Clinical trial NCT02946021
Conditions: Head and Neck Neoplasms Head and Neck Lymphedema Head and Neck Cancer
Keywords: Lymphedema Cancer Head Cancer Neck Cancer
Sponsor: Tactile Medical
Start date: 2016-10-01; Completion date: 2018-02-01
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Assessment of lymphatic structure and function pre- and post- treatment and during recovery in head and neck cancer related lymphedema patients using NIR fluorescence lymphatic imaging: Response to ICD therapy in HNC Patients.

Detailed description:
A non-randomized, non-blinded, single site pilot study designed to assess whether near-infrared fluorescence imaging can report on the efficacy of a pneumatic compression device to move lymph in head and neck cancer survivors with resulting head and neck lymphedema.

Arms: arm 1: Head and neck garments for pneumatic compression device for treatment of lymphedema (1 session per day) with imaging using NIRFLI with ICG (Indocyanine green). arm 2: Head and neck garments for pneumatic compression device for treatment of lymphedema (2 sessions per day) with imaging using NIRFLI with ICG (Indocyanine green).
Interventions: intervention 1: Head and neck garments for pneumatic compression device intervention 2: NIRFLI with ICG
Intervention descriptions: intervention 1: Pneumatic compression device cleared for use by patients who are under medical supervision for the treatment of 1) lymphedema (primary or secondary); 2) edema resulting from mastectomies, trauma, sports injuries or post immobilization; 3) venous insufficiencies; 4) wounds; and 5) stasis dermatitis, venous stasis ulcers, arterial leg ulcers and diabetic foot ulcers and treatment of head and neck lymphedema intervention 2: Near-infrared Fluorescence Lymphatic Imaging following the off-label use of Indocyanine Green as a lymph contrast agent and the use of a custom designed fluorescence imager to dynamically follow lymphatic movement in subjects.

Protocol documents:
Prot_SAP_000.pdf: 
HSC-MS-16-0465, version 1.10
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Protocol Title:
Near-infrared fluorescence lymphatic imaging to assess improved lymphatic 
drainage in head and neck cancer survivors after a single- use and two weeks 
use of the Flexitouch Head and Neck System
Protocol Number and 
Version
HSC-MS-16-0465; Version 1.10
Principal Investigator:
John C. Rasmussen, PhD
Co-Investigators:
Eva M. Sevick-Muraca, PhD; Ron J. Karni, MD; Carolina Gutierrez, MD
Study Coordinator:
John R. Morrow
Sponsor:
Tactile™ Medical
Population:
A total of ten (10) subjects who complete both, over the age of 18, from the 
patient population at UT Physician’s Otorhinolaryngology Outpatient Clinic 
who have undergone surgery and/or radiation therapy for treatment of 
cancer of the head and/or neck
Number of Sites:
Single site: UT Physician’s Otorhinolaryngology Outpatient Clinic
Study Duration:
Three (3) months
Subject Duration:
Twenty-four (24) hours over Two (2) weeks
1.0
General Information 
There were nearly 62,000 new head and neck cancer (HNC) cases last year accounting for 3% of all 
cancers in the US (1) with an increasing incidence among younger adults due to the human 
papillomavirus (HPV) infection.  Treatment is typically surgical resection of primary lesions and 
extensive lymph node (LN) dissection, followed by fractionated radiation therapy (RT).  Because 
the neck and cervical region contains 1/3 of the body’s LNs (2) surgical disruption of the lymphatic 
vasculature and LNs together with subsequent RT of the head and neck region results in the 
debilitating condition of lymphedema and extensive fibrosis in an estimated 75% of all HNC 
survivors (3, 4). Although the cure rate of these patients is high with extensive LN dissection and 
RT, the debilitating effects of this treatment significantly reduces the quality of survivorship. HNC 
lymphedema can have a profound effect on the range of motion, swallowing, and evening 
breathing.   
Unlike breast cancer where a 10% increase in arm volume is used for diagnosis of lymphedema, 
there is no accepted objective measurement to base the diagnosis of HNC lymphedema.  Weight 
loss and extensive surgery can mask the early signs of edema and lymphedema. As a result, HNC 
patients/survivors are not screened for lymphedema and early treatment of manual lymphatic 
drainage to move accumulated tissue fluid and prevent irreversible tissue changes is typically not 
offered to HNC cancer survivors.   
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2.0
Background Information  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
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3.0
Objectives 
The primary objective of the pilot study is to use NIRF imaging to assess whether pneumatic 
compression can move lymph in HN cancer patients and survivors.  The secondary objectives are 
to assess whether compliant use over a two week period can reverse or reduce the dermal 
backflow that is associated with HN lymphedema and to collect patient feedback on the ease of 
use and perception of symptom alleviation with the Flexitouch System and associated head and 
neck garments after two weeks of daily home use. 
The Flexitouch System and associated garments for extremities and trunk are approved for use by 
patients who are under medical supervision for the treatment of 1) lymphedema (primary or 
secondary); 2) edema resulting from mastectomies, trauma, sports injuries or post immobilization; 
3) venous insufficiencies; 4) wounds and 5) stasis dermatitis, venous stasis ulcers, arterial leg 
ulcers and diabetic leg ulcers.  The variety of garments and accessories available with the 
Flexitouch system are designed to provide targeted compression therapy to different areas of the 
body. Tactile MedicalTM secured FDA clearance via the 510(k) program to market their newly 
designed head and vest garments and Flexitouch Treatment Program H1 (Appendix A, p14). When 
the head garment and vest garment are used together, the resulting compression directs fluid 
from the head to the axilla in one continuous motion, presumably moving fluid from the head and 
neck region into the axilla for uptake into the regional lymphatic. 
We will assess whether the Flexitouch System can move lymph from the region by using NIRF 
imaging before and after treatment with the Flexitouch system, as well as, after 2 weeks of 
compliant home use.  We will assess whether Flexitouch usage is associated with alleviation of 
lymphedema symptoms.
4.0
Study Design 
A non-randomized, non-blinded, single site pilot study designed to assess whether NIRF imaging 
can report on the efficacy of the Flexitouch System used to move lymph in HNC survivors.   
Specifically, we will assess whether the Flexitouch System can move lymph from the region by 
using NIRF imaging before and after treatment with the Flexitouch system, as well as, after 2 
weeks of compliant home use.  Participation will require approximately 24 hours over 2 weeks.  
Enrollment is targeted to be completed within 3 months. 
Assessment of efficacy and safety 
 
