Prospective Evaluation of a Surgical Solution for Breast Cancer-Associated Lymphedema
Phase: NA
Conditions: Lymphedema, Edema
Sponsor: Stanford University

IRB-37161 
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Prospective Evaluation of a Surgical Solution for Breast 
Cancer-Associated Lymphedema 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305  
Protocol Director  
Stanley Rockson, MD 
Falk Cardiovascular Research Center  
300 Pasteur Dr, Stanford, CA   94305-5406  
650-725-7571 (office); 650-725-1599 (fax)  
rockson@stanford.edu  
Co-Investigators 
Dung H Nguyen, MD, PharmD 
770 Welch Road, 
Stanford, CA  94305-5715 
Office:   
nguyendh@stanford.edu  
Andrei Iagaru, MD 
Nuclear Medicine 
300 Pasteur Dr, 
Stanford, CA  94305-5281 
Office:   
aiagaru@stanford.edu 
Biostatistician 
 
Associate Director, Clinical Trials Program 
1070 Arastradero Road  
Palo Alto, California 94304-5559 
 
Study Coordinator 
 
Falk Cardiovascular Research Center;   
Stanford, CA  94305-5406 
 
 
 
 
IRB-37161 
BRS0095 
NCT02734979 
IDE-G160271 
SRC-approval:  13 May 2019;  16 October 2019  
Version  4 February 2020 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................. 4 
SCHEMA ....................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 6 
1.1. 
PRIMARY OBJECTIVE ....................................................................................................... 7 
1.2. 
SECONDARY OBJECTIVES ................................................................................................. 7 
2. 
BACKGROUND ................................................................................................................... 7 
2.1 
STUDY DISEASE ............................................................................................................... 7 
2.3 
RATIONALE .................................................................................................................... 10 
2.4 
STUDY DESIGN .............................................................................................................. 11 
2.5 
CORRELATIVE STUDIES BACKGROUND .......................................................................... 11 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .......................... 13 
3.1 
INCLUSION CRITERIA ..................................................................................................... 13 
3.2 
EXCLUSION CRITERIA .................................................................................................... 14 
3.3 
INFORMED CONSENT PROCESS ....................................................................................... 16 
3.4 
RANDOMIZATION PROCEDURES ..................................................................................... 16 
3.5 
STUDY TIMELINE ........................................................................................................... 16 
4. 
TREATMENT PLAN ......................................................................................................... 16 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............... 20 
4.2 
CRITERIA FOR REMOVAL FROM STUDY .......................................................................... 22 
4.3 
ALTERNATIVES .............................................................................................................. 23 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ............... 24 
5.1 
 INVESTIGATIONAL AGENT/DEVICE/PROCEDURE ........................................................... 24 
5.2 
AVAILABILITY ............................................................................................................... 27 
5.3 
AGENT ORDERING ......................................................................................................... 27 
5.4 
AGENT ACCOUNTABILITY .............................................................................................. 27 
6. 
DOSE MODIFICATIONS ................................................................................................. 27 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES ........................................... 27 
7.1 
POTENTIAL ADVERSE EVENTS ....................................................................................... 27 
7.2 
ADVERSE EVENT REPORTING......................................................................................... 28 
7.3 
STOPPING RULE ............................................................................................................. 28 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................ 28 
8.1 
LABORATORY CORRELATIVE STUDIES ........................................................................... 28 
9. 
STUDY CALENDAR ......................................................................................................... 30 
10. 
MEASUREMENTS ........................................................................................................ 30 
10.1 PRIMARY OUTCOME ........................................................................................................... 31 
10.2  
SECONDARY OUTCOME .................................................................................................. 31 
10.3  
EXPLORATORY OBJECTIVES AND ENDPOINTS ................................................................ 32 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL .......................................................................... 36 
11.2 
DATA AND SAFETY MONITORING PLAN ......................................................................... 36 
11.3 
DATA MANAGEMENT PLAN ........................................................................................... 36 

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12. 
STATISTICAL CONSIDERATIONS .......................................................................... 37 
12.1 
STATISTICAL DESIGN ..................................................................................................... 37 
12.2 
INTERIM ANALYSES ........................................................................................................ 37 
12.3 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS ................................... 37 
12.4 
PRIMARY ANALYSIS ....................................................................................................... 37 
12.5 
SECONDARY ANALYSIS .................................................................................................. 39 
12.6  
SAMPLE SIZE .................................................................................................................. 41 
12.7 
CRITERIA FOR FUTURE STUDIES ..................................................................................... 42 
13.  
REFERENCES ................................................................................................................ 43 
APPENDIX A:  PARTICIPANT ELIGIBILITY CHECKLIST ............................................................. 46 
APPENDIX B:  LYMPHEDEMA QUALITY OF LIFE SURVEY ....................................................... 50 

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PROTOCOL SYNOPSIS 
TITLE 
Prospective Evaluation of a Surgical Solution 
for Breast Cancer-Associated Lymphedema 
STUDY PHASE 
N/A (randomized, controlled, device study) 
INDICATION 
Upper extremity lymphedema secondary to 
breast cancer treatment 
INVESTIGATIONAL PRODUCT  
BioBridge scaffold 
PRIMARY OBJECTIVE(S) 
To determine whether the addition of the 
BioBridge scaffold to vascularized lymph 
node transfer will improve the outcome of 
surgical treatment of secondary arm 
lymphedema resulting from treatment of 
breast cancer.  
Primary endpoint is the post-surgical % 
change in excess limb volume, measured at 
12 months following the surgical procedure.  
SECONDARY OBJECTIVE(S) 
Secondary endpoint is change in 
measurement of dermal thickness, screening 
evaluations to Month 12, as measured by 
caliper skin fold thickness. 
TREATMENT SUMMARY 
Vascularized lymph node transfer (VLNT) 
with placement of BioBridge scaffold 
SAMPLE SIZE  
BioBridge:  48;  Control:  12 
STATISTICAL CONSIDERATIONS Open-label, randomized, control trial.  This 
study is open-label due to visibly apparent 
differences between the recipients of the 
surgery.   
 

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SCHEMA 
 
Participant selection 
Stage II lymphedema secondary to breast cancer treatment, BrCA stage 0-II, treatment 
completed 3 years prior to enrollment, NED, 18-75yrs 
                              ↙ 
                  Screening Visit 1     →      Screening Visit 2       →       Screening Visit 3 
(10 days after Bx)   
                   Measurements                 Measurements, Bx,              Measurements 
                   (L-Dex > 10)                     Research labs, LSG                       ↓ 
VLNT with implantation of BioBridge Scaffold or 
VLNT only (control group) (3+ weeks after S3 visit) 
                             ↙ 
    Treatment Visit 1   →   Treatment Visit 2   → Treatment Visit 3  →  Treatment Visit 4  →    
     3 mo. Post-op                  6 mo. Post-op           9 mo. Post-op           12 mo. Post-op     
      
     Measurements              Measurements          Measurements          Measurements,               
                                                
Bx, LSG        
 
Research Labs         
 
Treatment Visit 5      →   Treatment 6   →   Treatment 7 
10-day after Bx                 2 yr. FU                     3 yr. FU 
Measurements   
2 yr and 3 yr FU for intervention group only  
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACS 
American Cancer Society 
IV 
Intravenous 
ADL 
Activities of daily living 
LLN 
Lower limit of normal  
AE 
Adverse event 
LNF 
Lymph node fragments 
ALND 
Axillary lymph node dissection 
LSG 
Lymphoscintigraphy  
BB 
BioBridge 
L-Dex 
Lymphedema index 
BIS 
Bioimpedance spectroscopy 
LV 
Limb volume 
BrCA 
Breast Cancer 
LVA 
Lymphaticovenous anastomosis 
BSA 
Body surface area 
LymQoL 
Lymphedema Quality of Life 
Bx 
Biopsy 
MFBIA 
Multiple Frequency Bioimpedance 
Analysis 
CBC 
Complete blood count 
NED 
No evidence of disease 
CDPT/CDT 
Completed Decongestive 
Physiotherapy/Therapy 
PLT 
Platelet 
CDRH 
Center for Devices and Radiological 
Health  
PT/PTT 
Prothrombin Time/Partial Thromboplastin 
Time 
CI 
Confidence interval 
RNA 
Ribonucleic acid 
CMP 
Comprehensive metabolic panel 
ROI 
Region of Interest 
CNS 
Central nervous system 
RR 
Response rate 
CRF 
Case report/record form 
SAE 
Serious adverse event 
CTCAE 
Common Terminology Criteria for 
Adverse Events 
SLND 
Sentinel lymph node dissection 
CXR 
Chest x-ray 
SOC 
Standard of Care 
DSMB 
Data Safety Monitoring Board 
UE 
Upper extremity 
DVT 
Deep vein thrombosis  
ULN 
Upper limit of normal 
ECG/EKG 
Electrocardiogram 
UNK 
Unknown 
Hgb 
Hemoglobin 
VS 
Vital signs  
HTN 
Hypertension 
VEGF-C 
Vascular Endothelial Growth Factor-C 
ICG 
Indocyanine Green 
VM 
Volume measurement 
IDE 
Investigational Device Exemption 
VLNT 
Vascularized lymph node transfer 
IRB 
Institutional Review Board 
WBC 
White blood cell 
ISL 
International Society of Lymphology 
WHO 
World Health Organization 
 

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1. 
OBJECTIVES 
1.1. 
Primary Objective 
• 
To determine whether the addition of the BioBridge scaffold to vascularized lymph node 
transfer will improve the outcome of surgical treatment of secondary arm lymphedema 
resulting from treatment of breast cancer.  Primary endpoint is the post-surgical % 
change in excess limb volume, measured at 12 months following the surgical procedure.  
Intervention participants will be consented for safety follow-up for up to 36 months. 
1.2. 
Secondary Objectives 
• 
Change in measurement of dermal thickness, screening evaluations to Month 12, as 
measured by caliper skin-fold thickness. 
1.3. 
Exploratory Objectives 
• 
Change in L-Dex bioimpedance ratio, screening evaluations to Month 12 
• 
Changes in dynamic lymphatic function by serial radionuclide LSG, performed at 
enrollment and 12 months after surgery.  
• 
Changes in Lymphedema Quality of Life (LymQOL) score, screening evaluations to 
Month 12.  
• 
Changes in quantifiable skin histopathology; cutaneous punch biopsies performed at 
enrollment and 12 months after surgery.  
2. 
BACKGROUND 
2.1 
Study Disease 
Lymphedema 
Secondary (acquired) lymphedema is a serious, progressive and global disease that develops 
when the lymphatic system is physically compromised and unable to sufficiently transport 
interstitial fluid and macromolecules from affected region(s) of the body to the central circulation.  
In Western countries, it most commonly occurs as a delayed result of cancer treatment, most 
frequently in survivors of breast and gynecological cancers.  In this highly prevalent condition, 
lymph node extirpation and the associated structural damage to the lymphatic vasculature leads 
to the inexorable accumulation of interstitial fluid, accompanied by regional compromise of 
immune function and, ultimately, irreversible structural changes of the affected tissues of the 
limb(s). 1  Lymphedema is a chronic, debilitating disease with profound functional and 
psychosocial implications. 2  
According to the American Cancer Society (ACS), in women there will be an estimated 252,710 
new cases of invasive breast cancer, 63,410 of in situ breast cancer, and in men, 2,470 cases.24  
In 2017, approximately 40,610 women and 460 men are expected to die from breast cancer.  

