An Investigator-initiated Study Assessing the Effect of Intermittent Pneumatic Compression (IPC) on Symptoms and Quality of Life in Women With Lipo-lymphedema (Lipedema With Swelling)
Phase: NA
Conditions: Lipedema, Lipolymphedema
Sponsor: Thomas Wright, MD

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 1 of 38 
 
 
 
 
 
 
 
An investigator-initiated study assessing the effect of 
intermittent pneumatic compression (IPC) on symptoms and 
quality of life in women with lipo-lymphedema (lipedema with 
swelling) 
 
 
 
 
Protocol Number: 1000 
 
 
December 11, 2020 
Protocol Version 2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 2 of 38 
 
 
 
 
 
TABLE OF CONTENTS 
1.0 
Contact Information ............................................................................................................. 4 
1.1 
Sponsor and Principal Investigator Contact Information ............................................. 4 
2.0 
Introduction .......................................................................................................................... 4 
2.1 
Background and Rationale............................................................................................ 4 
2.2 
Ethics ............................................................................................................................ 5 
2.3 
Device Description ....................................................................................................... 5 
3.0 
Study Objective .................................................................................................................... 6 
4.0 
Study Design ........................................................................................................................ 6 
4.1 
Endpoint Mapping ........................................................................................................ 7 
4.2 
Subject Selection .......................................................................................................... 8 
4.3 
Point of Enrollment ...................................................................................................... 9 
4.4 
Treatment Assignment and Duration ............................................................................ 9 
4.5 
Study Timeline ............................................................................................................. 9 
5.0 
Study Assessment ................................................................................................................ 9 
6.0 
Study Procedures ............................................................................................................... 10 
6.1 
Informed Consent ....................................................................................................... 10 
6.2 
Demographics & Medical History .............................................................................. 10 
6.3 
Laboratory Testing ..................................................................................................... 11 
6.4 
Vital Signs .................................................................................................................. 11 
6.5 
Randomization ............................................................................................................ 11 
6.6 
InBody 770 Bioimpedance Measurements ................................................................. 11 
6.7 
Circumferential Measurements................................................................................... 13 
6.8 
Physical Exam ............................................................................................................ 14 
6.9 
QOL, Symptoms, Mobility & Pain Assessments ....................................................... 15 
6.10 
Treatment .................................................................................................................... 16 
6.11 
Adverse Events, Device Observations, & Complications .......................................... 16 
7.0 
Subject Discontinuation or Exit ......................................................................................... 18 
7.1 
Early Discontinuation ................................................................................................. 18 
7.2 
Study Exit ................................................................................................................... 19 
8.0 
Risk Analysis and Adverse Events .................................................................................... 19 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 3 of 38 
 
8.1 
Treatment Risks .......................................................................................................... 19 
8.2 
Procedure Risks .......................................................................................................... 19 
8.3 
Risk Mitigation ........................................................................................................... 19 
8.4 
Potential Benefits ........................................................................................................ 20 
9.0 
Provisions to Protect the Privacy of Study Participants/Information Security Plan .......... 20 
10.0  Deviation from Study Plan................................................................................................. 20 
11.0  Quality Assurance Procedures ........................................................................................... 20 
11.1 
Data Safety Monitoring .............................................................................................. 20 
11.2 
Reports and Records ................................................................................................... 21 
12.1 
Change to Investigational Plan ................................................................................... 22 
13.0  Statistical Methods ............................................................................................................. 22 
13.1 
Sample Size Determination ........................................................................................ 22 
13.2 
Statistical Analysis ..................................................................................................... 22 
14.0  Publication Plan ................................................................................................................. 23 
15.0  References .......................................................................................................................... 23 
 
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 4 of 38 
 
1.0 
Contact Information 
1.1 
Sponsor and Principal Investigator Contact Information 
Thomas Wright, MD, FACPh, FACP, RVT 
Laser Lipo and Vein Center 
1630 Market Center Boulevard, Suite 201  
O'Fallon, MO 63368  
Phone: 636-397-4012  
twrightmd2004@gmail.com  
2.0 
Introduction 
2.1 
Background and Rationale  
Lipedema is a connective tissue disorder that affects up to 10% of women. It is 
characterized by painful, swollen subcutaneous tissue and disproportionate fat 
accumulation (primarily in the lower limbs, however it can spread to the abdomen 
and arms). Patients are often not aware they are affected by this disease; rather, they 
think they are just overweight or obese.    
Patients with lipedema often feel frustrated and uncomfortable as symptoms such as 
heaviness, pain, and easy bruising impact quality of life. Affected limbs can 
become so large and heavy that daily tasks such as walking, cleaning, or shopping 
become impossible.  
Lipedema is a progressive disease. There are currently 3 primary stages that 
describe disease severity: stage 1 involves thickening of subcutaneous tissue and 
disproportion accumulation of subcutaneous tissue in the extremities (tissue 
remains smooth and is generally not heavy or swollen), stage 2 is characterized by 
increased fibrous tissue, leading to a nodular feel in the subcutaneous tissue which 
results in increased swelling and tenderness of the affected areas, stage 3 involves 
progression to the formation of lobules of skin and subcutaneous tissue.  
Symptomatic lipedema patients at stage 2 and higher almost always have secondary 
swelling on physical exam. This swelling results from the fat on the legs, thighs, 
and ankles blocking transport of lymphatic fluid; which ultimately may lead to 
infection. This lipo-lymphedema (or lipedema with swelling) is a secondary 
lymphedema, much like veno-lymphedema, and can be easily distinguished from 
primary lymphedema as it spares the hands and feet.  
There is currently no cure for lipedema, thus treatment focuses on symptom 
management and improved patient-reported outcomes. At present, the two main 
courses of treatment include non-surgical conservative treatment (e.g., 
Comprehensive Decongestive Therapy (CDT), diet, exercise, 
emotional/psychological/social support) and lymph-sparing liposuction performed 
by a surgeon trained in lipedema treatment. The primary goals for treatment 
include: reduction/elimination of inflammation, swelling, and pain; increase in 
lymphatic flow, which reduces/eliminates excessive fluid and swelling; overall 
management of the physical impact of lipedema; and quality of life improvements 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 5 of 38 
 