 
 
 
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The Flexitouch System, when used for upper and lower extremity lymphedema is a standard-of-
care PCD treatment device used routinely in the clinic and for at-home use.  In this study, we seek 
to deploy NIRF imaging to assess the efficacy of the Flexitouch system for moving lymph in HNC 
survivors and to assess whether this correlates with symptom alleviation.  
 
 
 
 
5.0
Study Population
5.1
Inclusion Criteria
1) Participants must be 18 years of age or older
2) Participants must be diagnosed with Lymphedema of the Head and/or Neck
3) Participants must be diagnosed with squamous cell carcinoma of the oral cavity, 
oropharynx or larynx and underwent surgery and/or radiation as part of their standard-
of-care treatment plan.
4) Participants must be ≥ 4 weeks post-radiation therapy
5) Female participants of childbearing potential must have a negative urine pregnancy test 
≤ 36 hours prior to study drug administration
6) Female participants of childbearing potential must agree to use a medically accepted 
method of contraception for a period of one month after each imaging session
7) Participants must be willing to use the Flexitouch® System at home daily for two (2) 
weeks
5.2
Exclusion Criteria
1) Women who are pregnant or breast-feeding
2) Persons who are allergic to iodine
3) A female of child-bearing potential, who does not agree to use an approved 
contraceptive for one month after study participation
4) Persons who do not meet inclusion criteria
5) Persons with pulmonary edema, thrombophlebitis, congestive heart failure, deep vein 
thrombosis, episodes of pulmonary embolism, infections and inflammation, or acute 
cancer
6) Persons with uncontrolled hyperthyroidism or parathyroidism (for with an 
endocrinologist recommends against neck compression)
7) Carotid sinus hypersensitivity syndrome
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8)  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)
9) Symptomatic bradycardia in the absence of a pacemaker
10) Internal jugular venous thrombosis, acute or within 3 months
11) Known intracranial pressure or other contraindication to internal or external jugular 
venous compression
12) Acute radiation dermatitis, unhealed surgical scar, unhealed or open wound(s), 
surgical flap less than 6-8 weeks post-operative
13) Facial or head and neck dermal metastasis
14) Acute facial infection (e.g., facial or parotid gland abscess)
15) Any condition where increased venous and lymphatic return is undesirable
5.3
Risks/Discomforts
Near-infrared fluorescence lymphatic imaging
 
 
 
 
 
 
 
 
 
 
 
 
 
Flexitouch® Advance Pneumatic Compression System
Participants enrolled in the sub-study are not expected to be at any higher or additional 
risk than those who use non-study pneumatic compression devices (PCD), or static 
compression garments approved for use in head and neck region since pressures do not 
exceed the pressures of static compression garments. There is risk associated with using 
any PCD.  These risks include, but are not limited to, risk of explosion if the device is used in 
the presence of flammable gases, risk of electrical shock if the device is immersed in water, 
or it the housing is broken and subject attempts to service the unit.
5.4
Potential Benefits
While there is no guarantee of a direct benefit to participants, there is a possible benefit of 
improved lymphatic function and decreased edema with use of the Flexitouch system. 
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5.5
Cost/Payment
 