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Development of upper extremity (UE) edema following axillary lymph node dissection for breast 
cancer treatment is the most common manifestation.  Conservative estimates place the 
incidence of UE edema after axillary lymph node dissection at 15-26%. 3,5-7  Conservative 
axillary management (SLND) has resulted in reduced incidents of breast cancer related 
edema. 8-10  
To decrease the risk of recurrence for early-stage breast cancer patients with a positive SLN, 
radiotherapy is typically recommended.  AMAROS trial results showed the rate of lymphedema 
in patients with early-stage breast cancer with positive SLN, was 15% at 1 year;  
13.4% at 3 years;  10.3 at 5 years.  Women who had ALND and axillary radiotherapy had the 
highest rates of lymphedema (25.6% at 1 year;  21% at 3 years;  20.8% at 5 years). 11  
2.2 
Study Device/Procedure 
The proposed study utilizes Fibralign’s BioBridge™ Collagen Matrix, a sterile implantable 
biocompatible and biodegradable surgical mesh ribbon comprised of highly purified porcine 
collagen.  The Class II device was cleared by CDRH Division of Surgical Devices on 
8 January 2016 under 510(k) K151083.  The device will be used for soft tissue surgical support 
at the time of vascularized lymph node transfer surgery (VLNT); the device will be used, 
specifically, for surgical support of the lymphatic component of the soft tissue.  
We previously completed and published a large animal study that employed a well-studied and 
widely-published model. 43  The model replicates the pathogenesis of iatrogenic human 
secondary lymphedema (surgical removal of lymph nodes, radiation ablation).  The study 
definitively demonstrated that, after BioBridge device implantation, the lymphatic tissue 
underwent repair during the period of experimental observation, with formation of new lymphatic 
vessels, restoration of function, and reduction in the tissue fluid accumulation that is associated 
with the untreated disease.  Contrast-enhanced CT imaging and vital dye imaging confirmed 
that, at study conclusion, lymphatic vessels were fully functional within the irradiated tissue 
region, where there had been no demonstrable lymphatic vascular function before implantation 
of the BioBridge device.  In the untreated control group, as expected, there was no observed 
improvement during this same period.  
Post-mortem macroscopic analysis of the implantation area after in vivo intradermal injection of 
methylene blue demonstrated that, in BioBridge recipients, newly developed lymphatic 
collectors could be identified; the development of new collectors was corroborated by 
post-treatment CT imaging.  During the course of the study, 120 BioBridge devices were 
implanted, with no identified complications during the 3 months after implantation or through 
histological analysis.   
This preclinical study demonstrates the efficacy and safety of BioBridge for the enhancement of 
lymphatic repair and revascularization following the development of post- surgical acquired 
lymphedema in an in vivo model that simulates the human condition of acquired lymphedema of 
the limb.  

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Transplantation of healthy tissues to replace or re‐route damaged lymphatic vessels, in which 
only arterial and venous vessels are reconnected, but in which lymphatic vessels cannot be 
re‐anastomosed, has shown improvements in limb edema, with evidence of lymphatic re‐routing 
and clinical evidence of spontaneous lymphatic regeneration.  Although lymph node transfer has 
been shown to provide some benefit in human lymphedema patients, autologous lymph nodes 
incorporate into existing lymphatic vasculature at a relatively low frequency, thus compromising 
the outcome, inasmuch as connection with lymphatic vessels is required for the maintenance 
and function of the transplanted lymph nodes.  It is our belief that the addition of the Fibralign 
BioBridge will address a key weakness of this procedure, by bridging across damaged tissue 
and providing the mechanical support needed to effectuate repair, lymphatic anastomosis and 
restoration of lymphatic function. 3 
Fibralign’s BioBridge Collagen Matrix consists solely of highly purified collagen with the 
immunogenic telopeptides removed.  This starting material is already used in commercial 
implant devices and sterilized after fabrication and packaging.  Extensive GLP biocompatibility 
testing has already been successfully completed in support of the 510(k) clearance and 
provided earlier to the FDA, including implantation studies that show BioBridge naturally and 
gradually incorporates into the host tissue within 6 to 9 months after implantation, ensuring a 
safe application in lymphedema treatment. 
One subject has been treated under this protocol (IRB-37161) prior to December 2019 revision 
cycle, which was implemented at the request of the NIH funding source.  The single 
previously-enrolled IRB-37161 subject underwent VLNT with BioBridge placement per protocol.  
Due to the significant change in this study, this patient will not be included in the final analysis.  
Since 2018, the BioBridge Collagen Matrix surgical mesh ribbon has been implanted as medical 
care in a number of lymphedema patients (personal communication, Dung Nguyen, MD.49  
Summary information is available at this time on 23 patients.  20 patients had secondary 
lymphedema post-cancer treatment, and a few had lymphangiomatosis or primary lymphedema.  
Of the cancer patients; 13 had breast cancer and 6 had gynecological cancer or melanoma.  All 
had undergone lymphatic surgery prior to BioBridge placement.  14 patients had undergone 
vascularized lymph node transfer (VLNT);  5 underwent LVA;  and 3 received combined VLNT 
with lymphaticovenous anastomosis (LVA).  The time interval between the lymphatic surgery 
and BioBridge placement ranged from 1 month to 28 months.  One patient, with secondary 
lymphedema post-cancer treatment for Hodgkins’s lymphoma, had the BioBridge implanted with 
their lymphatic surgery (liposuction and VLNT). 50  
Based on available data, 15 of 23 patients, covering pre-surgery assessments, pre-BioBridge 
placement surgery, and post-BioBridge placement data, all Dr Nguyen’s patients showed 
improvement of excess volume after their initial lymphatic surgery, ranging from 2% to 33% 
improvement in volume.  Of these, 13 of 15 showed improvement of excess volume after 
BioBridge placement that ranged from 1% to 29%.  In the remaining 2 patients, there was a 

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median increase of volume of 6.5% in limb volume.  The truncated cone formula, as described 
by Dr Håkan Brorson, was used to calculate excess volume. 42  
For clinicaltrials.gov compliance 
IRB-37161 information was entered into the ClinicalTrials.gov record in 2016 as NCT02734979) 
and will be updated after IRB approvals, as appropriate. 
2.3 
Rationale 
Currently, there is a paucity of effective treatment options for lymphedema of the limb(s).  These 
include compression garments, intermittent compression devices, complete decongestive 
physiotherapy (CDPT), skin care, and exercise.  The current standard of care is a combination 
of these approaches.  CDPT, which combines manual lymph drainage, multilayer short-stretch 
bandaging, exercise and skin care was recommended by a consensus panel of experts as the 
standard of care. 12-18  Utilizing this technique have resulted in reduction in excess limb volumes 
in the range of 50%. 4,19-21  Compete resolution is rarely achieved, is costly, and is time and 
labor intensive. 22  While modestly effective, the underlying cause is not addressed.  
In a completed large animal model (porcine) of human lymphedema, of the utilization of the 
Fibralign Biobridge, had the capacity to guide and augment lymphatic repair, and 
thereby reverse the pathologic burden of lymphedema on the tissues of the affected limb(s). 43  
The BioBridge is an implantable, interventional device comprised of a thread-like, multi-lumen 
collagen scaffold.  Biobridge’s highly aligned nanofibrils encourage the endothelial cell 
attachment, alignment and migration that are prerequisite to new vessel formation. 44,45  In our 
completed preclinical investigation, BioBridge implantation successfully induced lymphatic 
regeneration and ameliorated the pathology in a porcine lymphedema model (funded through a 
USAMRAA CDMRP Breast Cancer Research SBIR Phase II grant).  The results of these 
investigations have been presented at several national and international biomedical congresses 
and the manuscript is under peer review for publication.  On the basis of the completed 
preclinical investigations, the FDA has granted a 510(k) for this device.  IDE was presented and 
approved by the FDA.  An amended IDE application, for randomized study, will be presented to 
the FDA for their approval.  
On the strength of our preclinical findings, we propose a prospective clinical investigation of the 
impact of BioBridge as an adjunct to VLNT.  VLNT is an increasingly practiced surgical 
intervention for limb lymphedema, despite the fact that the documented success rate of the 
current procedure is not optimal.  Of published studies reporting limb volume outcomes after 
VLNT, volume changes range from an increase of 13% to a decrease of 64% (from presurgical 
volume). 34  Animal studies suggest that surgical failure may be due to inadequate lymphatic 
vascular engraftment of the transplanted node. 48  VLNT with placement of the BioBridge 
scaffold is intended to provide lymphatic soft tissue support that is needed for effective 
lymphatic revascularization of the transplanted node.  It is hoped to demonstrate that the 
BioBridge improves upon the less-than-optimal success rate of the currently practiced surgery 

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by facilitating the lymphatic connections to the transplanted node that are crucial to its viability 
and function. 34  The proposed study will evaluate the clinical efficacy of adjunctive BioBridge 
use in VLNT.  We hypothesize that BioBridge will have the capacity to substantially improve the 
efficacy of VLNT, providing the stable and optimally predictable outcomes that are 
currently lacking for the unaided procedure.  We have therefore designed a novel approach to 
treatment that directly addresses a component of the underlying cause and may be more 
effective as a treatment strategy.  
2.4 
Study Design 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance 
• 
Primary purpose of the protocol:  
o Treatment: protocol designed to evaluate one or more interventions for treating a 
disease, syndrome or condition 
• 
Interventional model:  
o Parallel: one of two groups in parallel for duration of study.  
• 
State the number of intervention arms 
o Two arms  
• 
State whether the study will be masked (at least one party is unaware of the treatment)  
o Open: no masking is used  
• 
State whether the study is randomized.  
o Randomized  
• 
Primary outcome or outcome that the protocol is designed to evaluate:  
o Efficacy 
2.5 
Correlative Studies Background  
We previously completed and published a large animal study that employed a well-studied and 
widely-published large animal model of lymphedema. 43  The porcine hindlimb model replicates 
the pathogenesis of iatrogenic human secondary lymphedema (surgical removal of lymph 
nodes, radiation ablation).  The study definitively demonstrated that, after BioBridge device 
implantation, the lymphatic tissue exhibited successful repair during the period of experimental 
observation, with formation of new lymphatic vessels, restoration of function, and reduction in 
the tissue fluid accumulation that is associated with the untreated disease.  Contrast-enhanced 
CT imaging and vital dye imaging confirmed that, at study conclusion, lymphatic vessels were 
fully functional within the irradiated tissue region, where there had been no demonstrable 
lymphatic vascular function before implantation of the BioBridge device.  In the untreated control 
group, as expected, there was no observed improvement during this same period.   

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Post-mortem macroscopic analysis of the implantation area after in vivo intradermal injection of 
methylene blue demonstrated that, in BioBridge recipients, newly developed lymphatic 
collectors could be identified; the development of new collectors was corroborated by 
post-treatment CT imaging.  During the course of the study, 120 BioBridge devices were 
implanted, with no identified complications during the 3 months after implantation or through 
histological analysis.  
The details of the model are described here.  A porcine model for secondary lymphedema in the 
minipig (Yucatan breed) was developed through meticulous resection of the lymphatic system of 
one hind limb and subsequent radiotherapy.  This procedure led to chronic edema in 44% of the 
animals at the 3-month time point, as defined by a bioimpedance spectroscopy (BIS) ratio 
greater or equal to 1.05.  The relative incidence of lymphedema in the porcine model and 
post-operative wound healing problems were comparable to those observed in humans after 
similar procedures. 1  Morphological features of chronic lymphedema in the minipigs were 
confirmed by computed tomography (CT) and MRI; the number of CT-identified lymphatic 
collectors correlated with the lymphatic dysfunction as determined by BIS. 28  Using BIS 
combined with CT imaging to identify active lymphedema, 50% of the animals in the untreated 
control group had an initial diagnosis of lymphedema at the 3-month time point, and in all these 
animals, the lymphedema persisted to the 6-month observation point. 
Lymphedema treatment with BioBridge  
Three months after lymph node resection and radiotherapy, animal subjects underwent surgical 
intervention, with implantation of BioBridge scaffolds spanning the area depleted of lymphatics.  
The treatment options included implantation of: 1) scaffold only;  2) transplantation of 
autologous lymph node fragments (LNF) supplemented with VEGF-C-enriched scaffold;  or 
3) a VEGF-C treated scaffold.  Untreated control subjects received no treatment. 
All animals with pre-treatment lymphedema in Group 2 (BioBridge with LNF) experienced 
resolution of the lymphedema, and those in Group 1 (BioBridge only) showed improvement after 
3 months as demonstrated by reduction of bioimpedance spectroscopy ratios and increase in 
CT-detectable lymphatic collectors vs pre-treatment levels.  In both of these treatment groups, 
animals without lymphedema prior to surgical treatment did not subsequently develop it.  In 
contrast, in Group 3 (BioBridge with VEGF-C) and the control group, the majority of the animals 
had lymphedema either persist or manifest after the treatment started.  
Post-mortem macroscopic analysis in animals with lymphedema resolved or improved showed 
that new lymphatic collectors in the area of prior surgery and radiation could be seen through 
the skin after prior peripheral injection of blue dye and were confirmed by CT-imaging to be in 
the vicinity of the implanted collagen threads.  Macroscopically, newly formed collectors had no 
abnormal architecture.  In contrast, in control animals from Group 3, post-mortem examination 
disclosed visible lympho-vascular conglomerates in the vicinity of the distal end of the implant.  