which can include emotional, psychological/mental, spiritual, and social 
enhancement in addition to physical management. 
Intermittent Pneumatic Compression (IPC) devices are often used as home-therapy 
to treat secondary lymphedema or lipo-lymphedema (lipedema with swelling) and 
may be helpful in preventing the progression of lipedema. IPC use moves lymphatic 
fluid and supports the elimination of proteinaceous fluids, thus leading to improved 
patient-reported symptoms, decreased limb girth and volume, increased elasticity of 
tissues, and fewer episodes of infection (1-3). Szolnoky reported daily treatment 
with CDT, IPC, and multilayered short-stretch bandaging performed for 5 days led 
to significant improvements in leg volume, capillary fragility, and pain in women 
with lipedema (4). 
The purpose of this study is to assess whether 3-4 weeks of IPC usage is associated 
with alleviation of symptoms and improvement in quality of life in women with 
lipo-lymphedema (lipedema with swelling).  
2.2 
Ethics 
This study will be submitted to a central IRB 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. 
2.3 
Device Description  
2.3.1 Flexitouch Plus 
The Flexitouch Plus (Tactile Medical™, Minneapolis, MN, USA) is a 
segmental, programmable, gradient advanced pneumatic compression 
device cleared for market in the USA (K170216, HCPCS code E0652). The 
device stimulates the lymphatic system by directing and moving excess fluid 
from an impaired lymphatic region to healthy regions where fluid can be 
absorbed and processed naturally by the body.  
The system consists of two primary components: a controller unit and 
garments. The controller unit has connector outlets for garment hoses to 
plug into such that air can pass through the hoses and deliver treatment 
through sequential inflation and deflation of air chambers within the 
garments. The garments are constructed of nylon and have 27-32 chambers, 
depending upon garment size. The pressure setting is variable between 
“decreased,” “normal,” and “increased.”  
The device is intended to provide in-home Manual Lymphatic Drainage 
(MLD) therapy for approximately 1 hour treatment duration. Indications for 
use include lymphedema, primary lymphedema, post-mastectomy edema, 
edema following trauma and sports injuries, post immobilization edema, 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 6 of 38 
 
venous insufficiency, reducing wound healing time, and treatment and 
assistance in healing stasis dermatitis, venous stasis ulcers, or arterial and 
diabetic leg ulcers.  
2.3.2 Conservative Care 
Standard care for patients under the Principal Investigator’s care includes 
30-40 mmHg graduated compression up to waist, dietary counseling, 
exercise, and a referral for Complete Decongestive Therapy (CDT). Based 
on each patient’s situation (e.g., insurance coverage, willingness/ability to 
independently comply with care, time constraints, etc.), some or all of these 
recommendations are typically followed. In this “real-world” study, no 
attempt is being made to control what will or won’t be used in terms of 
conservative care since it varies in clinic practice for each patient.  
3.0 
Study Objective 
The primary objective of the study is to assess the effectiveness of bilateral Flexitouch Plus 
use with conservative care based upon:                                                                                                            
 Circumferential measurements at ankle, mid-calf, lower thigh, upper thigh, hip, 
and waist,  
 Quality of life (RAND 36-Item Health Survey 1.0), and  
 Patient-reported symptoms and pain intensity (PROMIS Pain Interference – 
Short Form 6b, Wong-Baker Faces Scale, and the NIH Toolbox numerical 
rating scale (NRS)). 
Exploratory endpoints include:                                                                                                                        
 Mobility (PROMIS Mobility v2.0), and 
 Bioimpedance measurements (Whole Body and Segmental Extracellular 
Water/Total Body Water (ECW/TBW) ratios using InBody 770). 
 Comparing all objectives and endpoints between treatment groups. 
4.0 
Study Design 
This is a prospective, randomized, two-arm study comparing Flexitouch Plus with 
conservative care to conservative care alone (Figure 1). This post-market study involves on 
label use of the Flexitouch Plus device given eligible patients must have concurrent 
diagnosis with lymphedema (as noted by Stage 2/3 lipedema with presence of secondary 
swelling upon physical exam) and obtain the device through normal commercial means 
(self-pay, patient assistance, or insurance programs).   
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 7 of 38 
 