 
 
 
 
 
 
6.0
Sample Size/Data Analysis/Subject Withdrawal and Replacement
In this pilot sub-study of a total of ten patients who complete both study visits, we will assess 
whether there are any changes to lymphatic function after a single use of the pneumatic 
compression device and after a two week period of daily home use.   Five patients will undergo 
daily ICD of approximately 32 minutes while another five patients will undergo daily ICD of 
approximately 60 minutes in order to assess the effect of duration on response to therapy.  If, 
after the initial consent and imaging session are completed, a subject withdraws, opts not to 
complete the daily home therapy (<75% of total treatments), OR does not properly use the device 
as instructed, they may be dropped from the study cohort and a replacement subject may be 
enrolled to ensure a full cohort of 10 subjects completes the study.
 
 
 
 
 
 
 
 
  
  
Because this is a pilot study, we cannot statistically power the study for conclusions.  Instead we 
will assess results to visualize trends for a subsequent properly powered study to statistically test 
the hypothesis that the Flexitouch system can restore lymphatic function.   
7.0
Study Procedures 
The sub-study consists of two NIRF lymphatic imaging sessions (see Section below for NIRF 
procedure) separated by approximately two (2) weeks. At each session, measurements of the 
subject’s head and neck will be recorded and 3D images and/or digital photographs will be taken 
before and after treatment. Participants will don the head and neck and vest garments before 
undergoing Treatment Program H1 with the Flexitouch System.  Imaging with NIRFLI system will 
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occur before, during and after treatment with the Flexitouch System. The first NIRF lymphatic 
imaging session will establish the presence of lymphatic dysfunction as visualized with the NIRFLI 
System.  The subject will be loaned the Flexitouch® Advanced Pneumatic Compression system 
along with the Head Garment and Vest for Head & Neck.  The subjects will be instructed in the 
proper fitting of the garments and the use of the Flexitouch system.  The subjects will complete 
the Flexitouch Treatment Program H1 (~30-40 minutes or ~60 minutes) daily for approximately 
two (2) weeks. Participants will be asked to keep a diary of their daily use on the Flexitouch 
System.  After approximately two (2) weeks of daily use, the subject will return for the second and 
final NIRF lymphatic imaging session, at which time they will return the Flexitouch System and 
associated garments to the research team.  Subjects will then be asked a series of questions 
related to the ease of use of the Flexitouch System and their perception of the treatment they 
received while using the Flexitouch System.   
NIRF Lymphatic Imaging
 
 
  
  
 
 
 
 
 
  
 
  
8.0
Data and Safety Monitoring 
The Principal Investigator will be responsible for the monitoring of study data and subject safety.  
Due to the small number of research subjects, the most comprehensive and effective method of 
monitoring will be an individual case review by the PI (Eva M. Sevick-Muraca, PhD) and  clinical 
investigators (Ron J. Karni, MD; Erik A. Maus, MD; and physician designates). As this has always 
been the policy of the PI, the researchers and study team are under specific instructions to make 
the PI aware of all adverse events, expected or unexpected; therefore, the responsibility for 
reporting adverse events is shared with the PI and the research team.
Case Report Forms (CRFs) containing all monitoring information will be completed by the PI, 
clinical investigator(s) or designee and reviewed by the PI and clinical investigator(s).  Case report 
forms (CRFs) will be kept in a locked office or archive. 
 
 
 
 
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9.0
Statistics 
In this pilot sub-study we will assess whether there are any changes to lymphatic function after a 
single use of the pneumatic compression device and after a two week period of compliant use.  
 
 
 
 
 
 
 
  Specifically, we seek to determine the change in the percentage of area that 
is demarked by dermal backflow in response to the Flexitouch System use after a single session 
and after two seeks of compliant use.  
  