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Standard histological analysis demonstrated integration of the nanofibrillar collagen scaffold into 
the irradiated tissues. 
Confocal immunohistochemistry revealed a higher number of lymphatic collectors in the 
proximity of the implanted collagen scaffold, when compared to the surrounding irradiated tissue 
or to untreated irradiated tissue.  The number of blood vessels was also increased in this area, 
however the balance between the lymphatic and blood vessels in the vicinity of the scaffold was 
shifted toward lymphatics, as shown by the increase in the lymphatic fraction of the total 
microvascular density (lymphatic + blood) when compared to untreated irradiated tissue. 
In summary, this preclinical large animal study demonstrated the efficacy and safety of 
BioBridge for the enhancement of lymphatic repair and revascularization following the 
development of post- surgical acquired lymphedema in an in vivo model that simulates the 
human condition of acquired lymphedema of the limb. 
In subjects with lymphedema, implantation of BioBridge 1) normalized or reduced the 
extracellular liquid volume and 2) increased the number of functional lymphatic collectors, 
accompanied by 3) BioBridge integration into irradiated tissue and 4) formation of new 
microvasculature with increased lymphatic fraction in the proximity of the scaffold.  Implantation 
of BioBridge supported by lymph node fragment transfer had the most beneficial effect, with all 
animals showing no signs of lymphedema at the experimental conclusion, while BioBridge 
supplemented with VEGF-C, a surgical control in which the directional signaling was aborted, 
did not improve lymphedema condition.  Careful consideration of current methods to treat 
lymphedema in established clinical practice suggests that supplementing the vascularized 
lymph node transfer procedure with BioBridge will increase the magnitude of the clinical 
response in lymphedema patients. 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Inclusion Criteria 
The subject must be a breast cancer survivor, at least 3 years beyond completion of cancer 
therapy, free of clinical disease, and eligible for surgical intervention.  Participants who are not 
able to safely undergo general anesthesia and/or perioperative care for VLNT are excluded 
(See Exclusion Criteria 3,2,2). 
3.1.1 Ages 18 to 75 years (inclusive)  
3.1.2 Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2 
3.1.3 Life expectancy > 2 years 
3.1.4 Acquired (secondary) upper limb lymphedema secondary to breast cancer treatment 
3.1.5 The participant must be eligible for surgical intervention 
3.1.6 Swelling of 1 limb that is not completely reversed by elevation or compression   

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4 February 2020 
3.1.7 Stage II or greater lymphedema at screening, based on the International Society of 
Lymphology (ISL) staging system 
3.1.8 Participants must have no evidence of disease (NED), have completed breast cancer 
therapy 3 years prior to enrollment;  use of endocrine therapy is allowed. 
3.1.9 Completion of a full course of complete decongestive therapy (CDT), according to ISL 
guidelines at least 8 weeks prior to screening, including use of compression garments 
for at least 8 weeks without change in regimen   
3.1.10 Willingness to maintain a stable regimen of self-care, with consistent use of compression 
garments from screening through the entire study duration (through the safety follow-up 
visit).  Self-bandaging, use of nighttime compression garments, and intermittent 
pneumatic compression devices are allowed, but the procedures and  regimens are 
expected to remain consistent from screening though the entire study duration. 
3.1.11 Consistent use of an appropriately-sized compression garment for daytime use 
3.1.12 ,Two consecutive measurements of limb volume (LV) in the affected limb, taken at least 
1 day apart during the screening period, must be within 10% of each other.  A maximum 
of 3 measurements can be taken.  Affected limb volume ratio must be ≥ 20% (compared 
to unaffected limb);  volume measurements will be performed and volume ratio will be 
calculated at S1 and S2 visit. 
3.1.13 Evidence of abnormal bioimpedance ratio, if feasible, based upon unilateral disease:  
L-Dex > 10 units; bioimpedance performed at S1 and S2 
3.1.14 Willingness and ability to comply with all study procedures, including measurement of 
skin thickness using skin calipers 
3.1.15 Willingness and ability to understand, and to sign a written informed consent form 
document 
3.2 
Exclusion Criteria 
3.2.1 Edema arising from increased capillary filtration will be excluded (venous 
incompetence).  
3.2.2 Inability to safely undergo general anesthesia and/or perioperative care related to 
vascularized lymph node transfer  
3.2.3 Concurrent participation in a clinical trial of any other investigational drug or therapy, 
regardless of indication, within 1 month before screening or 5 times the drug's half-life, 
whichever is longer  
3.2.4 Recent initiation of (≤ 8 weeks), or intention to initiate, CDPT or maintenance 
physiotherapy for lymphedema at any time during the duration of the study  

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3.2.5 Other medical condition that could lead to acute limb edema, such as (but not limited to) 
acute venous thrombosis  
3.2.6 Other medical condition that could result in symptoms overlapping those  of 
lymphedema in the affected limb (eg, pain, swelling, decreased range of motion)  
3.2.7 History of clotting disorder (hypercoagulable state)  
3.2.8 Chronic (persistent) infection in the affected limb  
3.2.9 Any other infection (unrelated to lymphedema) within 1 month prior to screening 
3.2.10 Currently receiving chemotherapy or radiation therapy 
3.2.11 Current evidence of active malignancy, or a history of malignancy within the past 3 years 
(except for non-melanoma skin cancer or cervical cancer in situ treated with curative 
intent).  If the participant has undergone cancer treatment, this must have been 
completed > 3 years prior to enrollment.  
3.2.12 Current evidence of any high risk for recurrence of breast cancer  [eg, Stage III or IV;  
estrogen receptor (ER) / progesterone receptor (PR) / HER-2 negative (ie, 
“triple-negative”) cancer;  locally-advanced breast cancer;  inflammatory breast cancer;  
> 3 positive axillary lymph nodes;  extracapsular nodal extension;  invasive 
micropapillary breast carcinoma;  or if performed, genetic testing, eg, BRCA1;  BRCA2;  
Oncotype DX (high-risk recurrence score);  or Mammaprint (poor risk signature) 
indicating a high risk for breast cancer recurrence  
3.2.13 Significant or chronic renal insufficiency (defined as serum creatinine > 2.5 mg/dL or an 
estimated glomerular filtration rate [eGFR] < 30 mL/min at screening) or requires dialytic 
support  
3.2.14 Hepatic dysfunction, defined as alanine transaminase (ALT) or aspartate transaminase 
(AST) levels > 3 × upper limit of the normal range (ULN) and/or bilirubin level > 2 × ULN 
at screening  
3.2.15 Absolute neutrophil count < 1500 mm3 at screening  
3.2.16 Hemoglobin concentration < 9 g/dL at screening  
3.2.17 Known sensitivity to porcine products 
3.2.18 Hypersensitivity to iodine 
3.2.19 Pregnancy or nursing  
3.2.20 Substance abuse (such as alcohol or drug abuse) within 6 months prior to screening  
3.2.21 Any reason (in addition to those listed above) that, in the opinion of the investigator, 
precludes full participation in the study  

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3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB-approved informed consent prior to participation in any study specific procedure.  
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the medical record or research file.  
3.4 
Randomization Procedures 
We will use a blocked randomization design.  Approximately 60 subjects will be randomized in a 
4:1 ratio to the intervention arm (VLNT + BioBridge): control arm (VLNT alone).  Randomization 
will be done within blocks (of size 5) so that the balance between treatments is preserved 
throughout the trial, where A = VLNT/Biobridge and B = VLNT alone.  
The order in which these blocks will be assigned to the enrolled subjects will be prospectively, 
independently determined through a random number generator function. 
3.5 
Study Timeline 
 
 
Primary Completion: 
• 
The study will reach primary completion 48 months from the time the study opens to 
accrual.  
 
 
Study Completion: 
• 
The study will reach study completion 72 months from the time the study opens to 
accrual.  
4. 
TREATMENT PLAN 
Pre-op procedure: 
• 
LSG baseline (it may be the same as one performed for research purposes) 
• 
Venous duplex to evaluate the superficial and deep venous systems for clots and 
valvular insufficiency 
• 
ICG fluorescence lymphatic mapping to assess the superficial lymphatic system   
• 
Labs:  CBC, CMP, PT/PTT, EKG, CXR 
• 
Research samples: blood and skin samples; optional for control group  
• 
Baseline photograph of limbs 
Post-op: 
• 
LSG at 12 months (it may be the same as one performed for research purposes) 
• 
ICG fluorescence lymphatic mapping at 12 months 

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• 
Research samples: blood and skin samples; skin biopsies are optional for control group  
• 
Photograph at 12 months  
Time of procedure:  
Operating time ~6 hours, additional 45 min for BioBridge placement; anesthesia 
~10 to 12 hours, positioning, IV and arterial line placement, OR, etc (time is variable).  
Description of procedure:  
On the day of surgery, the patient will be sent to radiology for injection of Technecium-99 in the 
second web space of bilateral feet or contralateral arm in preparation for intraoperative lymph 
node transfer.  Patient will be marked in the preoperative area.  Patient will then be taken to the 
operating room, placed on the operating room table in the supine position with both arms 
abducted.  Perioperative antibiotic will be given on-call to the OR.  After general endotracheal 
anesthesia is established, the entire anterior chest, abdomen, proximal thighs and arm(s) will be 
prepped and draped in the usual sterile fashion.  A surgical pause is taken to identify the patient 
and the procedure(s) to be performed. 
Attention will be turned to the left or right groin lymph node region or right or left neck for 
supraclavicular lymph node region.  A Doppler is used to confirm the location of the lymph node 
pedicles.  Next, reverse lymphatic mapping is used as an additional method to confirm the 
location of the lymph nodes.  Technecium-99 will be injected preoperatively into the foot or hand 
(depending on donor site).  A gamma probe is used to localize the sentinel lymph node draining 
the extremity, which will be avoided during flap harvest.  The highest gamma probe count is 
noted and the donor site is deemed suitable only if the gamma probe count for the planned 
lymph node donor site is <10% of the previously noted maximum.  Indocyanine green (ICG) 
0.2 mL is injected intraoperatively into several sites along the periphery of the donor flap (lower 
abdomen or supraclavicular) for lymphatic mapping.  Fluorescence angiography is used to 
visualize the lymph nodes draining the lower abdominal wall or supraclavicular region.   
Groin donor flap:  
The lymph nodes draining the lower abdomen are visualized and correlated with the 
SCIA-based lymph nodes.  An incision is made into the lower (left or right) abdomen and the 
skin flaps are elevated just above the Scarpa fascia.  At the superior edge of the flap, the SCIV 
and SIEV are both identified and divided, with the knowledge that most of the target lymph 
nodes will lay between these vessels.  The flap will be elevated lateral to medial just above the 
sartorius fascia.  The SCIA branch to the Sartorius muscle is divided, and the SCIA and 
branches of the SCIV are mobilized to their origin and are harvested for transfer.  
The groin wound is irrigated with an antibiotic solution and hemostasis is achieved.  The 
inguinal fascia, if needed, may be reinforced with an onlay polypropylene mesh, secured with 
interrupted and running 2-0 Prolene sutures.  A Blake drain will be placed to drain the groin 

