey

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3.1
Introduction
3.2
Background and Rationale:
Secondary head and neck lymphedema (HNL) is a frequent side effect in patients
treated for head and neck cancer (HNC) as the primary cancer or factors related to
treatment (surgery, radiation, or chemotherapy) either destroy or obstruct lymphatic
vessels and damage adjacent soft tissue.1,4 HNL occurs in over 90% of patients
following HNC treatment.2 HNL may involve external structures (soft tissues of the
face, neck and eyes) or internal structures (oral cavity, mucous membranes, larynx
and pharynx) but most often both are involved simultaneously.3 The resultant
clinical impact is dependent on the anatomic sites involved and the extent of
associated lymphatic dysfunction. Symptoms can range from mild to severe. The
most common areas of external swelling and fibrosis are in the submental region
and the neck.2,4 In severe cases, HNL may affect critical physical functions (e.g.,
respiration, mastication, swallowing, communication and vision). HNL, comparable
to lymphedema at other sites, is often associated with psychological distress and
degradation to quality of life.3, 4
In a recent study of 1,202 HNC patients, the majority of patients reported cosmetic
concerns and discomfort. More than one third reported functional complaints,
including difficulty swallowing (68%) and difficulty breathing (39%).2 Internal
swelling may be directly related to these symptoms. The most common functional
complaint among patients who underwent total laryngectomy was difficulty
breathing, often related to tracheostomal obstruction from submental edema.2
HNL patients often experience tightness and discomfort in the muscles of the neck
and shoulders, which may impede range of motion and function of this muscular
groups.3 Damage to the muscles in the affected region, may occur after radiation,
resulting in atrophy, weakness and altered sensation.
Damaged lymphatics result in high-protein fluid collection in the affected tissues.
Lymphedema is also associated with chronic inflammation, which may lead to a
self-perpetuating and progressive course and exacerbation of symptoms .5 A study
of filariasis disease, whose cardinal signs are lymphedema and massive fibrosis,
found elevated TNF-Din early stages and determined that IL-6 and IL-8 were
potential biomarkers for acute and chronic (highly fibrotic) stages of the disease.7
Pre-clinical models suggest cytokine driven pathways are involved in late-effect
radiation-induced soft tissue damage and that persistent, elevated levels of some
cytokines may foreshadow fibrosis after radiation.8, 9, 10 Even more relevant are
results from, a descriptive, longitudinal study of 93 patients with head and neck
cancer, conducted at Vanderbilt University, that followed lymphedema and fibrosis
overtime, that found IFNg TNF-D, TGF-ȕ IL-1b, IL-6, MMP-2, MMP-9, and CRP
were associated with lymphedema and fibrosis (confidential personal
communication). Inflammation is clearly an area of concern for this patient
population. One study (N=9), of individuals with chronic primary or secondary leg
lymphedema, found that TNF-Dsignificantly decreased after volume reduction
treatment.10 Thus, manual therapy, may play a role in reduction of inflammatory
cytokines and further exploration of such is warranted.

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The standard treatment for HNL utilizes modified techniques of in-clinic complete
decongestive therapy (CDT), including manual lymph drainage (MLD). Currently,
some patients are able to continue simplified versions of these techniques at home,
yet, many patients with HNL experience difficulty performing the treatment and/or
find the treatment is insufficient in effectively managing their symptoms long-term.
Clinicians and patients have therefore identified a need for additional effective
options for at home treatment of HNL. In response, Tactile Medical™has
developed a garment for the treatment of HNL utilizing The Flexitouch® System
pneumatic compression device (FT). Tactile Medical™seeks to complete a study
designed to evaluate the feasibility and potential effectiveness of the Flexitouch®
on swelling/inflammation, symptom burden, and quality of life when used for
lymphedema self-care.
3.3
Device Description :
Flexitouch® System (Tactile Medical™, Minneapolis, MN, USA): The
Flexitouch® System is a segmental, calibrated, gradient pneumatic compression
device that has been cleared for market in the US (K153311) (Appendix A), (US
HCPCS code E0652) for the treatment of head and neck lymphedema. The device
consists of a specifically designed garment set that covers the head, neck and chest
and connects to an advanced pneumatic pump that includes programs specific for
head and neck treatment. The Flexitouch® head and neck garment set is
constructed of nylon and has up to 14 pneumatic chambers covering the head, neck 
and chest. The device applies brief applications of dynamic pressure in a wave-like 
manner to the treatment area. Used in conjunction with the Flexitouch® controller,
the head and neck garment set is intended to treat lymphedema affecting the head
and neck by stimulating the adjacent axillary lymphatic tributary regions and
directing fluid from the affected area to healthy, functioning regions. (See
Appendix A)
4.1
Study Objectives/Aims
4.2
Objective: The study will evaluate the feasibility, and preliminary effectiveness of
the Flexitouch® head and neck treatment plus standard home care compared to
standard home care regimen alone.
4.3
Primary Aim: To determine the feasibility of use of the Flexitouch® Head and
Neck system, specifically a) to evaluate implementation fidelity (adherence) and
barriers to implementation fidelity, b) to establish safety, and c) to assess
satisfaction.
4.4
Secondary Aim: To determine the preliminary efficacy of Flexitouch® Head and
Neck system compared to a wait-list control for the following outcomes: a)
reduction in swelling/inflammation, b) function (cervical, jaw, and shoulder range
of motion), c) symptoms, and d) quality of life.