   
 Figure 1. Study Design 
 
 
4.1 
Endpoint Mapping 
Endpoint 
Outcome Measure 
Analysis 
Primary 
 
 Circumferential 
Measurements 
 Calculate percent reduction at 
Follow-up compared to 
Baseline for 6 sites on each 
leg as well as a composite 
total. 
Primary 
 
 Quality of Life 
 Compare Follow-up RAND 
SF36 score to Baseline.1 
Primary 
 
 Symptoms & Pain 
Intensity 
 Compare Follow-up PROMIS 
Pain Interference2, Wong-
Baker Faces Scale, and the 
NIH Toolbox numerical 
rating scale (NRS) scores to 
Baseline. 
Exploratory 
 
 Mobility 
 Compare Follow-up PROMIS 
Mobility score to Baseline.2  
 
1 https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html 
 
2 http://www.healthmeasures.net/index.php?option=com_instruments&task=Search.pagination&Itemid=992 
Follow‐up Clinic 
Visit (4‐12 
weeks)
Baseline Clinic 
Visit (Day 0)
Consent
Assess Eligibility via Medical History and Physical Exam
Complete Measurements & PROs
Randomize
FT Plus + Conservative 
Care
(N=15)
Complete 
Measurements/PROs 
after 4‐12 weeks of 
treatment 
Conservative Care
(N=15)
Complete 
Measurements/PROs 
after 4‐12 weeks of 
treatment 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 8 of 38 
 
Endpoint 
Outcome Measure 
Analysis 
Exploratory 
 Bioimpedance 
Measurements 
 Calculate mean reduction at 
Follow-up compared to 
Baseline for the Segmental 
(Right/Left Arm/Leg, Trunk) 
and Whole Body 
Extracellular Water 
(ECW)/Total Body Water 
(TBW) ratios. 
4.2 
Subject Selection 
The target population includes patients who have bilateral lipedema, meet the 
criteria listed below, and have provided informed consent.  
4.2.1 Inclusion Criteria: 
1. Female age 18-70 years. 
2. Stage 2-3 (Schmeller Type 2-3) lipedema with secondary 
lymphedema. 
3. Willing and able to follow prescribed care for study period. 
4. Able to access (via self-pay, patient assistance, or insurance 
programs) prescribed care within 60 days of Baseline visit.  
4.2.2 Exclusion Criteria: 
1. BMI > 50. 
2. Heart failure (acute pulmonary edema, decompensated acute heart 
failure). 
3. Pacemaker or implantable cardioverter defibrillator (ICD). 
4. Acute venous disease (acute thrombophlebitis, acute deep venous 
thrombosis, acute pulmonary embolism). 
5. Severe peripheral artery disease (critical limb ischemia including 
ischemic rest pain, arterial wounds, or gangrene). 
6. Active skin or limb infection/inflammatory disease (acute 
cellulitis, other uncontrolled skin or untreated inflammatory skin 
disease) on the arms or trunk. 
7. Active cancer (cancer that is currently under treatment, but not yet 
in remission). 
8. Poorly controlled kidney disease (glomerular filtration rate < 30 
mls per minute), hypoproteinemia, pulmonary hypertension, 
hypothyroidism, cyclic edema, or Munchausen Syndrome. 
9. Any circumstance where increased lymphatic or venous return is 
undesirable. 
 
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 9 of 38 
 
10. Currently pregnant or trying to become pregnant. 
4.3 
Point of Enrollment  
Subjects will be considered enrolled in the study once the Informed Consent Form 
is signed and eligibility criteria are met. The investigator will keep a record, or 
subject screening log, of subjects who enter screening. Any subjects who do not 
meet inclusion/exclusion criteria will be considered screen failures. 
4.4 
Treatment Assignment and Duration 
Eligible patients will be randomized (1:1) using sealed envelopes to one of the 
following treatment cohorts:   
 Conservative care alone (may include 30-40 mmHg graduated compression 
up to waist, dietary counseling, exercise, and/or referral for CDT); or 
 Flexitouch Plus with conservative care.  
Following randomization, a product demo may take place to confirm the subject is 
able to tolerate prescribed care. 
4.5 
Study Timeline  
The expected study duration is approximately 24 months with 1 month spent in 
activation, 21 months enrolling and following subjects, and 2 months completing 
the data analysis. 
5.0 
Study Assessment 
Case Report Forms (CRFs) and Data Clarification Forms (DCFs) will be used for data 
collection and query handling. The Investigator will ensure the accuracy, completeness, 
and timeliness of the data recorded.  
All data will be entered into an Excel spreadsheet and validated to confirm integrity of data 
entry. Data may be transferred to an electronic data capture system at some point.  When 
all data have been coded, validated, and signed, the database will be locked (password 
protected with copy saved as PDF), and available for analysis. 
The study schedule of activities is shown in Table 1.  
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 10 of 38 
 
Table 1. Schedule of Activities 
Procedures 
Baseline            
(Day 0) 
Follow-up            
(4-12 weeks) 
Informed Consent 
X 
 