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wound.  The wound is closed with interrupted 2-0 Vicryl sutures for the Scarpa, interrupted 3-0 
Vicryl sutures for the dermis and 4-0 Monocryl running subcuticular stitch.  
Supraclavicular donor flap:  
A transverse incision, 1 cm above the clavicle in the posterior neck triangle, will be made.  The 
superior skin flap will be elevated in the subplatysmal plane using a bovie.  Dissection will 
proceed medial to lateral to include all the intervening subcutaneous tissues and lymph nodes in 
the posterior triangle below the omohyoid muscle.  The transverse cervical artery and vein will 
be identified.  Once the flap is islandized on its pedicle, a handheld Doppler is used to confirm 
perfusion in the lymph node flap.  
The pedicle to flap will be ligated and clipped.  The donor site is irrigated and hemostasis 
confirmed.  A Blake drain will be placed in the wound, and secured to the skin with Nylon suture.  
The platysma is reapproximated with 3-0 Vicryl sutures, and the wound will be closed with 
interrupted 3-0 Vicryl sutures for the dermis and 4-0 Monocryl running subcuticular stitch.  The 
incision is cleaned and dressed with dermabond, Telfa and a sterile pressure dressing. 
Next, the recipient vessels are dissected in the upper arm.  A curvilinear incision will be made in 
the medial posterior aspect of the arm above the elbow crease.  The skin flaps are elevated off 
the underlying structures using a bovie to create a pocket for the fascial-lymph node flap.  Small 
superficial veins are identified and dissected free.  The basilic vein and medial cutaneous nerve 
of the arm are identified and preserved.  The superior or inferior recurrent ulnar artery is 
identified, and dissected distally to gain pedicle length.  The lymph node dermal fat flap is then 
harvested; the SCIA and SCIVs are anastomosed to the distal end of the superior or inferior 
recurrent ulnar artery and its vena commitantes using interrupted 10-0 or 11-0 nylon sutures for 
the arterial anastomosis and venous couplers.  
SutureEase device will be used to tunnel five 15 cm long Fibralign BioBridge Collagen Matrix 
individually in the subcutaneous tissue from the lymph node flap down to the mid forearm.  
3 additional 15 cm long BioBridge Collagen Matrix are similarly tunneled proximally pass the 
shoulder toward the neck and two 15 cm long BioBridge Collagen Matrix are tunneled to the 
axilla.  Prior to implantation, the BioBridge is moistened in saline, to facilitate gliding in tissue.  
Once this is completed, the skin flaps are redrapped over the fascial-lymph node flap and 
closed with interrupted 3-0 Vicryl sutures for the dermis and 4-0 Monocryl running subcuticular 
stitch for the skin.  The total length of time spent on placement of the Biobridges is about 
45 minutes. 
At the end of the procedure, Doppler signal from the flap, correct sponge and needle counts will 
be verified.  Minimal blood loss is expected.  The patient will be awakened;  extubated;  and 
transferred to the recovery room. 

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Standard PACU recovery:  1 to 1.5 hrs.  
Hospitalization:  2 to 3 days, managed postoperative in accordance to the institution 
standardized free flap protocol. 
Post-op instructions (specific to this procedure-VLNT): patients are instructed to keep their 
surgical arm elevated x 3 weeks at level of heart or above.  Otherwise, patient may ambulate, 
eat and resume normal light activities that does not require use of treated arm.  Patients will be 
instructed to not wear compression garments for 3 weeks post-operative. 
Participants will be given consent form and contact information to take home for their 
consideration.  Samples (skin punch biopsy and blood) may be retained for future research use 
if patient has given consent (in ICF).  Pre-treatment and post-treatment photographs will be 
taken.  
Study Visits 
There are 3 screening visits.  
S1:  after obtaining written consent, medical history, symptoms, current medications, and 
allergies will be reviewed, height/weight/VS, physical exam by PI will be conducted, limb 
measurements performed (volume, BIS, caliper), and LymQoL survey completed.  
S2:  VS, weight, medication and allergy review, measurements; if measurements are 
consistent, will proceed to skin punch biopsy (optional for control group); research labs will 
be drawn.  No compression garment wear x 10 days.  
S3:  VS, weight, medication and allergy review, measurements, stitch removal, LSG.  
Patients resume wearing compression;  after 3 weeks, eligible to proceed with surgery.  
VLNT, 2 groups;  one with BioBridge scaffold (intervention group), one VLNT only 
(control group), will occur between S3 and T1 visits.  
T1 (3 months following surgery):  physical exam, measurements, LymQoL survey, 
medication and symptom/AE review, VS, weight.  
T2 (6 months following surgery):  physical exam, measurements, LymQoL survey, 
medication and symptom/AE review, VS, weight  
T3 (9 months following surgery):  physical exam, measurements, LymQoL survey, 
medication and symptom/AE review, VS, weight.  
T4 (12 months following surgery):  physical exam, measurements, LymQoL survey, 
medication and symptom/AE review, VS, weight, skin punch biopsy (optional for control 
group), research labs.  No compression garment wear x 10 days.  
T5 (10 days after T4 visit):  measurements, LymQoL survey, medication and symptom/AE 
review, VS, weight, stitch removal, LSG 

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T6 (2 years following surgery, BioBridge participants/intervention group):  physical exam, 
medication and symptom/AE review, VS, weight.  
T7 (3 years following surgery, BioBridge participants/intervention group):  physical exam, 
medication and symptom/AE review, VS, weight. 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
For VLNT, the following is routinely used pre-operatively (standard of care, SOC):   
Chlorhexidine gluconate scrub. 
Anesthesia risks (anesthesia and intubation) (SOC for VLNT placement; research for BioBridge 
placement): 
Intubation injury;  aspiration;  anesthesia awareness;  difficulty breathing after surgery;  
malignant hyperthermia;  reaction to anesthesia drugs;  nausea;  vomiting;  dry mouth;  
sore throat;  shivering;  sleepiness;  confusion;  hoarseness.  
For VLNT, the following medications are routinely used intra-operatively (SOC for VLNT 
placement; research for BioBridge placement):   
Midazolam;  fentanyl;  lidocaine;  propofol;  rocuronium;  dexamethasone;  ketamine;  
hydromorphone;  acetaminophen;  ondansetron;  antibiotic (usually cephalexin unless allergic);  
scopolamine;  magnesium;  IV fluids (saline, lactated ringers).  
Arterial line risks (SOC): Bleeding;  hematoma;  thrombosis;  infection.   
Rare risks:  permanent arterial occlusion;  pseudoaneurysm, sepsis. 
Surgical risks (SOC for VLNT placement; research for BioBridge placement): 
Bleeding;  deep vein thrombosis (DVT);  delayed healing;  death;  infection;  injury during 
surgery;  medical complications (pneumonia;  MI;  CVA;  itching;  scarring;  numbness;  
neurovascular injury;  tingling around surgical site(s);  pain;  persistent edema;  seroma;  
flaps loss;   donor site lymphedema;  bruising;  and need for reoperation.  
For VLNT, the following medications are routinely used post-operatively (SOC):   
Oxycodone;  aspirin;  ondansetron;  Bacitracin zinc ointment;  Lovenox;  hydromorphone;  
heparin infusion 
Lymphoscintigraphy (SOC for VLNT placement; research for BioBridge placement):  
LSG will be performed for both research purposes and standard of care (1-2 scans pre-surgery 
and 1 to 2 scans 12 months post-surgery).  
Lymphoscintigraphy requires four injections of 250uCi Sulfur Colloid, is performed at baseline 
and 12 months after surgery, and involves exposure to radiation.  The LSG for research are not 
necessary for medical care.  The additional amount of radiation exposure is about 7 mSv, which 
is approximately equal to 14% of the limit that radiation workers (for example, a hospital X-ray 

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technician) are allowed to receive in 1 year.  This amount of radiation involves minimal risk and 
is necessary to obtain the research information desired. 
Because the doses of radiotracer administered are small, diagnostic nuclear medicine 
procedures result in relatively low radiation exposure to the patient and the radiation risk is low.  
Nuclear medicine diagnostic procedures have been used for more than 5 decades, and there 
are no known long-term adverse effects from such low-dose exposure.  Allergic reactions to 
radiopharmaceuticals may occur but are extremely rare and are usually mild.  Injection of the 
radiotracer can be painful and may cause redness which should rapidly resolve.  
Technetium 99m sulfur colloid is a nuclear imaging agent.  The most frequently reported 
adverse reactions include rash;  allergic reaction;  hives;  allergic shock;  and low blood 
pressure.  Less frequently reported adverse reactions are fatal cardiopulmonary arrest;  
seizures;  shortness of breath;  wheezing;  abdominal pain;  flushing;  nausea;  vomiting;  
itching;  fever;  chills;  perspiration;  numbness;  and dizziness.  Local injection site reactions;  
including burning;  blanching;  redness;  swelling;  and scarring, have also been reported.  
ICG fluorescence lymphatic mapping (SOC, at baseline and 12 months post-surgery) 
ICG (indocyanine green) is a water-soluble tricarbocyanine dye, has a short plasma half-life of 3 
to 5 minutes in humans, is excreted exclusively by the liver into the bile, and is not associated 
with risk for nephrotoxicity. ICG contains sodium iodide and is contraindicated in patients with 
iodine hypersensitivity. Anaphylaxis or other allergic reactions may occur. 
Skin punch biopsy (research): 
Skin biopsies of affected limb will be performed at baseline and at 12 months following surgery 
(optional for control group).  Potential side effects include pain, infection and bleeding.  
Participants will receive 48 hours of prophylactic oral antibiotic to mitigate the potential for 
infection.  Bleeding should be minimal as only a 6 mm biopsy lesion will be utilized.  Each 
incision is closed with one suture.  
For biopsy, xylocaine with epinephrine: 
Xylocaine with epinephrine is used as a local anesthetic.  Potential risks include:  
feeling anxious;  shaky;  dizzy;  restless;  or depressed;  drowsiness;  vomiting;  ringing in your 
ears;  blurred vision;  confusion;  twitching;  seizure (convulsions);  fast heart rate;  rapid 
breathing;  feeling hot or cold;  weak or shallow breathing;  slow heart rate;  weak pulse; or 
feeling like you might pass out.  Less serious side effects include: mild bruising;  redness;  
itching;  or swelling where the medication was injected; mild dizziness; nausea; numbness in 
places where the medicine is accidentally applied.  

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For biopsy, cephalexin (unless allergic to this antibiotic): 
Cephalexin is an antibiotic.  Possible adverse effects include the following: 
• 
Central nervous system: Agitation, confusion, dizziness, fatigue, hallucinations, 
headache 
• 
Dermatologic: allergic swelling, severe rash, Stevens-Johnson syndrome, toxic 
epidermal necrolysis, hives 
• 
Gastrointestinal: Abdominal pain, diarrhea, stomach burning, gastritis, nausea , colitis, 
vomiting  
• 
Genitourinary: Genital itching, genital thrush, vaginitis, vaginal discharge  
• 
Hematologic: elevated white blood cell counts  
• 
Hepatic: abnormal liver function, jaundice , transient hepatitis  
• 
Neuromuscular & skeletal: joint aching and swelling, joint disorder  
• 
Renal: kidney inflammation  
• 
Miscellaneous: Allergic reactions 
Phlebotomy (SOC and research): 
Risks of blood samples being drawn include:  pain;  bruising;  bleeding;  inflammation;  infection;  
temporary redness of the skin where the injection is given;  and light headedness.  Care will be 
taken to avoid these difficulties.  
Bioimpedance spectroscopy (BIS) (research): 
Placement of and/or removing the pads may cause skin irritation; BIS analysis is painless. 
Calipers (research):  
The calipers may cause some discomfort due to the pinching of the skin. 
Stanford Experience 
Dr Nguyen has performed more than 100 cases of VLNT over the last 5 years.  The average 
volume reduction is 55 to 65%.  There has not been any flap loss.  There is < 5% post-operative 
infection;  < 5% wound dehiscence;  2% of seroma;  2% of hematoma;  1% post-operative deep 
vein thrombosis (DVT).  There have had no major complications.  To date, there has been 
no incidence of donor site lymphedema.  In general, this is a well-tolerated operation.  The 
positive outcome is, in part, dependent upon patient compliance with postoperative instructions. 
4.2 
Criteria for Removal from Study 
It will be documented whether or not each subject completed the clinical study.  Subjects who 
discontinue from the study early will be asked to return for a final study visit within the 4 weeks 
following the decision to withdraw.  If a subject withdraws, all efforts will be made to complete 