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5.1
Study Design
This study is an open label, multi-site, stratified by site, randomized, wait list control, pilot
study. Vanderbilt University will serve as the multi-site coordinating center.
Within each study site:
5.2
Study Endpoints :
5.2.1
Primary Endpoints: The primary endpoint will occur when subjects complete
the 8th week of treatment and provide: a) evaluation of implementation
fidelity (adherence) and barriers to implementation fidelity, b) review of
adverse events, and c) report satisfaction.
5.2.2
Secondary Endpoints: The secondary endpoints will be a) reduction in 
swelling/inflammation, b) function (range of motion cervical, jaw, and 
shoulder), c) symptoms, and d) quality of life.
5.3
Subject Selection
The study sample will be drawn from patients who have received head and neck
cancer therapy and have developed HNL secondary to their cancer treatment.
Approach
Participant 
Assess Eligibility/ 
Consent
Randomization 
Flexitouch® + 
Standard Regimen 
(8 weeks) 
Wait List 
Standard Regimen 
(8 weeks) 

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Patients will be recruited from the head and neck cancer clinic at Vanderbilt
University and similar clinics at the other investigational sites(s). The patient must
have undergone (or attempted and failed) complete decongestive therapy (CDT), or
is unable to access CDT as outlined in the inclusion criteria. Only patients who
meet the criteria listed below will be considered for the study. A total sample of 40
subjects (20 per group balanced within each site) will be enrolled and those
withdrawn for lack of adherence will be replaced, thus we may enroll up to 50
individuals.
5.3.1
Inclusion Criteria :
x Age  years
x A previous diagnosis of histologically defined head and neck cancer
x A diagnosis of head and neck lymphedema
x Must be able and willing to participate in all aspects of the study and
provide informed consent prior to study participation
x Complete cancer treatment with no evidence of active cancer; all post-
surgical swelling must be resolved.
x The head and neck garments must fit appropriately. For patients with a
tracheostomy, the fit will be assessed to ensure that the garments do not
interfere with their tracheostomy.
x The subject must have experienced at least one of the following:

Completion of phase 1 lymphedema care in the past 8 weeks

The inability to participate/complete phase 1 care due to:
o
lack of available therapist/clinic
o
lack of insurance coverage or funding to support cost of care.
5.3.2
Exclusion Criteria: Subjects will be determined to be ineligible for this study
if they meet any of the criteria described below :
x
Uncontrolled hyperthyroidism or parathyroidism (for which
endocrinologist recommends against neck compression)
x
Carotid sinus hypersensitivity syndrome
x
Symptomatic carotid artery disease, as manifested by a recent transient
ischemic attack (within 30 days), ischemic stroke, or amaurosis fugax
(monocular visual ischemic symptoms or blindness)
x
Symptomatic bradycardia in the absence of a pacemaker
x
Internal jugular venous thrombosis, acute or within 3 months
x
Increased intracranial pressure or other contraindications to internal or
external jugular venous compression
x
Acute radiation dermatitis, unhealed surgical scar, unhealed or open
wound(s), surgical flap less than 6-8 week post-operative
x
Facial or head and neck dermal metastasis
x
Acute facial infection (e.g., facial or parotid gland abscess)
x
Any condition in which increased venous and lymphatic return is
undesirable
x
History of pulmonary edema or decompensated congestive heart failure
with in six (6) week of enrollment.
x
Subject is pregnant or trying to become pregnant