Demographics & Medical History 
X 
 
Inclusion/Exclusion Assessment 
X 
 
Pregnancy Test (if applicable) 
X 
 
Vitals 
X 
X 
Physical Exam 
X 
X 
Circumferential Measurements 
X 
X^ 
Bioimpedance Measurements 
X 
X^ 
QOL Assessment (RAND SF-36) 
X 
X 
Mobility Assessment (PROMIS Mobility) 
X 
X 
Symptom & Pain Intensity Assessment (PROMIS Pain 
Intensity, NRS Pain & Symptom Scale, Wong-Baker 
Faces Scale) 
X 
X 
Randomization 
X 
 
Training on Flexitouch Plus and/or Conservative Care* 
X 
 
Adverse Event, Complication, & Device Observation 
Assessment 
X 
X 
* If subject is unable to obtain prescribed care and complete training on use within 60 days of the Baseline visit 
(e.g., due to insurance coverage/scheduling delays, etc.), the subject will be considered a screen failure.  
^ Optional: Circumferential and bioimpedance measurements may be taken again after an in-clinic treatment with 
Flexitouch Plus. 
6.0 
Study Procedures 
6.1 
Informed Consent  
Subjects will need to sign an informed consent form that has been approved by 
both the Sponsor and reviewing IRB to be considered for participation in this study. 
Subjects must meet all of the inclusion and none of the exclusion criteria.   
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.  
6.2 
Demographics & Medical History 
Demographics will be collected including age, ethnicity, race, and sex. Significant 
medical history, including lipedema and lymphedema history, will be collected.  
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 11 of 38 
 
6.3 
Laboratory Testing  
Any women who are not surgically sterile or ≥1 year post-menopause will be tested 
for pregnancy according to the site specific procedures at the Baseline visit. If the 
pregnancy test is positive, the subject will not be enrolled in the study. 
Subjects must agree to use one of the following forms of birth control prior to 
starting and during treatment with the Flexitouch:  
 Abstinence (not having sexual relations with a person of the opposite sex) 
 Implantable hormone (e.g. Norplant) 
 Intrauterine Device  
 Male partner must have a vasectomy 
 Female sterilization  
 Hormonal injection 
 Oral contraceptives  
6.4 
Vital Signs  
Height and weight (without shoes or coat) will be collected at Baseline and Follow-
up. Results will be recorded on the respective data collection forms. If the BMI is > 
50 at the Baseline visit, the subject will not be enrolled in the study. 
6.5 
Randomization 
If the subject meets all of the inclusion criteria and none of the exclusion criteria, 
they will be randomly assigned to Flexitouch Plus with conservative care or 
conservative care alone. Randomization codes will be generated in a permuted 
block design. The block size will be balanced within each block, and will maintain 
a 1:1 ratio between the treatment groups.  
The randomization code will be distributed by sealed envelope and assigned 
sequentially as soon as an eligible subject completes the Baseline measurements. 
The appropriate staff member will obtain the next sequentially sealed 
randomization envelope and open it while the subject is present. 
The randomization assignment cannot be changed or chosen by the subject or the 
investigator. The randomization envelope, as well as evidence of treatment group 
assignment, should be placed in the subject’s binder. 
6.6 
InBody 770 Bioimpedance Measurements 
The InBody is a medical-grade bioimpedance device that measures body water and 
composition, providing objective measures of fluid and muscle-fat balance. The 
unit is non-invasive and generates a comprehensive results sheet that provides 
accurate, objective, and easily understandable measurements in less than 60 seconds 
to evaluate a patient’s current health status and track efficacy of treatments and 
interventions. Clinicians can use the InBody to: monitor body water and 
composition for early detection and treatment of lymphedema, identify fluid 
imbalances through tracking segmental body water values and edema index 
variables, and evaluate additional health risks related to muscle-fat balance. 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 12 of 38 
 
For the purposes of this study, bioimpedance measurements will be collected at the 
beginning of the Baseline and Follow-up visit (immediately before and after 
removal of graduated compression). Subjects will be asked to: 
 Stand on the InBody 770 with graduation compression on (covering the 
foot and heel pads while holding the hand pieces). The arms will then be 
raised up and away from the trunk for 20 seconds while the testing begins. 
 Remove shoes and socks, clean hands and feet with a wipe, and stand on 
the InBody 770 (covering the foot and heel pads while holding the hand 
pieces). The arms will then be raised up and away from the trunk for 20 
seconds while the testing begins.  
Data from the Body Water and Composition Analysis will be recorded on the 
respective data collection forms and a copy of each comprehensive results sheet 
will be retained in the subject’s medical record (Figure 2 and 3). 
 