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and report the observations, particularly the follow-up examinations, as thoroughly as possible.  
A sincere effort will be made to contact subject either by telephone, letter, email, to determine 
the reason why they failed to return for the necessary visits or withdrew from study, and 
reason(s) will be documented. 
Reasons that a subject may discontinue participation in a clinical study may include the 
following: 
• 
Intercurrent illness that prevents continuation in study 
• 
Potential health hazard to patients, as indicated by the incidence or severity of AEs 
• 
The subject may choose to withdraw from the study at any time for any reason  
• 
General or specific changes in the patient's condition that render the subject 
unacceptable for further treatment in the judgment of the investigator  
• 
Severe non-compliance to protocol as judged by the investigator  
• 
Death  
• 
Closure of study  
4.3 
Alternatives 
Alternatives to participation in this trial include enrollment in VLNT without the addition of the 
BioBridge scaffold or standard of care treatments for lymphedema.  These include, but are not 
limited to, compression sleeves or compression devices, decongestive therapy, intermittent 
pneumatic compression devices.  In general, there are 4 types of surgical intervention for 
lymphedema, as follows. 35,36,46-48  
Lymphatic Microsurgical Preventive Healing Approach (LYMPHA), aimed at lymphedema 
prevention, was developed at the University of Genoa. 37,38  At the time of axillary lymph node 
dissection, a lymphaticovenous anastomosis (LVA) is performed to restore lymphatic flow.  
While a comparatively new procedure, for patients undergoing ALND, results have been very 
promising. 39  However, since it is aimed at lymphedema prevention, LYMPHA is not an 
appropriate alternative for this participant population, since inclusion into this trial requires a 
diagnosis of lymphedema.  
Excisional surgery, suction-assisted protein lipectomy (SAPL), pioneered by Dr Håkan Brorson, 
is performed for chronic non-pitting lymphedema.  SAPL is highly effective at removing the 
excess solid tissue (hypertrophied adipose tissue) but does not restore lymphatic function.  
Dr Nguyen, who trained with Dr Brorson, frequently performs this procedure.  Post-operatively, 
the continuous use (24 hours/day, 7 days/week) of custom compression garments is required.  
These may need to be frequently replaced in the 1st year after the procedure.  Maintenance of 
reduction is dependent on patient compliance with continuous compression garment use. 40  
SAPL is also not an appropriate alternative, since its aim is removal of excess tissue and not the 
restoration of lymphatic function.  

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Microvascular reconstruction with LVA is also performed by Dr Nguyen.  A large study, by 
Chang, et al, noted that LVA, is most effective in early stage lymphedema of the upper 
extremity.  Early volume reduction may be seen in the first postoperative week but maintenance 
of response is unknown due to short follow-up. 41  Additionally, LVA may not enhance the 
regional immune impairment that accompanies lymphedema. 
Tissue transfer, ie, vascularized lymph node transfer (VLNT), when successful, is intended to 
optimally restore both lymphatic circulatory and immune function.  The BioBridge scaffold has 
been designed, and tested in preclinical animal models, to optimize the surgical outcome 
specifically in vascularized lymph node transfer.  It is this surgical intervention that is under 
specific investigation in this protocol. 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
 Investigational Agent/Device/Procedure   
Complete information about the investigational device can be found in the Investigator’s 
Brochure and IDE document.  
The BioBridge Collagen Matrix is a sterile implantable biocompatible and biodegradable surgical 
mesh ribbon comprised of highly purified porcine collagen that is designed to provide 
mechanical support and repair for weaknesses and deficiencies in soft tissue.  The device was 
cleared by CDRH Division of Surgical Devices on 8 January 2016 under 510(k) K151083 for use 
as a collagen-derived surgical mesh for plastic and reconstructive surgery.  For the purposes of 
this investigation, the commercially-available device will not be altered or modified in any way. 
The collapsed ribbon structure of BioBridge is comprised of a single sheet of cross-linked 
collagen collapsed into multiple folds forming a thin membrane with aligned collagen fibrils in the 
same lengthwise direction.  This scaffold structure provides mechanical properties that 
contribute to strong tensile strength, which provides support to weaknesses and deficiencies in 
soft tissue and aids in bridging a connection between two healthy soft tissues. 
BioBridge is fabricated using a proprietary manufacturing process that produces a narrow and 
very thin ribbon-like membrane comprised of aligned collagen fibrils, creating a multi- luminal 
structure that can be sutured, and provides the desired mechanical properties for support of soft 
tissue repair.  This approach presents the opportunity to enable the use of highly purified 
collagen, in a defined structure that has mechanical properties similar to those of the predicates, 
but without undesirable telopeptides found in collagen matrices derived from animal dermis.  
The smaller ribbon-like form factor also gives the surgeon greater flexibility for minimally 
invasive delivery and to tailor their procedures to better address a specific patient need, where 
one or more BioBridge devices can be implanted depending on the surgeon’s discretion. 
Fibralign sources the highly purified Type I porcine-derived collagen from a FDA registered and 
ISO-qualified supplier.  Fibralign employs a proprietary manufacturing process that takes highly 
purified Type I porcine-derived collagen and produces narrow, ribbon-like membranes 

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comprised of highly aligned collagen fibrils that mimic desired mechanical properties found in 
natural extracellular matrices.  A chemical crosslinking agent, known as EDC 
[N-ethyl-N’-(3 -dimethylaminopropyl)carbodiimide], is used during the manufacturing process to 
promote the crosslinking of the collagen but the crosslinker itself is not added to nor bound to 
the collagen matrix.  The crosslinker residuals are water soluble and are removed by product 
rinsing at the end of the production process.  The final product is packaged into individual 
storage tubes and then sealed in a multi-pack and terminally sterilized. 
BioBridge is fabricated using a proprietary manufacturing process that collapses a single sheet 
layer along the width direction to form a scaffold, comprised of collagen fibrils (see Figure 1). 
 
Figure 1. BioBridge Collagen Matrix. 

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BioBridge has a thickness in a range of 0.10 mm to 1.0 mm, and the device is available in 
lengths over 1500 mm. 
Extensive safety and performance testing has been completed for BioBridge in support of the 
510(k) clearance, including biocompatibility and degradation studies, as well as full material 
characterization of the collagen content and manufacturing reagents used in fabricating 
BioBridge (provided as part of the 510(k) submission).  Significant efforts have been made in 
sourcing materials, product design and device manufacturing to minimize potential risks 
associated with the device.  
These include: 
1)  BioBridge is made of highly-purified, pepsin-treated porcine Collagen Type I.  The material 
is sourced from Datum Dental, which is referenced in the FDA 510(k).  The same material is 
used in ColBar Ossix and ColBar Ossix Plus which have 510(k) clearance and CE mark and 
been used in over 350,000 implant procedures worldwide.  Porcine-derived collagen matrix 
products have a long history of safe use as a surgical support device where the physical 
construct of the implant can provide a bridging material to support a desired surgical 
outcome.  This same type of collagen is commonly used in very sensitive applications like 
dura layers involving the spinal cord and brain. 
2) BioBridge is manufactured from this highly purified collagen in a GMP cleanroom facility 
under Class-100 hoods with upmost care and then e-beam sterilized after packaging.  This 
has been supported by shelf life age testing and sterilization validation. 
3) The BioBridge matrix is a very narrow ribbon, a thread-like structure that has a similar form 
factor to suture.  In practice, the proposed treatment involves a very small amount of bulk 
material (10 mg/device, with 4 to 10 devices/patient) being implanted subcutaneously. 
4) BioBridge has been shown to be biologically more inert than catgut suture, which is being 
commonly used in the surgical procedures proposed in the study.  This was demonstrated in 
four GLP implantation studies that were performed in support of the 510(k) application.  The 
subcutaneous implantation studies (2, 13 and 26 week) have shown that BioBridge was 
considered non-irritant and determined to have less inflammatory reaction than the control 
articles (catgut suture).  These implantation studies have also shown that BioBridge 
integrates well and safely absorbs in subcutaneous tissue in 6 to 9 months. 
5) Based on review of approved surgical meshes and earlier testing of BioBridge, it is not 
anticipated that implanting this small amount of purified collagen into this treatment area will 
create additional complications to the damaged lymphatic tissue.  None of BioBridge’s 
predicate devices have counter indications for use with patients that have lymphedema.  A 
further review of the larger surgical mesh devices that are made of extracellular matrix and 
widely used in breast reconstruction surgical procedures for similar patients also did not 
show any contraindications for lymphedema.  Preliminary results from the Dominican 
Republic pilot study provide assurance about this safety, no complications have been 
reported to date with 55 devices implanted in 8 subjects.  Furthermore, in the preclinical 

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large animal lymphedema study, there were neither overt complications nor any histological 
evidence of significant inflammatory reaction or other complications observed with the 120 
devices implanted. 
6) In this proposed treatment, BioBridge is not intended to replace normal body structure or 
provide full mechanical strength.  The device will be implanted in the surgical area during 
transplantation in subcutaneous soft tissue and not intended to come in direct contact with 
damaged lymphatic vessels.  Even if the device ends up not providing the mechanical 
function as intended (fails), it is not expected to be catastrophic or to materially impact the 
subject.  If a failure occurs, the surgical outcome would be expected to be the same as the 
control group receiving the ALNT procedure without the device, which is the current 
standard of care for lymphedema patients. 
5.2 
Availability 
The investigational device will be provided by Fibralign Corporation.  It will be ordered 
specifically for each subject and will be shipped directly to the PI/Co-PI.  
5.3 
Agent Ordering 
Request for shipments will be coordinated between Stanford PI/Co-PI and Fibralign 
Corporation.  
Fibralign Corporation 
32930 Alvarado-Niles Rd,  Suite 350 
Union City, CA 94587 
xxx-xxx-xxxx 
5.4 
Agent Accountability 
The investigational device will be stored in secure location.  Only authorized OR staff and study 
staff will have access to this device.  Study investigators will perform accountability. 
6. 
DOSE MODIFICATIONS 
N/A (device) 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events  
BioBridge is contraindicated for use in any patient with known sensitivity to porcine products.  
Possible adverse reactions may include, but not limited to contamination, infection, 
inflammation, allergic reaction, adhesions, and tissue encapsulation.  If infection or allergic 
reaction occurs, the entire matrix may have to be revised or removed.  
From October 2015 to Oct 2016, a pilot study was conducted in the Dominican Republic.  A total 
of 55 BioBridge threads were implanted into 8 participants with no reported complications 

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(Hadamitzky, 2016. 43  Personal communication, Drs M Escarraman and C Hadamitzky, 
4 April 2017).  
Physical exam will be performed at study visits to assess patient safety.  Additionally, the 
subjects will have direct contact information for use 24 hours/day, 7 days/week to report 
concerning symptoms.  Adverse events will be reported as below. 
7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v5.  Both Serious and Non-Serious Adverse 
Events will be clearly noted in source documentation and listed on study specific Case Report 
Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse Event (AE) to 
determine whether it is unexpected according to the Informed Consent, Protocol Document, or 
Investigator’s Brochure, and related to the investigation.  All Serious Adverse Events (SAEs) will 
be tracked until resolution, or until 30 after the last dose of the study treatment.  
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation.  Following review by the 
DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the IRB 
using e-Protocol within 10 working days of DSMC review, or within 5 working days for deaths or 
life-threatening experiences. 
7.3 
Stopping Rule  
The study will be terminated if more than 1 of the first 10 subjects experience an infection 
related to the BioBridge device.  If, after the first 10 subjects are treated, a rate > 10% of 
BioBridge-related infections is observed, accrual will be paused for a safety review.  The 
Stanford Cancer Institute (SCI) Data Safety Monitoring Committee (DSMC) will be informed of 
any such review.  
8. 
CORRELATIVE/SPECIAL STUDIES  
8.1 
Laboratory Correlative Studies 
Pre-treatment and post-treatment skin punch biopsies will be performed by PI.  All research 
samples (blood and tissue) will be coded with the study participant identifier, and are collected 
by research team members.  Experimental processing will be performed in PI's research lab in 
CCSR.  
8.1.1 The histologic analysis will be performed by means of immunohistochemistry (IHC) and 
hematoxylin and eosin (H&E) staining of pre and post treatment biopsied tissue will be 
undertaken.  Participants in this study will be consented for skin punch biopsies of the affected 
arm prior to treatment as well as post treatment (optional for control group).  Two 6 mm 
full-thickness skin punch biopsy specimens will be obtained from the medial aspect of the 
forearm of affected limb, with an Acu-Punch (Fort Lauderdale, FL) disposable device.  Biopsy 