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5.3.3
Subject Withdrawal or Early Termination:
Subjects will exit the study if they meet any of the following criteria:
x
Subject death
x
Subject voluntarily withdraws
x
Subject experiences a serious adverse event that in the investigator’s
clinical judgment necessitates study discontinuation
x
Subject acquires any of the exclusion criteria, except
o
In the case of a subject acquiring an infection, they may remain in
the study per the discretion of the investigator. Detailed
information regarding the infection, nature, treatment, and
duration, will be recorded.
x
Non-adherence with any study procedures as defined by no use of
device during a consecutive 7-day period as documented on the diary
or failure to complete required documents.
5.4
Dosage:
Wait-list Control Group: Subjects will continue their home care regimen as defined
by their physician/healthcare provider. The home care regimen may include:
x
self-MLD
x
exercise
x
skin care
x
wearing an appropriate compression garment.
After 8 weeks, the subject will then receive treatment as outlined below in the
investigational group if they so desire.
Investigational Group: Subjects in the investigational group will use the
Flexitouch® pneumatic compression device in addition to the home care regimen
defined by their treating physician/healthcare provider. The subject will complete
two treatment session daily using the Flexitouch® head and neck system for the
full 8 weeks of study participation. The twice daily treatment will include the H1
program for the head, neck and chest with an approximate 25-43 minute single
cycle time as outlined in the Flexitouch® System User Guide (Appendix A).
Instructions for the application of the head and neck garments are located in 
Chapter 6 of the Flexitouch® System User Guide (Appendix A). The home care
regimen may include:
x
self-MLD
x
exercise
x
skin care
x
wearing an appropriate compression garment, if applicable

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5.5
Study Timetable:
 
1- 3months
4-6 months
7-9 months
10-14 months
IRB Review
X
 
 
 
Enrollment
X
X
X
 
Treatment
 
X
X
 
Data Entry
 
X
X
 
Data Analysis
 
 
X
 
Manuscript Draft
 
 
X
 
Publication
 
 
 
X
6.1
Study Visit Summaries
6.2
Screening:
The subject will provide written informed consent prior to screening. The study
will be explained to each subject. An Informed Consent Form (ICF) will be signed
by each subject before study participation as mandated by FDA regulations and the
institutional review board (IRB). (See Appendix B) A blank copy of the IRB
approved informed consent form must be kept on-site and by Tactile Medical™. A
copy of the ICF will be given to the subject to read and take home to consider, if
they prefer. All the subject’s questions must be answered prior to signing the ICF.
Research procedures cannot be performed until the subject provides consent. The
signed original for each subject must be kept in the subject’s research records. A
copy of the signed consent form will be given to each subject.
After informed consent is obtained, screening will commence. (See Appendix C:
Screening Form) The subject’s head and neck measurements will be taken to assist
with garment size selection. For subjects with a tracheostomy, the fit will be
accessed further to ensure that the garments do not interfere with their
tracheostomy. The head and neck garment measuring guide is included in
Appendix A. Should the head and neck measurements indicate the garment will not
fit, no further information will be obtained and the subject will be withdrawn.
After the garment fit has been confirmed the remaining inclusion and exclusion
criteria will be evaluated to ensure that the subject meets all entrance criteria. The
subject should not undergo any study specific procedures until after the informed
consent process and screening processes are complete.
6.3
Baseline Visit:
The screening and baseline visit can occur on the same day or different days
depending on the needs of the subject. At this visit, the subject will undergo the
baseline data collection procedures as outlined in the Study Schedule of Activities
in section 7.4.
Randomization:
After completing the informed consent process and baseline data collection
(including the endoscopy) subjects enrolled at each site will be randomized (1:1) to
either the investigational group or wait-list control group via the use of a computer-
generated, permuted block program executed by the study biostatistician. Each site
will have its own unique randomization list.

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Subjects randomized to the investigational group at each site will follow the Study
Schedule of Activities table in section 7.4 and will complete the study in 8 weeks.
The subjects that are randomized to the waitlist groupat each site will complete all
study activities as outlined below in table 7.4. After completing the 8 weeks of the
standard regimen, the subjects may choose to receive the same treatment as was
implemented in the investigational group. No study data will be completed;
however, patients opting to use the device will be seen at weeks 9, 12, and 16 for a
documented safety check as outlined in section 7.4.
Research team members will provide the subjects with a self-care kit and provide
instructions on how to use the kit. All subjects will leave the initial baseline visit
with the self-care kit (Appendices D & E) that includes:
x
Subject Diary (intervention group only)
x
Self-care checklist
x
Dates and Times for their upcoming appointments
x
Contact information and instructions to call if any questions
6.4
Follow Up Visit(s):
The subject follow up visits will occur at 1 and 4 weeks (± 3 days). The study staff
will collect the checklist and review the subject diary with the intervention patients
during each visit to ensure that all entries are complete and understood by the study
staff. Any corrections must be made by the subject, and initialed and dated by
them. At the visit, the subject will undergo the study procedures as outlined in the
Study Schedule of Activities in section 7.4.
6.5
Final Visit:
The final study visit will occur at 8 weeks (± 3 days). At this visit, the subject will
undergo the study procedures as outlined in the Study Schedule of Activities in
section 7.4. The study staff will collect the checklist and review the subject diary
with the subject during each visit to ensure that all entries are complete and
understood by the study staff. Any corrections must be made by the subject, and
initialed and dated by them.
7.1
Study Procedures
7.2
Data Collection
7.2.1
Vital Signs/Height and Weight:
Vital signs including blood pressure, pulse and weight will be taken at each
study visit . Height will be taken only at baseline by the study team. Each
measure will be taken twice and averaged.
7.2.2
Laboratory Testing
Women of childbearing potential, defined as premenopausal, intact ovaries
and uterus, and not on birth control, will be tested for pregnancy using a self-
administrator urine pregnancy test. If the pregnancy test is positive, the
subject will be excluded from the study.