Because this is a pilot study, we cannot statistically power the study for conclusions.  Instead we 
will assess results to visualize trends for a subsequent properly powered study to statistically test 
the hypothesis that the Flexitouch system can reduce dermal backflow and restore lymphatic 
function.  
10.0 Ethics
This sub-study will be submitted to the local IRB, the Committee for the Protection of Human 
Subjects (CPHS), for approval to begin research and study oversight.  
Informed consent will be conducted by a member of the research team.  When possible, a copy of 
the consent will be provided to the study candidate prior to the clinic visit.  At the first clinic visit, 
a private room will be used to review the consent with the candidate and to answer any questions 
or concerns they may have regarding participation in the research study.   
11.0 Data handling and record keeping
Physical records related to the study are kept in a secure location, with controlled access.  
Electronic records are maintained on a secure server, behind a firewall, with restricted access by 
username and password.  A study specific identifying will be assigned to each participants in lieu 
of personal identifiers.  
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12.0 Quality control and assurance
This study will be conducted in accordance with Good Clinical Practice (GCP) and International 
Conference on Harmonization (ICH) Guidelines, Code of Federal Regulations (CFR), state and local 
guidelines and institutional research policies and procedures to ensure subject safety and quality 
of data.
Raw data will be collected on the appropriate source document worksheets.  Data collected in the 
source will be transcribed by the research staff onto paper Case Report Forms (CRFs).
12.1
Product Release Information
Product release information for ICG will be maintained by the manufacturer.
12.2
Accountability of Test Products
Indocyanine Green (ICG)
A record of lot number and expiration date will be maintained for ICG used in this study. 
Near-infrared fluorescence lymphatic imaging (NIRFLI)
 
 
Flexitouch® Advanced Pneumatic Compression System
Site personnel must maintain a device accountability log.  Completion of this log will ensure 
that all Flexitouch® Advance Pneumatic Compression pumps and garments are properly 
tracked and accounted for throughout the study, from the time they are received by the 
research team to the time they are returned to Tactile Medical. Device location, subject ID 
assigned, date and final disposition (e.g. return to Tactile Medical, garment discarded, etc.) 
of all control units and garments will be documented.
12.3
Protocol Modifications / Deviations
Protocol amendments will be submitted to the UTHSC-H CPHS (IRB) for approval prior to 
implementation.  Protocol deviations will be acknowledged according to UTHSC-H CPHS 
policies, including electronic notification through the iRIS system at UTHSC-H.  Exceptions 
to the protocol will be approved by the UTHSC-H CPHS prior to implementation.
12.4
Subject Compliance
Flexitouch® Advanced Pneumatic Compression System
Subject compliance will be evaluated through a daily diary completed by each subject.
13.0 Publication Plan
All information obtained in this study may be used for publications, presentations and conferences 
of a medical or scientific nature. All patient identifiers will be removed before data is disseminated 
in presentations and publications and any image will be de-identified to the greatest extent 
possible.
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14.0 Key Roles
Sponsor Contact: 
 
Principal Investigator:
 
Co-Investigator:
 
Clinical Investigator(s):
 
 
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Study Monitor(s):
 
15.0 References
1.
Society, A.C. 2016. Cancer Facts and Figures 2016. Atlanta: American Cancer Society.
2.
Foldi, M.a.F., E.,. 2006. Textbook of Lymphology for Physicians and Lymphedema Therapists.: 
Elsevier,Urban&FischerVerlag.
3.
Deng, J., Ridner, S.H., Murphy, B.A., and Dietrich, M.S. 2012. Preliminary development of a 
lymphedema symptom assessment scale for patients with head and neck cancer. Support Care 
Cancer 20:1911-1918.
4.
Deng, J., Ridner, S.H., Aulino, J.M., and Murphy, B.A. 2015. Assessment and measurement of 
head and neck lymphedema: state-of-the-science and future directions. Oral Oncol 51:431-437.
5.
Rasmussen, J.C., Tan, I.C., Marshall, M.V., Adams, K.E., Kwon, S., Fife, C.E., Maus, E.A., Smith, 
L.A., Covington, K.R., and Sevick-Muraca, E.M. 2010. Human Lymphatic Architecture and 
Dynamic Transport Imaged Using Near-infrared Fluorescence. Transl Oncol 3:362-372.
6.
Adams, K.E., Rasmussen, J.C., Darne, C., Tan, I.C., Aldrich, M.B., Marshall, M.V., Fife, C.E., Maus, 
E.A., Smith, L.A., Guilloid, R., et al. 2010. Direct evidence of lymphatic function improvement 
after advanced pneumatic compression device treatment of lymphedema. Biomed Opt Express 
1:114-125.
7.
Rasmussen, J.C., Aldrich, M.B., Tan, I.C., Darne, C., Zhu, B., O'Donnell, T.F., Jr., Fife, C.E., and 
Sevick-Muraca, E.M. 2016. Lymphatic transport in patients with chronic venous insufficiency and 
venous leg ulcers following sequential pneumatic compression. J Vasc Surg Venous Lymphat 
Disord 4:9-17.
16.0 Attachments
Appendix A: Flexitouch User’s Guide
IRB NUMBER: HSC-MS-16-0465
IRB APPROVAL DATE: 12/04/2017