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specimens will be immediately placed in formalin.  Following biopsy, the skin edges will be 
sutured with a single butterfly suture, and the participant will receive a prophylactic antibiotic 
regimen of cephalexin 250 mg, 4 times daily for 2 days, or an equivalent regimen (if allergic to 
cephalexin).  Skin punch biopsy will be performed at baseline and at completion (12 months 
post-treatment).  
Paraffin-embedded tissue sections will be stained with hematoxylin-eosin (H&E, Richard-Allan 
Scientific, USA), goat polyclonal anti-LYVE-1 antibody (1:200, Santa Cruz Biotechnology, USA), 
5-LO (Cell Signaling 3289), macrophage (Agilent Dako KP1), or neutrophil 
(anti-Myeloperoxidase antibody, Ab9535 Abcam); cutaneous lymphatic microvascular area will 
be quantitated through immunohistochemical staining of podoplanin with anti-D2-40 antibody 
(Dako IS072).  Tissue samples will be sliced in 10 µm-thick sections, and evaluated 
microscopically.  
The impact of treatment on cutaneous histopathology will be evaluated through the use of an 
empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, 
deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was 
developed by a dermatopathologist.  The scoring of the specimens for this study will be 
performed by a blinded observer.  Each characteristic will be weighted equally and each 
specimen will be assigned a cumulative subscale score (0 to 5) will be summed for a total score 
(0 to 20); higher scores indicate a greater degree of pathology.  A quantitatively higher negative 
change will indicate a more favorable histological therapeutic response. 
8.1.2  Luminex Bead Assays.  Blood will be drawn in standard fashion, centrifuged for 10 
minutes in 4°C room (CCSR 3112), plasma divided into microfuge tubes, and frozen at −80°C 
for biomarker analysis.  
Custom human 62-plex kits (Affymetrix, Santa Clara, CA) will be utilized according to the 
manufacturer’s recommendations with modifications as described below.  Plasma samples will 
be mixed with antibody-linked polystyrene beads on 96-well filter-bottom plates and incubated at 
room temperature for 2 hours followed by overnight incubation at 4°C.  Plates are 
vacuum-filtered and washed twice with PBS+0.2% Tween-20, followed by incubation with 
biotinylated detection antibody for 2 hours at room temperature.  Samples are filtered and 
washed twice as above and re-suspended in streptavidin-PE.  After incubation for 40 minutes at 
room temperature, 2 additional vacuum washes are performed, and the samples are 
re-suspended in Reading Buffer.  Each sample will be measured in duplicate.  Plates will be 
read using a Luminex 200 instrument with a lower bound of 100 beads per sample per analyte.  
8.1.3  RNA analysis.  Tissue from the skin biopsies may be homogenated in a laboratory 
blender.  These samples will be stored frozen at -80° C, and later analyzed for total RNA 
content;  integrity,  up- and down-regulation analysis;  and possibly other tests, except the RNA 
samples will not be used for sequencing analyses.  

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9. 
STUDY CALENDAR 
 
Pre-
Study S1 
S
2 S3 
Surgery:  VLNT 
with BioBridge 
(BB) Or 
VLNT only 
T1 
Mo. 3 
T2 
Mo. 6 
T3 
Mo. 9 
T4 
Mo. 12 
T5 
D-10
FU 
T6 2-yr FU 
(BB group 
Only) 
T7 3-yr FU 
(BB group 
Only) 
Investigational Device 
(BioBridge Matrix) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Performance status 
(ECOG) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, platelets 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Measurements (BIS, VM, 
calipers) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
LymQoL survey 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
Skin punch biopsy  
(optional for control group) 
 
 
X 
 
 
 
 
 
X 
 
 
 
Research labs 
 
 
X 
 
 
 
 
 
X 
 
 
 
Radiologic evaluation 
(Lymphoscintigraphy) 
 
 
 
X 
 
 
 
 
 
X * 
 
 
Pregnancy test (as 
indicated) 
 
 
 
 
 
 
 
 
 
 
 
 
* BioBridge Matrix recipients only. 
10. 
MEASUREMENTS  
Primary and Secondary Assessments  
For each analysis undertaken, primary and secondary, participants will be randomized into one 
of two groups:  VLNT (control arm) or VLNT-BioBridge (intervention arm).  Change in 
intervention group compared to control group will be evaluated.  

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10.1 Primary Outcome 
To determine whether the addition of the BioBridge scaffold to vascularized lymph node transfer 
will improve the outcome of surgical treatment of secondary arm lymphedema resulting from 
treatment of breast cancer.  Primary endpoint is % change in (excess) limb volume, from 
baseline to Month 12, in the intervention group relative to control group.  Dispersion (variance) 
will be assessed as the standard deviation.  
The single subject enrolled to this study prior to the December 2019 revision will not be included 
in the primary outcome analysis nor the final analysis, due to the significant changes in the 
study.  
10.1.1 Relevant Subset  
Target population, for both groups, are participants with unilateral upper extremity lymphedema, 
secondary to breast cancer treatment, who plan to undergo VLNT.   
10.1.2 Measurement Definition 
Quantitative assessment of limb volume (mL) of the affected limb at study end (Month 12) will 
be compared to pre-intervention (baseline) value.  Baseline value is defined as the arithmetic 
mean of measurements obtained at the two qualifying screening visits.  Mean difference in limb 
volume in the intervention group relative to control group at study end (Month 12) following 
surgical intervention will be evaluated.   
10.1.3 Measurement Methods 
Limb volume quantification, of affected and non-affected limbs, will be performed using 
circumferential measurements of the limb, at 4 cm intervals beginning at the wrist.  The limb 
volume will be determined using a truncated cone formula{(volume = πh(R2 +Rr +r 2)/3, let h be 
the height, R the radius of the lower base, and r the radius of the upper].  Limb circumference, 
for calculation of limb volumes, will be serially measured at screening evaluations and in 
follow-up to study end (Month 12).  For quantitative analysis, the volume of the ipsilateral arm 
will be expressed as a percentage of the unaffected arm volume and of the pre-treatment 
volume of the ipsilateral arm. 
10.1.4 Measurement Time Points 
Limb circumference, for calculation of limb volumes, will be measured at screening evaluations 
to scheduled follow-up visits (Month 3, 6, 9, 12).  The primary endpoint will be assessed at time 
point, 12 months.  
10.1.5 Response Review 
Results will be evaluated by a designated, independent, blinded reviewer.  
10.2  Secondary Outcome 
Change in measurement of dermal thickness, as measured by caliper skin fold thickness, from 

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baseline to Month 12, in the intervention group relative to control group. 
10.2.1 Relevant subset 
The target population are participants with unilateral upper extremity lymphedema, secondary to 
breast cancer treatment, who plan to undergo VLNT.  
10.2.2. Measurement Definition 
Measurement of dermal thickness at study end (Month 12) will be compared to pre-intervention 
(baseline) value.  Baseline value is defined as the arithmetic mean of values (with standard 
deviation) obtained at the two qualifying screening visits.  Mean difference in dermal thickness 
measurement in the intervention group relative to control group at study end (Month 12) 
following surgical intervention will be evaluated.  Dispersion (variance) will be assessed as the 
standard deviation.  
10.2.3 Measurement Methods 
Skin thickness measurements (in mm) will be performed with a Lange skinfold caliper (Beta 
Technology, Santa Cruz, CA).  For each participant, at each assessment, 3 measurements will 
be obtained: the dorsum of the hand, the midpoint of the volar aspect of the forearm, and the 
midpoint of the medial aspect of the upper arm.  At the initial evaluation, a dermatographic 
pencil is used to mark the site of each measurement.  Once the locations are determined, the 
location is noted (measured from the wrist).  These locations will be re-utilized for serial 
measurements for each follow-up visit.  Calipers are calibrated prior to each use.  Assessor will 
be blinded to treatment status.  Pre and post-surgical aggregate scores of lymphedema-affected 
limb will be utilized and reported.  
10.2.4 Measurement Time Points 
Skin thickness measurements will be performed at screening evaluations to scheduled follow-up 
visits (Month 3, 6, 9, 12). 
10.2.5 Response Review 
Results will be evaluated by a designated, independent, blinded reviewer.  
10.3  Exploratory Objectives and Endpoints 
Exploratory Outcomes have not been defined for ClinicalTrials.gov. 
10.3.1 Change in lymphedema Quality of Life (LymQOL)  
Change in lymphedema Quality of Life (LymQOL) aggregate score, from screening evaluations 
to scheduled follow-up visits (Month 3, 6, 9, 12).  
10.3.1.1 Relevant Subset 
The target population is comprised of patients with unilateral upper extremity lymphedema, 
secondary to breast cancer treatment, who plan to undergo VLNT.  

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10.3.1.2 Measurement Definition 
LymQoL survey is a validated, self-reported outcome questionnaire, developed by experienced 
healthcare professionals in the lymphedema service in the UK (Keeley, et al, 2010).  Questions 
cover four areas: symptoms, body image/appearance, function and mood.  Answers are scored 
1 to 4 (less severe to severe).  LymQoL survey will be used to assess change as a result of 
intervention.  Change = Month 12 aggregate score - baseline aggregate score).  Baseline score 
is defined as the arithmetic average of values obtained at the 2 qualifying screening visits.  
10.3.1.3 Measurement Methods 
Participants will complete the LymQoL survey at each visit, starting with S1 visit through 
Month 12.  The LymQoL will be completed prior to performance of efficacy assessments 
(volume measurements, skin caliper measurements, L-Dex BIS).  
10.3.1.4 Measurement Time Points 
LymQoL surveys will be administered at baseline to Month 12 follow-up visit (Month 3, 6, 9, 12). 
10.3.1.5 Response Review 
Results will be evaluated by a designated, independent, blinded reviewer.  
10.3.2 Change in lymphatic flow function  
Change in lymphatic flow function by serial radionuclide lymphoscintigraphy (LSG).  
10.3.2.1 Relevant Subset 
The target population are participants with unilateral upper extremity lymphedema, secondary to 
breast cancer treatment, who plan to undergo VLNT.  
10.3.2.2. Measurement Definition 
For LSG, a significant improvement in the scintigraphic uptake of the transplanted LN 
(continuous variable); improvement in the uptake of the radionuclide in a defined 
region-of-interest (ROI) within the proximal LN drainage pathway (axilla); improvement in the 
reduction of scintigraphic density in a defined ROI for dermal  backflow,  and  improvement  in  
the  disappearance rate  constant  from  the injection site. 
10.3.2.3 Measurement Methods 
LSG: Universal protocol (correct patient, site, procedure) will be adhered to prior to instigation of 
procedure.  After bilateral fingers webs are prepped in a sterile manner, technetium 99m-labeled 
colloid (radioactive tracer) is injected intradermally around the web spaces of the second and 
fourth digits (total of 4 point injections).  Immediate and delayed (2 hours and 4 hours) static 
planar images are obtained.  
10.3.2.4 Measurement Time Points 
LSG will be performed at baseline and 12 months post procedure 