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7.2.3
Feasibility (Appendix E):
7.2.3.1 Adherence and barriers (Both Groups): Subjects will keep a diary
of device use and list barriers to use of device (investigational
group). A self-care checklist will be completed each week they
are in the study (both groups).
7.2.3.2 Safety (Both Groups) will be evaluated using CTCAE V4.011
7.2.3.3 Pre and Post treatment Survey (Intervention Group Only):
Subjects will complete a pre and post treatment survey. The
survey will be administered at the baseline visit and at the end of
the intervention.
7.2.4
Swelling/Inflammation (Appendix F):
7.2.4.1 Endoscopy with Modified Patterson Scale: The Patterson Scale
evaluates internal edema in the pharynx and larynx. The
Modified Patterson Scale, with established face validity, includes
anatomical sites that may develop internal edema.12
7.2.4.2 Cytokines: The study nurse or phlebotomist will draw blood at
baseline and at the 8-week visit. The following inflammatory
markers will be assessed: IFNg TNF-D, TGF-ȕ IL-1b, and IL-6.
MMP-2, MMP-9, and CRP will also be assessed if testing is
available.
7.2.4.3 Digital Photography: At the visits outlined in the Study Schedule
of Activities table in section 7.4, subjects will have photos taken
of their affected areas to evaluate external
swelling/inflammation. These photos will be taken according to
the standard procedure as outlined in Appendix F.
7.2.4.4 Grading of External Lymphedema: Trained study personnel will
complete a physical examination of the head and neck area.
Grading will be documented via the Head and Neck
Lymphedema and Fibrosis Assessment criteria.13
7.2.5
Function (Appendix G):
7.2.5.1 Neck Disability Index (NDI): This 10-item instrument assesses
components of daily life that may be affected by neck pain and
dysfunction. Items include pain, personal care, lifting, reaching,
headache, concentration, work, driving, sleeping, and recreation.
Internal consistency of the 10-item scale is adequate Į .89 -
.92).14, 15 Factor analysis identified one dimension. Stability of
the instrument also is adequate (r = .89). Validity of the NDI was
supported by the moderate to strong correlations with self-
reported activity improvement following treatment and pain.
7.2.5.2 Voice Handicap Index (VHI): This 30 item instrument taps
function, emotion, and physical areas that may be affected by

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voice disorders such as those caused by chemo-radiation therapy
for HNC.16 Internal consistency of the 30-item scale is adequate
(r=0.95).
7.2.5.3 Cervical and Shoulder ROM: These measurements will be taken
according to the instructions provided in Appendix G. The
measurements will be taken at intervals outlined in the Study
Schedule of Activities table (section 7.4).
7.2.5.4 Jaw ROM: The TheraBite Jaw ROM Scale will be used to
measure jaw opening. The Trismus grading criteria from the
CTCAE v4.0 also be will be recorded.11
7.2.6
Symptoms and Quality of Life (Appendix H)
7.2.6.1 Vanderbilt Head and Neck Symptom Survey plus General
Symptom Survey version 2.0 (VHNSS v2.0 plus GSS): The
VHNSS v2.0 assesses the prevalence and severity of treatment-
related symptoms and their functional impact in patients with
head and neck cancer.17 The VHNSS v.2.0 consists of 50-items
within 13 domains including nutrition, swallowing, xerostomia,
mucositis, excess mucus, speech, hearing, taste change, smell,
dental health, mucosal sensitivity, range of motion, and pain.
Items are scored on a numeric scale rating the severity of the
symptom from 0 (none) to 10 (severe). The VHNSS v.2.0 takes
approximately 10 minutes to complete. VHNSS v2.0 plus GSS
includes 12 additional items directed at the systemic effects of
therapy. The instrument will be completed by the subjects at the
intervals outlined in the Study Schedule of Activities table in
section 7.4.
7.2.6.2 Lymphedema Symptom Intensity and Distress Survey (L SIDS-
Head and Neck): Lymphedema Symptom Intensity and Distress
Survey-Head and Neck, assesses the measurement characteristics
of a measure of symptom burden for patients with head and neck
lymphedema and is a modified versions of the Lymphedema
Symptom Intensity and Distress Survey-Arm.18
7.2.7
Quality of Life: The 5-item Linear Analog Self-Assessment will be used to
evaluate quality of life. The scale assesses physical, emotional, spiritual,
intellectual, and over-all well-being, on a 0-10 scale. It has been successfully
used in cancer populations.19
7.3
Study Device Application: The garment will be applied initially with the assistance
of the study staff. After the study staff has successfully instructed the subject on
how to apply the garment, the subject will be asked to apply the garment with
limited assistance, complete a treatment session and then remove the garment.
After the removal of the garment, the subject will be asked to don and doff the