Figure 2. Body Water Analysis 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 13 of 38 
 
 
Figure 3. Body Composition Analysis 
At the Follow-up visit, additional bioimpedance measurements (including whole 
body ECW/TBW ratio, as well as segmental ratios for the Right/Left Arm, 
Right/Left Leg, and Trunk) may be collected immediately after an approximately 
60-minute in-clinic treatment with FT Plus. The measurements will be collected and 
recorded in the same fashion outlined above.   
Generally speaking, if there is any type of inflammation or water retention 
occurring in the body, body water will accumulate in the extracellular space. Thus, 
injuries, disease, aging, high sodium diets, as well as low muscle mass, will cause 
the ECW/TBW to increase. The unit renders a whole body ECW/TBW ratio, as 
well as segmental ratios for the Right/Left Arm, Right/Left Leg, and Trunk. A 
whole body or segmental ECW/TBW ratio of >0.39 is considered abnormal. The 
segmental ratios are used to identify problem areas for fluid retention and 
inflammation. A 0.005 difference in ECW/TBW between right and left limbs may 
be indicative of inflammation or water retention. Larger discrepancies are required 
between upper and lower body given the legs have a slightly higher ECW/TBW 
ratio due to gravity and increased blood volume.  
6.7 
Circumferential Measurements 
Circumferential measurements will be taken at Baseline and Follow-up per 
standard care at the beginning of the visit at 4 sites on each leg (immediately after 
biocompression measurements and the removal of graduated compression), 1 site at 
the hips, and 1 site at the waist (for a total of 10 measurements) using a Gulick II 
tape measure. Sites include: 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 14 of 38 
 
 Site 1=narrowest part of the ankle (right and left leg),  
 Site 2=largest part of the calf (right and left leg),  
 Site 3=top of knee cap for lower thigh (right and left leg),  
 Site 4=thickest part of the upper thigh (right and left leg),  
 Site 5=widest part of the hips, and  
 Site 6=narrowest part of the waist. 
Results will be recorded in centimeters on the respective data collection form.  
At the Follow-up visit, additional circumferential measurements (including 4 sites 
on each leg, 1 site at the hips, and 1 site at the waist using a Gulick II tape measure) 
may be collected immediately after an approximately 60-minute in-clinic treatment 
with FT Plus. The measurements will be collected and recorded in the same fashion 
outlined above. . 
6.8 
Physical Exam 
The investigator (or designee) will perform a physical exam at Baseline and 
Follow-up to assess stage of lipedema and lymphedema, presence of edema at Sites 
1-6 (where circumferential measurements were taken), and presence/absence of 
clinical symptoms. It is important to note that progression to lipo-lymphedema 
(lipedema with swelling), a requirement of this study, typically develops during 
Stage 2/3 of lipedema. 
 Lipedema Stage: 
o Stage 1 = Smooth/normal skin surface with enlarged 
hypodermis/homogenous thickening of the subcutis.  
o Stage 2 = Bumpy, wave-like skin surface with indentations/nodular 
structures (masses, lipomas, angiolipomas) in the thickened 
subcutis.  
o Stage 3 = An increase in nodular changes/deformations and 
overhanging masses of tissue (especially on the thighs and around 
the knees).  
 Lymphedema Stage: 
o Stage 0 = Latent or subclinical condition where swelling is not yet 
evident despite impaired lymph transport, subtle alterations in tissue 
fluid/composition, and changes in subjective symptoms. 
o Stage 1 = Early accumulation of fluid relatively high in protein 
content which subsides with limb elevation. Pitting may occur. 
o Stage 2 = Limb elevation alone rarely reduces the tissue swelling and 
pitting is manifest. Later in state 2, the limb may not pit as excess 
subcutaneous fat and fibrosis develop. 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 15 of 38 
 
o Stage 3 = Symptoms of lymphostatic elephantiasis where pitting can 
be absent and trophic skin changes such as acanthosis, alterations in 
skin character and thickness, further deposition of fat and fibrosis, 
and warty overgrowths have developed. 
 Edema at Sites 1-6:  
o None = No pitting 
o 1+ = Trace: Tissue returns to normal almost immediately  
o 2+ = Mild: Tissue returns after 15-59 seconds 
o 3+ = Moderate: Tissue returns after 1-2 minutes  
o 4+ = Severe: Tissue returns after > 2 minutes 
o NA = Tissue no longer pits due to induration 
6.9 
QOL, Symptoms, Mobility & Pain Assessments 
The following assessments will be completed by the subject at the Baseline and 
Follow-up visits. Subjects will be instructed to answer all of the items (i.e., 
questions or statements) presented. Prior to departure, study personnel will review 
each assessment for missing data to ensure the subject addressed each item. 
6.9.1 QOL 
The RAND 36-Item Health Survey (Version 1.0) taps eight health concepts: 
physical functioning, bodily pain, role limitations due to physical health problems, 
role limitations due to personal or emotional problems, emotional well-being, 
social functioning, energy/fatigue, and general health perceptions. It also includes a 
single item that provides an indication of perceived change in health. (Appendix A) 
6.9.2 Mobility  
The PROMIS Mobility v2.0 (29 November 2016) is a 15-item questionnaire 
completed by subjects that focuses on activities of physical mobility such as getting 
out of bed/chairs to activities such as running. The adult Mobility measures include 
selected items from the full Physical Function item bank. (Appendix B)  
6.9.3 Pain Interference & Symptoms 
To assess pain and symptoms related to lipo-lymphedema (lipedema with 
swelling), subjects will complete: 
 The PROMIS Pain Interference - Short Form 6b v1.0 (2 May 2016) 
measures self-reported consequences of pain on relevant aspects of a 
person’s life and may include the extent to which pain hinders engagement 
with social, cognitive, emotional, physical, and recreational activities. 
(Appendix C)  
 The Wong-Baker Faces Pain Rating Scale is a pain scale that shows a series 
of faces ranging from a happy face at 0, or "no hurt," to a crying face at 10, 
which represents "hurts like the worst pain imaginable." Based on the faces 
and written descriptions, the patient chooses the face that best describes 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 16 of 38 
 