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10.3.2.5 Response Review 
LSG will be evaluated by the co-investigator, Andre Iagaru, MD, Chief of Nuclear Medicine, who 
will be blinded the subjects’ treatment status.  
10.3.3  Change in L Dex bioimpedance  
Change in L-Dex bioimpedance spectroscopy (L-Dex BIS), from baseline to Month 12, in the 
intervention group relative to control group. 
10.3.3.1 Relevant Subset 
The target population are participants with unilateral upper extremity lymphedema, secondary to 
breast cancer treatment, who plan to undergo VLNT.  
10.3.3.2 Measurement Definition 
L-Dex BIS value of the affected limb at study end (Month 12) will be compared to 
pre-intervention value.  Baseline value is defined as the arithmetic average of values obtained at 
the two qualifying screening visits.  Mean difference L-Dex BIS values in the intervention group 
relative to control group at study end (Month 12) following surgical intervention will be 
evaluated.  
10.3.3.3 Measurement Methods 
L-Dex BIS utilizes transcutaneous transmission of a very low frequency, subliminal electrical 
current to determine extracellular fluid volume.  It is a form of widely used body composition 
analysis.  
After cleaning the skin (to remove body oils), electrodes are placed on top of the skin of the limb 
being measured (for arms, at wrist and top of arm).  A 4-electrode configuration will be used to 
non-invasively assess the extracellular and intracellular fluid contents of the limb.  The probes 
are attached to the electrode itself.  Measurement setting is selected and the bioimpedance at 
an extrapolated frequency = 0 (R0) correlates to the volume of extracellular fluid.  The applied 
current used is 200uA RMS, at a variable frequency of 4 kHz to 1000 kHz.  
Participant data will be entered into the device software (encrypted research-dedicated laptop).  
Data will be analyzed according to Cole theory, using the manufacturer's software (ImpediMed 
Ltd.), to provide values for a bioimpedance ratio (Ro), the resistance of the extracellular fluid 
including lymph, R∞ the resistance of total tissue fluid and Ri, the resistance of the intracellular 
fluid.  For unilateral lymphedema, the ratio of Ro in the affected:unaffected limbs will be 
analyzed as a measure of the bioimpedance attributable to the extracellular fluid content.  Ro 
level of 1.034 is considered normal; values ≥1.034 are considered abnormal.  Efficacy profile in 
lymphedema has been widely documented and this technology is currently utilized for 
subclinical lymphedema screening of the relevant cancer survivor population in the Stanford 
Cancer Institute.   

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10.3.3.4 Measurement Time Points 
L-Dex BIS will be performed at screening evaluations to scheduled follow-up visits (Month 3, 6, 
9, 12). 
10.3.3.5 Response Review 
Results will be evaluated by a designated, independent, blinded reviewer.  
10.3.4  Change in cutaneous histological architecture 
Change in cutaneous histological architecture, from baseline to Month 12, in the intervention 
group.  
10.3.4.1 Relevant Subset 
The target population are participants with unilateral upper extremity lymphedema, secondary to 
breast cancer treatment, who plan to undergo VLNT.  
10.3.4.2 Measurement Definition 
Quantitative assessment of paired histological specimens of lymphedema skin pre- and 
post-intervention.  The impact of intervention on cutaneous histopathology will be evaluated 
through the use of an empirically-derived scoring system (comprised of dermal thickness, 
intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this 
quantitative assessment was developed and will be performed by a dermatopathologist.  Each 
characteristic will be weighted equally and each specimen will be assigned a cumulative 
subscale score of 0 to 5 (normal to severe).  The scores were summed for a total score (range: 
0 to 20) which is presented here.  Higher scores indicate a higher degree of pathology.  
A quantitatively higher negative change indicates a more favorable therapeutic response in the 
histology. 
10.3.4.3 Measurement Methods 
Standard protocol (correct patient, site, procedure) will be adhered to prior to instigation of 
surgical procedures.  After consent is obtained and completion of time-out, area will be prepped 
in a sterile manner, area anesthetized, and skin punch biopsies of the affected arm will be 
performed (optional for control group) by PI.  Two 6 mm full-thickness skin punch biopsy 
specimens will be obtained from the medial aspect of the forearm of affected limb, with an 
Acu-Punch (Fort Lauderdale, FL) disposable device.  Biopsy specimens will be immediately 
placed in formalin, or an OCT (optimal cutting temperature compound), or frozen for RNA 
analysis (will not be used for sequencing analysis).  Skin punch biopsy will be performed at 
baseline and at Week 48 visit.  
Paraffin-embedded tissue sections will be stained with hematoxylin-eosin (H&E, Richard-Allan 
Scientific, USA);  goat polyclonal anti-LYVE-1 antibody (1:200, Santa Cruz Biotechnology, 
USA);  cutaneous lymphatic microvascular area will be quantitated through 
immunohistochemical staining of podoplanin with anti-D2-40 antibody (Dako IS072).  Tissue 

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samples will be sliced in 10 µm-thick sections, and evaluated microscopically.  
The impact of treatment on cutaneous histopathology will be evaluated through the use of an 
empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, 
deep dermal collagen content, and perivascular infiltrate);  this quantitative assessment was 
developed by a Stanford dermatopathologist published lymphedema studies.  The 
dermatopathologist for this investigation will be blinded to participant treatment status.  Each 
characteristic will be weighted equally and each specimen will be assigned a cumulative 
subscale score (0 to 5) will be summed for a total score (0 to 20);  higher scores indicate a 
greater degree of pathology.  A quantitatively higher negative change will indicate a more 
favorable histological therapeutic response.  
10.3.4.4 Measurement Time Points 
Pre- and post-intervention (Month 12) skin punch biopsies, of affected limb will be performed. 
10.3.4.5 Response Review 
Histology will be assessed by a dermatopathologist blinded to the participant’s treatment status.  
11. 
REGULATORY CONSIDERATIONS 
11.1 Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (eg, advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.  The Protocol Director will disseminate the protocol amendment information to 
all participating investigators. 
11.2 Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study: regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review serious 
adverse events and protocol deviations associated with the research to ensure the protection of 
human subjects.  Results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as 
needed. 
11.3 Data Management Plan 
The Protocol Director and his research team will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific 

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Case Report Forms (CRFs) will document treatment outcomes for data analysis.  Case report 
forms will be developed using the Oncore database system and will be maintained by Principal 
Investigator and his research team.  CRFs (paper documents) will be kept in a secure location, 
not accessible to the public.  
12. 
STATISTICAL CONSIDERATIONS 
12.1 Statistical Design 
This study is open-label due to visibly apparent differences between the recipients of the 
surgery.  
Primary Endpoint:  
The primary outcome is the post-surgical % change in excess limb volume, measured at 
12 months, following the surgical procedure.  
Secondary Endpoint: 
For secondary endpoint, the mean response of the intervention group will be compared to the 
control group, for change in measurement of dermal thickness, as measured by caliper skin fold 
thickness, from screening evaluations to Month 12.  
12.1.1 Randomization 
A blocked randomization design will be used for randomization.  Sixty subjects will be 
randomized in a 4:1 ratio to the intervention arm (VLNT + BioBridge) or control arm (VLNT 
alone).  
12.2 Interim analyses 
Not planned.  
12.3 Descriptive Statistics and Exploratory Data Analysis 
Not planned.  
12.4 Primary Analysis  
Limb circumference of the affected and unaffected limbs of each participant will be measured for 
calculation of the volume of the arm through the truncated cone formula. 23  Circumferential 
measurements of each limb will be obtained with a low stretch gauged tape measure applied at 
specified intervals of 4 cm (starting from the 3rd metacarpal head) along the axis of the arm, 
beginning at the wrist.  Anatomic landmarks are recorded to facilitate reproducibility between 
pre- and post-surgical measurements.  This method is inexpensive, reproducible, and easily 
applied.  These measurements will be performed at initial evaluation and at each scheduled 
follow-up visit.  The pre-surgical baseline volume for each limb will be defined as the average of 
the two measurements obtained on study day S1 and study day S2.  For quantitative analysis, 
the excess volume of the limb is defined as the arithmetical difference between the affected 

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limb (Lpre) and the contralateral normal limb (Cpre) and the % excess volume at the beginning of 
the study is defined by:   
100% * [(Lpre – Cpre)/Cpre]. 
The primary outcome is defined the post-surgical % change in excess limb volume: 
100* {1 - [(Lpost – Cpost)/( Lpre – Cpre)]} 
Analysis Population 
Participants are randomized into 1 of 2 arms, the intervention arm (VLNT with BioBridge) or 
control arm (VLNT-only).  The primary analysis will include all participants who have completed 
all required study visits.  However, for participants who do not complete the study, their data will 
be censored and analyzed with the current population.  Treatment summary and adverse event 
data will also be provided for each treatment category separately. 
Efficacy and safety analyses will be performed on all participants who have undergone VLNT 
(with or without BioBridge).  The primary analysis will include all participants who have 
completed all required study visits and procedures.  However participants who do not complete 
the study will be censored and their data will be analyzed, along with ongoing participants.  Data 
including adverse event data will be captured for each treatment category separately. 
Analysis Plan 
The final analysis will be undertaken after the final enrolled participant completes all planned 
study events.  At that time, the data will be unblinded and the analyses will be undertaken as 
described above.  There will be multiple analysis populations.  The primary analysis will use all 
subjects enrolled and assigned to treatment, categorized by their planned treatment.  A 
sensitivity analysis will use the set of subjects enrolled and treatment-assigned in the study who 
completed the study protocol, categorized according to treatment actually received. 
Generalized linear mixed effects models are maximum likelihood based methods that are ideal 
for handling missing outcome data.  More specifically, in prospective clinical trials such as the 
one proposed, a major concern is loss to follow up.  The model we have proposed 
accommodates anticipated loss to follow up and allows us to analyze subjects treated in the 
study even if they are lost to follow up, ie, if a subject is lost to follow up, the subject is included 
in the analysis if at least one post-baseline value is recorded prior to loss to follow up).  This 
model relies on a flexible assumption about the missing data, namely that the missing values 
are missing at random (ie, that missingness is related to observed values only such as baseline 
volume values and treatment arm).  Given the nature of the data generated, we believe this to 
be a reasonable assumption. 
To allow for the possibility that the response variable may not have a linear relationship with the 
time variable, we will treat time as a categorical variable to allow time to have a non-linear 
relationship with the response.  The categorical time variable can take on values of 3, 6, 9, or 

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12 months.  We will conduct the primary analysis to evaluate whether there is a difference 
between the treatment and control arms in the volume reduction of the affected limb at 
12 months.  We will fit the linear mixed effects model below assuming an AR(1) covariance 
structure.  We will evaluate the sensitivity of our assumption about the covariance structure by 
assuming an unstructured covariance in a sensitivity analysis.  Let 
 represent the reduction in 
volume of the affected limb for subject i at time j (for j = 3, 6, 9, and 12 months), 
 be the 
random intercept for subject i, 
 be the error for subject i at time j,  
 be an indicator for 
whether subject i is in the BioBridge arm, and 
;  
;  
;  
 be indicators for 
whether a measurement on subject i at time j was taken at Month 3;  6;  9;  or 12, respectively.  
To assess whether there is a volume reduction of the affected limb at 12 months, we will test the 
null hypothesis that 
 vs the alternative hypothesis of 
. 
 
 
We will  also perform a sensitivity analysis where we only include subjects with complete data 
who can provide quantitative changes.  Such an analysis relies on an assumption that the data 
are missing completely at random, an assumption that we do not feel is practical in most clinical 
trial settings and certainly not here.  The motivation for performing this analysis; however, allows 
us to assess how robust our findings are to deviations in our assumptions of missingness.  A 
final sensitivity analysis will be performed where we impute data using multiple imputation 
techniques that rely on an assumption that the data are NOT missing at random.  More 
specifically, our imputation model will assume those with missing values in the treatment arm 
are less likely to have a salutary treatment effect.  Such sensitivity analyses will provide a 
context in which we can appropriately interpret the primary findings.  In this sensitivity analysis, 
we will assume a range of volume reductions in the treatment arm (eg, 90%;  75%;  50% of the 
reduction observed in the control arm).  If we find a statistically significant reduction in the 
treatment arm as compared to the control arm, the range of reductions will be chosen such that 
the range covers the “tipping point” where the difference in the two arms is no longer statistically 
significant.  This “tipping point” analysis is in place of a worst-case sensitivity analysis because 
there is not a clearly defined “worst-case” in a non-binary outcome.  Our sensitivity analysis will 
follow the advice given in “Strategy for intention to treat analysis in randomized trials with 
missing outcome data.” 25  
12.5 Secondary Analysis 
For secondary endpoint, change in measurement of dermal thickness (screening evaluations to 
Month 12), as measured by caliper skin fold thickness, the mean response of the BioBridge 
recipients to ALNT only participants will be compared.  The statistical methods used for the 
secondary endpoints will follow the methods used for the primary endpoints. 