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garment again without assistance. All subjects will be asked to complete one self-
administered treatment under the observation of study team members.
7.4
Study Schedule of Activities:
 
Screening/
Randomization
Baseline Visit
Follow Up
Week 1
Follow Up
Week 4
Final
Week8
Patient Characteristics
 
 
 
 
 
Medical History
¥
¥
 
 
 
Height
 
¥
 
 
 
Weight
 
¥
я 
¥
¥
Garment Fitting
я 
Vital Signs (BP, Pulse)*
 
¥
¥
¥
¥
Demographics
¥ 
 
 
 
Pregnancy Testing*
¥
¥
 
¥
¥
Fidelity
 
 
 
 
 
Adherence-Diary**
 
 
¥
¥
¥
Barriers-Dairy**
 
 
¥
¥
¥
Self-care Checklist
 
 
weekly 
 
Safety
 
 
 
 
 
Adverse Events-
CTCAEV4.0*
 
 
¥
¥
¥
Satisfaction
 
 
 
 
 
Pretreatment survey**
 
¥
 
 
 
Post treatment survey **
 
 
 
 
¥
Swelling/Inflammation
 
 
 
 
 
Internal-
Endoscopy/PattersonScale
 
¥
 
 
¥
Digital Photography
¥
¥
¥
¥
Grading andStaging*
¥
¥
¥
¥
¥
Cytokines
 
¥
 
 
¥
Function
 
 
 
 
 
Range of motion-jaw,
shoulder, neck
 
¥
 
¥
¥
Patient Reported Outcome-
Neck Disability Index
 
¥
 
¥
¥
Patient Reported Outcome-
Voice Handicap Index
 
¥
 
¥
¥
Symptoms
 
 
 
 
 
Vanderbilt H and N Symptom
Survey
 
¥
 
¥
¥
Lymphedema Symptom
Intensity and Distress Scale
 
¥
 
¥
¥
Quality of Life
 
 
 
 
 
Linear Analog Self-
Assessment
 
¥
 
¥
¥
*=safety checks at week 9, 12, &16 for wait-list group opting to use the device
**=intervention group only

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8.0
Study Device Accountability (Appendix I):
The site must maintain a device accountability log for the Flexitouch®. Completion of this
log will ensure that all study devices are properly tracked and accounted for throughout the
study from the time they are received by the institution to the time they are returned to the
study sponsor or other designated site. Device location, subject ID assigned, date subject
returned to site, controller disinfected, and final disposition (e.g., returned to sponsor,
garments discarded) of all Flexitouch® controllers, and garments will be documented.
Tactile Medical™must also maintain device accountability documenting all shipments
and returns of study devices by serial number, date, and person completing the log.
Storage locations for the study devices and garments will be secure (i.e., locked and
away from other devices) with access restricted only to investigators and authorized
research personnel. At the conclusion of the treatment period, the subject will return the
Flexitouch® controller to the study site. Garments may be retained by the subject or 
discarded. Site personnel will return all controllers and any unused garments to Tactile 
Medical™at the completion of the study.
9.1
Risk Analysis and Adverse Events:
9.2
Risk Analysis: The subjects enrolled in the study are not expected to be at any
higher or additional risk than those who undergo in-clinic CDT. There is minimal
risk with CDT. These risks may include but are not limited to increased swelling
and pain.
9.3
Anticipated Adverse Events: Adverse events associated with lymphedema may
include increased swelling and pain. The severity of all anticipated events will be
graded according to the CTCAE.15 During the endoscopy it is possible that the 
following adverse events could occur 1) allergic reactions to the anesthesia or
decongestant if these are used 2) problems with heart rhythm 3) nosebleed or other 
bleeding 4) sore throat 5) fainting 6) headache and 7) chipped teeth.
9.4
Adverse Event Reporting: An adverse event includes 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 treatment. A serious adverse
event is defined as an event that: 1) results in death; 2) is life-threatening (places the
subject at immediate risk of death from the experience as it occurred); 3) results in a
persistent or significant disability/incapacity (substantial disruption of one’s ability
to carry out normal life functions); 4) results in medical or surgical intervention; 5)
results in or prolongs an existing hospitalization (even if the hospitalization is a
precautionary measure for observation); 6) is medically unexpected, regardless of
severity. Investigators must report all serious adverse events to Tactile Medical™
within 72 hours. Serious and/or unanticipated adverse events will be reported in
writing to the appropriate IRB in accordance with their policy, but not later than
five (5) days.
10.0 Deviation from Study Plan: Any deviation from this protocol undertaken to protect the life
or physical well-being of a subject in an emergency must be reported to Tactile Medical™
and the respective IRB as soon as possible, but in no event later than five (5) working days