their level of pain associated with lipo-lymphedema (lipedema with 
swelling). (Appendix D)   
 Subjects will be asked to rate their perceptions of swelling, heaviness, pain, 
fatigue, tenderness, and tightness independently for each leg using a 10-
point numerical rating scale where 0 represents none/not present and 10 is 
worst imaginable.3 (Appendix E) 
6.10 Treatment 
Following randomization, collection of measurements, and the completion of 
questionnaires, patients will be trained on the conservative care prescribed by the 
investigator (or designee).  
Patients randomized to the Flexitouch Plus will obtain a device through standard 
commercial means (via self-pay, patient assistance, or insurance programs). The 
standard prescription of ‘Full Leg and Core (L1)’ with daily simultaneous bilateral 
lower extremity treatment (~60 minutes) at normal pressure levels will be used 
unless alternate programming is selected by the investigator. Alternate 
programming (e.g., twice daily, high pressure, additional supplemental lower leg 
program, etc.) may be used at the investigators discretion if a subject reports 
inadequate control of lymphedema symptoms prior to the next study visit. While 
alternate programming is not expected to be necessary, it is important subjects have 
access to the best care possible at all times in a “real world” study. 
Once the prescription is submitted/processed at the Baseline visit, device shipment 
and training on device use must take place within 60 days or the subject will not be 
enrolled in the study. 
At the Follow-up visit, some or all subjects may receive an in-clinic treatment with 
Flexitouch Plus after the Follow-up data collection is complete. Additional 
circumferential (including 4 sites on each leg, 1 site at the hips, and 1 site at the 
waist using a Gulick II tape measure) and bioimpedance (including whole body 
ECW/TBW ratio, as well as segmental ratios for the Right/Left Arm, Right/Left 
Leg, and Trunk) measurements may be collected and recorded immediately after 
completion of the in-clinic Flexitouch Plus treatment. 
6.11 Adverse Events, Device Observations, & Complications 
Reportable events and device observations, as defined below, will be recorded in 
the subject’s medical record and on the appropriate forms.  
6.11.1 Serious Adverse Event (SAE) 
A serious adverse event is an untoward medical occurrence where the 
outcome is:  
 Death; 
 
3 Cook et al. Neurology. 2013 Mar 12; 80(11 Suppl 3): S49–S53. 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 17 of 38 
 
 Life-threatening event (places the subject at immediate risk of death 
from the experience as it occurred);  
 Hospitalization (initial or prolonged) if admission to hospital was 
warranted as a result of an adverse event; 
 Disability or permanent damage (substantial disruption of one’s 
ability to carry out normal life functions);  
 Congenital anomaly or birth defect; 
 Required intervention to prevent permanent impairment or damage; 
or 
 Important medical event that required medical or interventional 
treatment to prevent one of the previous outcomes. 
Investigators will record SAEs on the AE log and report to Tactile 
Medical and IRB (as required) within 10 working days of becoming aware 
of the event. 
6.11.2 Device-Related Adverse Event (AE) 
A device-related AE is defined as any untoward medical occurrence in a 
subject that is associated with the use of the Flexitouch Plus device.  
All device-related AEs will be recorded on the AE log. Complaint 
reporting will be reported through standard commercial means. 
6.11.3 Adverse Event Severity 
Severity will be assess by the investigator using the following definitions: 
 Mild: Subject awareness of sign or symptom, but easily tolerated. 
 Moderate: Interferes with normal activities. 
 Severe: Incapacitating, with inability to perform normal activities. 
6.11.4 Venous-, Lymphedema-, and Lipedema-Related Complications 
Information about venous-, lymphedema-, and lipedema-related 
complications, including cellulitis, lymphangitis, deep vein thrombosis, 
skin breakdown, lymphorrhea, and lymphangiosarcoma, will be recorded 
on the Complication & Healthcare Utilization log. 
6.11.5 Device Observations 
Device observations regarding the Flexitouch Plus will be recorded on a 
Device Observation log and reported to Tactile Medical to assess the need 
for complaint reporting. Device observations include device failures, 
device malfunctions, use errors, and user preferences, as defined below: 
 Device Failure  
A device failure has occurred when the device is 
used in accordance with the IFU but does not perform as described 
in the IFU and also negatively impacts treatment of the study 
subject. 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 18 of 38 
 
 Device Malfunction  
A device malfunction occurs when an 
unexpected change to the device that is contradictory to the IFU is 
observed, which may or may not affect device performance. 
 Use Error  
A device use error is an act or omission of an act that 
results in a different medical device response than intended by the 
manufacturer or expected by the user. Use error includes slips, 
lapses, and mistakes. An unexpected physiological response of the 
subject does not itself constitute a use error. 
 Device Issue  
Any other issue with the device that does not fall 
into one of the above categories. 
 User Preference  
Information on user expectations, likes, dislikes, 
motivations, and inclinations that drive subject satisfaction with 
the device. 
Any unexpected side effects, product quality problems, use errors, or 
therapeutic failures related to graduated compression will be reported 
through the standard commercial means, including: direct communication 
with manufacturer personnel or online filing by the investigator at 
MedWatch (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm). 
 