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12.5.1 Analysis Population 
N/A;  no subset analysis 
12.5.2 Analysis Plan 
The same analysis plan will be used for secondary endpoint as was used for the primary 
endpoint.  
Exploratory Endpoints and Outcomes 
L-Dex: Multiple frequency bioelectrical impedance analysis (MFBIA) will be performed with the 
impedance device.  This tool utilizes multiple frequency electrical current (1 kHz to 500 kHz) to 
determine extracellular fluid (ECF) volume.  At low frequency (< 50 kHz) current does not 
penetrate the cell membrane into the intracellular space, as opposed to high frequency current 
(> 200 kHz).  As a result, intracellular and extracellular volumes can be measured 
separately. 26-29  An impedance value, the L-Dex score, can then be calculated which is 
inversely proportional to the fluid content of the compartment.  This noninvasive approach has 
been evaluated for its capacity to detect subtle disease and to predict the advent of clinically 
relevant edema. 30-32  MFBIA is predicted to have the requisite sensitivity and specificity to 
detect the feasibly small differences in retained interstitial fluid that might discriminate the 
therapeutic responses of the treated patients.  MFBIA will be measured at screening evaluations 
and at each follow-up visit.  A standardized quantitative score, the L-Dex score, will be 
generated for the ipsilateral and contralateral limb. 30  This will be done as specified in the 
treatment plan above.  It has been established that a 10-point change in L-Dex score 
corresponds to 3 standard deviation(SD) range from the mean. 30,31  See Figure 3 below.   
 
Figure 3.  10-point change in L-Dex score corresponds to 3 SD range from the mean  
(obtained from ImpediMed L-DEX technical bulletin). 30,31  

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Change in lymphatic flow function by serial radionuclide lymphoscintigraphy (LSG): 
Significant improvement in the scintigraphic uptake of the radionuclide in a defined ROI within 
the proximal LN drainage pathway (axilla); improvement in the reduction of scintigraphic density 
in a defined ROI for dermal backflow, and improvement in the disappearance rate constant from 
the injection site. 
Change in the lymphedema Quality of Life (LymQOL) score: 
Greater improvement in the aggregate score on the validated instrument. 
Change in quantifiable skin histopathology, optional for control group:  greater reduction in 
dermal-epidermal thickness, greater reduction in dermal collagen thickness, and greater 
improvement in lymphatic vascular size and density. 
12.6  Sample Size 
12.6.1 Accrual estimates 
Dr Rockson directs a national referral center for lymphatic disorders and approximately 600 new 
patients with clinically significant lymphedema are seen in on a yearly basis.  Some of these 
patients are referred from the breast clinic but majority comes from local and regional physician 
offices.  Dr Nguyen performs 15 to 19 vascularized lymph node transfers yearly (of subjects who 
meet the eligibility criteria).  We expect to be able to accrue subjects to this study within 
48 months.  Once study has been approved and is enrolling, in order to facilitate enrollment in 
the allotted time frame, we plan to add 3 subsites in order to meet accrual goal.  
12.6.2 Sample size justification 
In order to successfully test the null hypothesis, we have performed sample size calculations.  
After careful review of the published literature, we are able to identify a study in which the effect 
of the surgery on limb circumference (as a surrogate for limb volume) has been quantitated and 
for which a published effect size of 51% reduction in limb volume with standard deviation of 19% 
is available for standard care. 33  We have utilized this published value (SD = 19%) to calculate 
our power in relationship to the detectable alternative If we allow for a 4:1 ratio of VLNT in 
intervention: control arms, and successful project completion of the protocol by 48 VLNT with 
BioBridge subjects and 12 controls (VLNT without BioBridge), we have utilized an alpha = 0.05 
and a power = 0.9 to predict that the detectable alternative would be ± 20%.  
12.6.3 Effect size justification 
An additional volume reduction of 20% ascribable to the BioBridge (versus VLNT only) would 
represent a substantial and clinically relevant amelioration in the surgical outcome when 
compared to current, standard VLNT without BioBridge supplementation.  This magnitude of 
treatment differential has been demonstrated for the BioBridge in lymphedema, both in our 
published large animal study as well as in pilot observations of the surgical effect of the 
BioBridge performed in the Dominican Republic (unpublished observations). 

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12.7 Criteria for future studies  
Future studies are not planned at this time.  

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13.  
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32. Cornish BH, Bunce IH, Ward LC, et al.  “Bioelectrical impedance for monitoring the efficacy of 
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33. Lin CH, Chen SC, et al.  “Vascularized groin lymph node transfer using the wrist as a recipient site for 
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2009;123:1265-1275. 
34. Shaitelman SF, Cromwell KD, Rasmussen JC, et al.  “Recent progress in the treatment and 
prevention of cancer-related lymphedema.”  CA Cancer J Clin.  2015;65(1):55-81. 
35. Rockson SG.  “Lymphedema after Breast Cancer Treatment.”  N Engl J Med.  
14 Feb 2019;380(7):694. 
36. Rockson SG, Keeley V, Kilbreath S, Szuba A, Towers A.  “Cancer-associated secondary 
lymphoedema.”  Nat Rev Dis Primers.  28 Mar 2019;5(1):22.  
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APPENDICES 
APPENDIX A:  Participant Eligibility Checklist 
Protocol Information 
Protocol Name: Prospective Evaluation of a Surgical Solution for Breast Cancer-Associated 
Lymphedema 
E-Protocol number: IRB-37161 / BRS0095 
Principal Investigator: Stanley Rockson, MD 
Participant Information 
Participant Name/ID: 
Date of Birth: 
Gender:    
 Male     
 Female 
Study Information                                                                                                                               
SRC-approved   
  IRB-approved  
   Contract signed 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB-approved protocol) 
Ye
s 
No 
Supporting 
Documentation 
1. Ages 18 to 75 years (inclusive)  
 
 
 
2. Eastern Cooperative Oncology Group (ECOG) 
Performance Status 0 to 2 
 
 
 
3. Life expectancy > 2 years 
 
 
 
4. Acquired (secondary) upper limb lymphedema 
(secondary to breast cancer treatment) 
 
 
 
5. The participant must be eligible for surgical intervention. 
 
 
 
6. Swelling of 1 limb that is not completely reversed by 
elevation or compression 
 
 
 
7. Stage II or greater lymphedema at screening, based on 
the International Society of Lymphology (ISL) staging 
system 
 
 
 
8. Participants must have no evidence of disease (NED), 
have completed breast cancer therapy 3 years prior to 
enrollment;  use of endocrine therapy is allowed. 
 
 
 
9. Completion of a full course of complete decongestive 
therapy (CDT), according to ISL guidelines at least 
8 weeks prior to screening, including use of compression 
garments for at least 8 weeks without change in regimen 
 
 
 

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10. Willingness to maintain a stable regimen of self-care, 
including use of compression garments from screening 
through the entire study duration (through the safety 
follow-up visit). Self-bandaging, use of nighttime 
compression garments, and intermittent pneumatic 
compression devices are allowed, but the procedures and 
regimens are expected to remain consistent from 
screening though the entire study duration.  
 
 
 
11. Consistent use of an appropriately-sized compression 
garment for daytime use.  
 
 
 
12. Two consecutive measurements of limb volume (LV) in 
the affected arm, taken at least 1 day apart during the 
screening period, must be within 10% of each other.  
A maximum of 3 measurements can be taken.  Affected 
limb volume ratio must be > 20% (compared to unaffected 
limb);  volume measurements will be performed and 
volume ratio will be calculated at S1 and S2 visit. 
 
 
 
13. Evidence of abnormal bioimpedance ratio, if feasible, 
based upon unilateral disease:  L-Dex > 10 units; 
bioimpedance performed at S1 and S2  
 
 
 
14. Willing and able to comply with all study procedures, 
including measurement of skin thickness using skin 
calipers  
 
 
 
15. Willing and able to understand, and to sign a provide 
written informed consent 
 
 
 
Exclusion Criteria 
(From IRB-approved protocol) 
Ye
s 
No 
Supporting 
Documentation 
1. Edema arising from increased capillary filtration will be 
excluded (venous incompetence).  
 
 
 
2. Inability to safely undergo general anesthesia and/or 
perioperative care related to vascularized lymph node 
transfer  
 
 
 
3. Concurrent participation in a clinical trial of any other 
investigational drug or therapy, regardless of indication, 
within 1 month before screening or 5 times the drug's 
half-life, whichever is longer.  
 
 
 
4. Recent initiation of (≤ 8 weeks), or intention to initiate, 
CDPT or maintenance physiotherapy for lymphedema at 
any time during the duration of the study  
 
 
 
5. Other medical condition that could lead to acute limb 
edema, such as (but not limited) to acute venous 
thrombosis  
 
 
 

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4 February 2020 
6. Other medical condition that could result in symptoms 
overlapping those of lymphedema in the affected limb 
(eg, pain, swelling, decreased range of motion)  
 
 
 
7. History of clotting disorder (hypercoagulable state)  
 
 
 
8. Chronic (persistent) infection in the affected limb  
 
 
 
9. Any other infection (unrelated to lymphedema) within 
1 month prior to screening  
 
 
 
10. Currently receiving chemotherapy or radiation therapy 
 
 
 
11. Current evidence, or a history of malignancy within the 
past 3 years (except for non-melanoma skin cancer or 
cervical cancer in situ treated with curative intent).  If the 
participant has undergone cancer treatment, this must 
have been completed > 3 years prior to enrollment.  
 
 
 
12. Current evidence of any high risk for recurrence of breast 
cancer [eg, Stage III or IV;  estrogen receptor (ER) / 
progesterone receptor (PR) / HER-2 negative (ie, 
“triple-negative”) cancer;  locally-advanced disease;  
inflammatory breast cancer;  > 3 positive axillary lymph 
nodes;  extracapsular nodal extension;  invasive 
micropapillary breast carcinoma;  or if performed, genetic 
testing, eg, BRCA1;  BRCA2;  Oncotype DX (high-risk 
recurrence score);  or Mammaprint (poor risk signature) 
indicating a high risk for breast cancer recurrence  
 
 
 
13. Significant or chronic renal insufficiency (defined as 
serum creatinine > 2.5 mg/dL or an estimated glomerular 
filtration rate [eGFR] < 30 mL/min at screening) or 
requires dialytic support  
 
 
 
14. Hepatic dysfunction, defined as alanine transaminase 
(ALT) or aspartate transaminase (AST) levels > 3 × upper 
limit of the normal range (ULN) and/or bilirubin level 
> 2 × ULN at screening  
 
 
 
15. Absolute neutrophil count < 1500 mm3 at screening  
 
 
 
16. Hemoglobin concentration < 9 g/dL at screening  
 
 
 
17. Known sensitivity to porcine products 
 
 
 
18. Hypersensitivity to iodine 
 
 
 
19. Pregnancy or nursing  
 
 
 
20. Substance abuse (such as alcohol or drug abuse) within 
6 months prior to screening  
 
 
 
21. Any reason (in addition to those listed above) that, in the 
opinion of the investigator, precludes full participation in 
the study 
 
 
 

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IV. Statement of Eligibility 
By signing this form of this trial I verify that this subject is □ eligible /□ ineligible for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual 
agreements as required by Stanford School of Medicine’s Research Management Group.   
_________________________________________________ 
        
______________________ 
       Treating Physician Signature 
 
 
    
            Date 
 
_________________________________________________ 
   Printed Name 
 
_________________________________________________                  
_______________________ 
      Second Reviewer Signature 
 
 
   
             Date 
 
_________________________________________________ 
    Printed Name 
_________________________________________________ 
        
_______________________ 
      Study Coordinator Signature 
 
 
    
             Date 
 
_________________________________________________ 
    Printed Name 

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APPENDIX B:  Lymphedema Quality of Life Survey 
 

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Lymphedema Quality of Life Scoring System