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after the deviation occurred. Anticipated deviations from the protocol in a non-emergency
situation must be pre-approved by Tactile Medical™via telephone, email, fax or mail. It is
preferred that deviations scheduled to be performed in a non-emergency situation not be
conducted until authorized by Tactile Medical™. All protocol deviations must be
documented. A deviation that may affect the scientific soundness of the study, or the rights,
safety or welfare of the subject must also be reported to the reviewing IRB. Protocol
deviations may necessitate the discontinuation of the subject or the site from the study.
11.1 Data/Safety Monitoring & Quality Assurance Procedures: This study will be conducted in
accordance with Good Clinical Practice (GCP) and International Conference on
Harmonization (ICH) Guidelines, 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.
The investigators will permit regular monitoring, audits and site inspections by the IRB,
the sponsor, government regulatory bodies and any institution compliance and quality
assurance groups of all study related documents (e.g. medical records, source documents,
regulatory documents, data collection instruments, study data, etc.). The investigator will
ensure the capability for inspection of applicable study related facilities. Clinical trial
monitoring may be conducted to ensure compliance to this protocol.
11.2
Site Qualifications: Tactile Medical™may conduct onsite visits or telephone
qualification (pre-study audit) prior to study initiation to verify adequate
resources, staffing and a sufficient subject pool.
11.3
Data Collection Procedures: All data storage, transmission and management will
be conducted using the Research Electronic Data Capture (REDCap) tool.20
REDCap is a software toolset and workflow methodology for the secure
electronic collection and management of research data. REDCap servers are
housed in a data center located in a HIPAA-compliant environment at Vanderbilt
with nightly backups. All web-based information transmission is encrypted.
REDCap was developed specifically around HIPAA Security guidelines.
REDCap has been disseminated for local use at more than 940 other
academic/non-profit consortium partners in 75 countries. Vanderbilt leads the
REDCap Consortium, which currently supports more than 99,000 projects and
128,000 users. The toolset supports research studies with data management
reports, data integrity reports for data cleaning and evaluation, and tracking
reports for longitudinal studies. In the event REDCap is unavailable or the
patients prefers to use hard copy, hard copy data will be double entered into
REDCap.
Each study site will have a site coordinator who will be responsible for ensuring
the quality of all data collected at that site and ensuring that the data have been
entered into the central study database. All data collected via paper will be double
entered and verified by site staff. The raw data will be collected on study specific
source document worksheets and/or site specific documentation if REDCap is not
available, which includes but are not limited to, medical records and site
generated source worksheets.

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11.4
Clinical Site Monitoring: Clinical sites will be monitored for compliance with the
clinical protocol, investigator agreement, and applicable regulations. Regular
contact will be maintained to ensure:
x
Subject safety
x
That clinical site staff is well informed on regulations and sponsor
requirements.
x
That the clinical protocol is followed
x
That data is gathered in a complete and timely way
x
That problems with data or data collection are addressed appropriately and
in a timely manner
x
That AEs are properly reported in a timely manner
Investigator and Institution will permit trial related monitoring, audits, IRB
review, and regulatory inspection(s), providing supervised direct access to
medical records, source data and documents as appropriate. Monitoring will be
performed by Tactile Medical™and/or designee.
11.5
Reports and Records: Records to be maintained by the investigator in a designated
study file include:
x
Investigational plan and all amendments
x
Signed Investigator Agreement
x
IRB approval letter, including a copy of the approved consent forms,
progress reports, Adverse Event Report
x
IRB roster or Assurance number, if applicable
x
All correspondences relating to the conduct of this study between the site
and sponsor, IRBs, and study monitor
x
Curriculum Vitae and professional license for all study personnel, if
applicable
x
Site personnel signature and documentation regarding the Investigator’s
delegation of responsibility
x
Clinical Site Visit log
x
Protocol/device related training records for all applicable study personnel
x
Investigational device inventory information including the date, quantity
and serial number of all devices and received identification of all subjects
who received treatment, and final disposition of the devices.
x
Screening log
x
Reports (see Table 2)
The following records must be maintained for each subject enrolled:
x
Signed and dated informed consent forms
x
Completed CRFs, queries and source document worksheets (if applicable)
x
Complete medical records including procedure reports, lab reports (if
applicable), etc.