7.0 
Subject Discontinuation or Exit  
7.1 
Early Discontinuation 
Subject participation may be discontinued prior to study completion for any of the 
following reasons: 
 Withdrawal of Consent   
Subjects may withdraw their consent to participate at any time. If a subject 
withdraws consent, previous information that has already been obtained 
will be available for analysis. 
 Adverse Event  
 
Subject experiences an adverse event that in the investigator’s clinical 
judgement necessitates discontinuation of their participation in this study.  
 Discretion of the Investigator 
Subjects may be withdrawn at the investigator’s discretion in the event of 
subject noncompliance, changes in the subject’s health, or other reasons 
based on the investigator’s clinical judgment. 
Subjects withdrawn prior to completing the study will be asked to return to clinic to 
complete Study Exit procedures.  
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 19 of 38 
 
7.2 
Study Exit 
A Study Exit form will be completed for all subjects to document the reason for 
discontinuation or the date of study completion. In addition, subjects randomized to 
conservative care who express an interest in continuing in-home treatment with the 
Flexitouch Plus outside of the study will receive information from a Tactile Medical 
representative per standard procedure.  
8.0 
Risk Analysis and Adverse Events   
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. The 
investigator will oversee all safety aspects of the study, report all adverse events to the IRB, 
and ensure each subject is treated identically. Should a subject choose to terminate his or 
her participation in the study, he or she will be treated according to the standard of care that 
applies at the point of withdrawal. 
8.1 
Treatment Risks 
Participants enrolled in this study are not expected to be at any higher or additional 
risk than those who use conservative care (compression garments), since IPC 
pressures do not exceed the pressures of static compression garments. IPC and static 
compression are minimal risk therapies with nominal complications or adverse 
events.  
Likely: 
 Local skin irritation 
 Pain or discomfort 
 Increased swelling 
Less Likely: 
 Cellulitis  
 New or increased edema in the trunk and/or genital region 
Highly Unlikely: 
 Electric shock (if Flexitouch Plus device is not maintained or used properly) 
8.2 
Procedure Risks 
All procedures and instruments used in this study are part of standard care. The 
Inbody 770 sends a minute current identical to current technology used on gym 
equipment, home scales, non-invasive heart monitors, watches, Fibit monitors, and 
the like. This technology is considered extremely safe with no known risks to 
patient health. 
8.3 
Risk Mitigation 
Subjects will be made aware of known complications and adverse events at the time 
of consent and monitored closely throughout the study. Subjects will be informed of 
any significant new findings that develop during the course of the study that may 
affect their willingness to continue participation. Should a subject choose to 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 20 of 38 
 
terminate his or her participation in the study, he or she will be treated according to 
the standard of care that applies at the point of withdrawal. 
The Investigator and study team will oversee all safety aspects and report adverse 
events to the IRB, as required. Should a subject choose to terminate his or her 
participation, he or she will be treated according to the standard of care that applies 
at the point of withdrawal. 
8.4 
Potential Benefits 
While there is no guarantee of a direct benefit to participants, there is a possible 
benefit of improved quality of life and relief of symptoms with use of the 
Flexitouch Plus. 
9.0 
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, so that no unneeded sensitive 
information is being collected.   
10.0 Deviation from Study Plan  
All deviations will be documented on the Deviation Log and reported to the IRB as 
required by IRB policies.   
11.0 Quality Assurance Procedures  
This study will be conducted in accordance with Good Clinical Practice (GCP), 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 Informed Consent form will be reviewed and approved, according to 21 
CFR §50 and §56, by each center’s IRB.  
11.1 Data Safety Monitoring  
The 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 
Investigator (or designee). The Investigator will be made aware of all serious and 
device-related adverse events; therefore, the responsibility for reporting adverse 
events is shared with the Investigator and research team. 
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 21 of 38 
 
11.2 Reports and Records   
Records to be maintained by the Investigator in a designated study file include: 
 Investigational plan and all amendments; 
 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, 
IRB, Tactile Medical, and study monitor; 
 Curriculum Vitae and professional license for key study personnel, if 
applicable; 
 Site personnel signature and documentation regarding the Investigator’s 
delegation of responsibility; 
 Protocol/device related training records for all applicable study personnel; 
 Screening log; and 
 Reports (shown below). 
The Investigator is required to prepare and complete reports on this investigation as 
required by regulations (Table 2).  
Table 2. Required Reports 
12.0 
 
Reports 
Submit To 
Timeframe 
SAE  
Tactile Medical 
 
 
Reviewing IRB 
10 business days of becoming 
aware. 
 
In accordance with 
IRB procedure. 
Progress Report 
Tactile Medical 
Reviewing IRB 
Annually, at a minimum. 
 