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Investigators are required to prepare and submit to the sponsor or its designees
complete accurate and timely reports on this investigation as required by
regulations. The types of reports to be submitted are summarized in Table 2.
Table 2: Investigator Reports
Reports
Submit To
Timeframe
Unanticipated
Adverse
Device Event
Sponsor and
Reviewing IRB
As soon as
possible but no 
later than 10
working days
Withdrawal of IRB
Approval
Sponsor
Within 5 working days
Progress
Sponsor and
Reviewing IRB
Annually, at a minimum
Final
Sponsor and
Reviewing IRB
Within 3 months following the
completion or termination of
the Investigator’s part
Subject study records, correspondence files, all supporting study documentation,
and reports must remain on file at the investigational site for a minimum of ten
years after the conclusion of this study. All investigators must contact Tactile
Medical™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™must be contacted if the 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.
11.6 Change to Study Plan:
Should changes in the study plan or protocol become necessary in the course of the
clinical trial, those specific changes will be discussed and agreed upon by the
Sponsor, its acting representative if appropriate, Investigator and appropriate IRB
approval obtained before the changes are implemented. All changes must be
documented.

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12.1 Statistical Methods and Determination of Sample Size
12.2 Data Management
Collection: All data will be collected using the Research Electronic Data Capture
(REDCap) tool.20 The sites will use hard copy source documents to collect all
physical measurements, assessment data, and subjects will complete self-reports
questionnaires only if REDCap is not available or patient prefer hard copy. Study
staff will keep all hard copies on site and in designated area with subject specific ID
numbers.
Storage: Source document forms will be stored in a secure area at each study site.
This will be accessible to study staff only and will be assigned a study ID number.
At the end of the study the documents will continued to be stored on site or moved
to a separate storage facility and held for the required duration.
Data Entry: Data will be added directly into REDCap when collected. If hard copies
are used data will be double entered from the source documents into REDCap as
soon as REDCap is available. The data will be reviewed for errors and data will be
cleaned prior to analysis. All staff at site will be trained by the sponsor, or designee,
or study PI on data collection procedures and protocol implementation.
12.3 Statistical Analysis Plan
Minimization of Bias: Stratified randomization to the study groupswithin each
study site will be conducted. Given that this is a wait list/control design, blinding is 
not possible. Each subject will be assigned a study ID number that will be used for
identification purposes in the data. The study statistician who will have no contact
with any study participants and will conduct all analyses.
Missing Data: Randomly missing item responses within the study survey measures
will be handled as specified by the measure developers. Nonrandom missing visit
data are informative for this study (i.e., may speak to feasibility) – no imputation
will be conducted.
Interim Analysis: Given that this is a feasibility study, no interim analyses will be
conducted. The primary reason for early stoppage would be adverse events.
Aims:
Primary Aim: To determine the feasibility of use of the Flexitouch® Head and
Neck Garment, specifically a) to evaluate implementation fidelity (adherence) and
barriers to implementation fidelity, b) to establish safety, and c) to assess
satisfaction.
Secondary Aim: To determine the preliminary efficacy of Flexitouch® Head and 
Neck Garment compared to a wait-list control for the following outcomes: a) 
reduction in swelling/inflammation, b) function (range of motion cervical, jaw, and 
shoulder), c) symptoms, and d) quality of life.

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12.4 Statistical Analyses:
Aim 1 (feasibility): Descriptive statistics (percentages) will be used to summarize
adherence to the protocol, barriers, adverse effects, and ratings of satisfaction.
Comparison of the rates observed within each of the study groups will be compared
using likelihood Chi-Square tests however it is expected that >=75% of the total
number of participants enrolled in the study as a whole will complete the study. At
the end of the study, it is expected that participants in the investigational group will
report acceptable levels of satisfaction with the device, as indicated by 80% rating
the satisfaction items above neutral.
Aim 2 (preliminary efficacy): Descriptive and graphical summaries of the measures
at each time of assessment will summarize the overall and group changes in each of
the outcome measures over the 8-week study period for each of the groups. Mixed
effects general linear models will be used to generate estimates of the interactive
effect of the Flexitouch® Head and Neck Garment and time in the study on the
primary outcomes. Such an interaction effect would be indicate, for example, larger
reduction in symptoms for the intervention group than that observed in the wait list
control over the same time period. Bias-corrected effect sizes of garment use on the
respective changes will be generated from each of the outcomes. While this study is
a preliminary study of efficacy and effect sizes, a maximum alpha level of .05 will
be used for statements of “statistical” significance.
Safety Analysis: During the time any participant is using the device, safety checks
(Adverse Evetns-CTCAEV4.0, B/P, Pulse, and staging) will be made at defined
intervals as noted in section 7.3.
Determination of Sample Size: The primary rationale for study size is the proposed
funded time of this study and the number of potential subjects that could be
recruited during that time. This is not a hypothesis testing study rather it is a
preliminary feasibility and efficacy study for generating observed effect sizes.
Nevertheless, samples of 20 individuals in each group (total=40) who successfully
complete the 8-week protocol will provide 80% statistical power to detect a
differential level of change of approximately 0.9SD (effect size). In other words,
assuming a baseline Neck Disability Index (NDI) of 20 (SD=10) and that the wait-
list control group demonstrates no change from baseline, a reduction in mean NDI
to 11 in the garment group would indicate a statistically significant difference (2-
sided alpha-0.05). We have no evidence to hypothesize differences of that
magnitude however; we do believe that our sample size will provide sufficient data
for estimating reasonable effect estimates for future studies.
13.0 Compensation:
Subjects may be compensated for time and travel at an amount determined by each site.

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14.0 Publication Plan:
All information obtained during the conduct of the study will be considered to be
confidential and is property of Tactile Medical™. Written permission from Tactile
Medical™is required before disclosing any information relative to this study. All
publications (e.g. manuscripts, abstracts, and slide presentations) based on this study must
be submitted to Tactile Medical™for corporate review and approval before submission or
according to the individual site clinical trial agreement.
15.1 References
1. Smith, B.G. and J.S. Lewin, Lymphedema management in head and neck cancer. Curr
Opin Otolaryngol Head Neck Surg, 2010. 18(3): p. 153-8.
2. Ridner, Sheila, et al., A Prospective Study of the Lymphedema and Fibrosis Continuum
in Patients with Head and Neck Cancer. Lymphatic Research and Biology Volume 14,
Number 4, 2016 p. 1.
3. Deng, J., et al., Preliminary development of a lymphedema symptom assessment scale for
patients with head and neck cancer. Support Care Cancer, 2012. 20(8): p. 1911-8.
4. Deng, J., et al., Prevalence of secondary lymphedema in patients with head and neck
cancer. J Pain Symptom Manage, 2012. 43(2): p. 244-52.
5. Avraham, T., et al., Radiation therapy causes loss of dermal lymphatic vessels and
interferes with lymphatic function by TGF-beta1-mediated tissue fibrosis. Am J Physiol
Cell Physiol, 2010. 299(3): p. C589-605.
6. Satapathy, A.K., et al., Human bancroftian filariasis: immunological markers of
morbidity and infection. Microbes Infect, 2006. 8(9-10): p. 2414-23.
7. Brush J., et al., Molecular mechanisms of late normal tissue injury. Semin Radiat Oncol.,
2007. 17(2): p. 121-30.
8. Delanian S., and J.L. Lefaix, Current management for late normal tissue injury:
radiation-induced fibrosis and necrosis. Semin Radiat Oncol., 2007. 17(2): p. 99-107.
9. Rubin P., et al., A perpetual cascade of cytokines postirradiation leads to pulmonary
fibrosis. Int J Radiat Oncol Biol Phys., 1995. 33(1): p. 99-109.
10. Földi E., et al., Effect of complex decongestive physiotherapy on gene expression for the
inflammatory response in peripheral lymphedema. Lymphology, 2000. 33(1): p. 19-23.
11. Common Terminology Criteria for Adverse Events, Version 4.03 (CTCAE v4.03) June
14, 2010.
12. Patterson, J.M., et al., Measuring edema in irradiated head and neck cancer patients.
Annals of Otology, Rhinology and Laryngology, 2007. 116(8): p. 559-564.
13. Deng, J., et al., Preliminary evaluation of reliability and validity of head and neck
external lymphedema and fibrosis assessment criteria. European Journal of Oncology
Nursing, 2016. Jun (22): p. 63-70.
14. Vernon H. and S. Mior, The Neck Disability Index: a study of reliability and validity. J
Manipulative Physiol Ther., 1991. 14(7): p. 409-15.
15. Hains, F., et al., Psychometric properties of the neck disability index. J Manipulative
Physiol Ther., 1998. 21(2): p. 75-80.
16. Jacobson, B.H., et al., The Voice Handicap Index (VHI): Development and Validation.
American Journal of Speech-Language Pathology, 1997. 6(3): p. 66-69.
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
17. . Murphy, B. A., Dietrich, M. S., Wells, N., Dwyer, K., Ridner, S. H., Silver, H.
J., Gilbert, J., Chung, C. H., Cmelak, A., Burkey, B., Yarborough, W. G., Sinard, R.,

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Netterville, J. (Jan 2010). Reliability and validity for the Vanderbilt Head and Neck
Symptom Survey (VHNSS): A new tool to assess symptom burden in patients undergoing
chemoradiation. Head and Neck, 32(1), 26-37.
18. Ridner, S.H., and M.S. Dietrich, Development and Validation of the Lymphedema
System and Intensity Survey-Arm. Support Care Cancer, 2015. Oct 23(10): p. 3103-12.
19. Locke D.E., et al., Validation of single-item linear analog scale assessment of quality of
life in neuro-oncology patients. J Pain Symptom Manage, 2007. 34(6): p. 628–638.
20. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic
data capture (REDCap)—A metadata-driven methodology and workflow process for
providing translational research informatics support. J Biomed Inf. 2009;42(2):377-381.