The following records must be maintained for each subject enrolled: 
 Original, signed and dated informed consent form, as well as documentation 
of the process of consent; 
 Completed CRFs, source document worksheets, and data clarification 
forms, 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 will remain on file for a minimum of six years after the conclusion of 
this study.  
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 22 of 38 
 
12.1 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 the IRB before any changes are implemented. All changes must be 
documented.  
13.0 Statistical Methods   
13.1 Sample Size Determination 
The study is not formally powered for a specific primary hypothesis, thus no formal 
power/sample size estimation was performed. The study sample size was 
determined based upon a desire to be able to estimate the means of the primary 
within group endpoints, using 95% confidence intervals, with the estimation of the 
endpoint means to have a precision (half width of the confidence intervals) of 
approximately 40% of the observed standard deviation. To achieve these 
parameters, we have determined a target analyzable sample size of 15 subjects (30 
total legs as the observational units) per group. To accommodate an expected 
attrition rate of up to 20%, a total of 3 subjects per arm will be replaced, if they fail 
to fully complete the study.  
13.2 Statistical Analysis 
For continuous variables, descriptive statistics will include the number of subjects 
(n), mean, standard deviation, median, inter-quartile range, minimum, and 
maximum, based upon subjects with reported data for the variable being analyzed. 
Frequencies (numerator and denominator), percentages, and 95% confidence 
intervals will be displayed for categorical data. Percentages by categories will be 
based on the number of subjects with no missing (unreported) data for the specific 
variable being analyzed and the count of the patients for each individual level of the 
categorical variable (the level specific numerators). Percentages will add up to 
100%, unless otherwise indicated. 
There are no plans to impute missing data and there are no plans to explicitly report 
missing data (counts and/or percentages) in the tables for all variables as part of the 
planned study report content. Variations in the reported sample sizes within and/or 
between relevant tables can be used to ascertain insights into unreported data. In 
some cases, unreported data may be due to it not being clinically relevant to a 
particular patient or may represent expected data that was not collected. Selected 
analyses pertaining to unreported and/or missing data may be discussed and 
considered as future findings warrant. 
The exploratory nature of the study suggests that the statistical focus will be on 
estimation and hypothesis generation and not hypothesis testing. Though p-values 
will be reported as apropos, point estimates, and 95% confidence intervals will be 
used to guide exploratory analyses for potentially clinically meaningful differences 
or changes to be discussed and evaluated. 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 23 of 38 
 
Primary within treatment group analyses of change from baseline will utilize paired 
tests (e.g. paired t-tests, McNemar chi-square) or similar non-parametric tests as 
appropriate, to compare the 30-day measurement to baseline. 
Secondary between treatment group comparative analyses of change from baseline 
will utilize ANCOVA or similar methods as appropriate. These methods will 
include the 30-day measurement as the dependent (response) variable, while the 
baseline measurement and treatment group will be the independent variables. 
Assessments of any interactions between the baseline measurement and treatment 
group will be performed. 
Other exploratory comparisons, when performed, will utilize chi-square, ANOVA, 
t-test, and appropriate non-parametric tests, unless otherwise specified. 
In the case of multiple comparisons, when performed, the Hochberg adjustment 
method (1988) will be used to control the family-wise error rate.  
Multivariable models (e.g., linear regression or logistic regression) may be used to 
assess the predictive relationships and control for possible confounding imbalances 
of selected multiple variables to specific outcome measures of interest. 
Any formal null hypothesis-based statistical comparisons will be made using two 
sided tests at the α=0.05 significance level unless specifically stated otherwise. All 
null hypotheses will be of no inter-group difference, all alternative hypotheses will 
be two-sided, unless specifically stated otherwise. 
All data processing, summarization, and analyses will be performed using R 
Version 3.6.0 or higher.  
14.0 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. 
15.0 References 
1 
Zaleska M, Olszewski WL, Durlik M, Kaczmarek M. A Novel Clinical Test for 
Setting Intermittent Pneumatic Compression Parameters Based on Edema Fluid 
Hydromechanics in the Lymphedematous Calf. Lymphat Res Biol. 2015 
Sep;13(3):208-14.  
2 
Blumberg SN, Berland T, Rockman C, Mussa F, Brooks A, Cayne N, Maldonado T. 
Pneumatic Compression Improves Quality of Life in Patients with Lower-Extremity 
Lymphedema. Ann Vasc Surg. 2016 Jan;30:40-4. 
3 
Muluk SC, Hirsch AT, Taffe EC. Pneumatic compression device treatment of lower 
extremity lymphedema elicits improved limb volume and patient-reported outcomes. 
Eur J Vasc Endovasc Surg. 2013 Oct;46(4):480-7. 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 24 of 38 
 
4 
Szolnoky G, Varga E, Varga M, Tuczai M, Dósa-Rácz E, Kemény L. Lymphedema 
treatment decreases pain intensity in lipedema. Lymphology. 2011 Dec;44(4):178-82. 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 25 of 38 
 
Appendix A. RAND SF-36  

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 26 of 38 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 27 of 38 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 28 of 38 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 29 of 38 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 30 of 38 
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 31 of 38 
 
Appendix B. PROMIS Mobility 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 32 of 38 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 33 of 38 
 
 
Appendix C. PROMIS Pain Interference 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 34 of 38 
 
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 35 of 38 
 
Appendix D. Wong Baker Faces Pain Scale 
 
 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 36 of 38 
 
Appendix E. NRS Symptom & Pain Scale 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 37 of 38 
 

 
 
Version 2.0 
CONFIDENTIAL 
 
 
 
 
 
Page 38 of 38