The BREAST Trial: A Randomized, Non-inferiority, Study Comparing the Complication Profile of Four Commercially Available Acellular Dermal Matrixes Used in Alloplastic Breast Reconstruction
Phase: NA
Conditions: Breast Reconstruction
Sponsor: University of British Columbia

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Trial registration 
Trial Registration Information 
Primary registry 
ClinicalTrials.gov 
NCT number 
TBD 
Primary Sponsor 
University of British Columbia 
Contact for scientific and 
public queries 
Dr. N. Van Laeken, email: Nancy@vanlaeken.com 
 
Public Title 
The BREAST Trial: a randomized comparison of the 
surgical outcomes from four ADM products utilized in 
breast reconstruction 
Scientific Title 
The BREAST Trial: A randomized, non-inferiority, pilot 
study comparing the complication profile of four 
commercially available acellular dermal matrixes used in 
alloplastic breast reconstruction 
Country of recruitment 
Canada 
Subjects 
Patients undergoing alloplastic breast reconstruction with 
the use of acellular dermal matrix for breast pocket 
creation 
Intervention 
Active comparators: AlloMax or DermACELL or FlexHD, 
Alloderm 
Study Type 
Interventional, randomized, parallel, single blinded, pilot 
study 
Date of first enrolment 
November 2020 
Target sample size 
40 participants for pilot (328 for complete trial) 
Recruitment status 
Actively recruiting 
Primary Outcome 
Proportion of clinically significant seromas 
Key Secondary 
Outcomes 
Incidence of complications (hematoma, capsular 
contracture, implant loss), time to drain removal, number 
of seroma aspirations, Subjective assessment of cosmetic 
outcomes, Evaluation of the satisfaction and quality of life 
of patients undergoing breast surgery using the BREAST-
Q 

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The BREAST Trial: A randomized, non-inferiority, pilot study comparing the 
complication profile of four commercially available acellular dermal matrixes used in 
alloplastic breast reconstruction 
 
Senior Authors: 
 
Dr Nancy Yvonne Van Laeken 
 
 
 
 
Clinical Professor 
 
 
 
 
Plastic & Reconstructive Surgery Service 
University of British Columbia 
#1000-777 W. Broadway 
Vancouver, BC V5Z4J7 
 
 
 
 
Nancy@vanlaeken.com 
 
Dr. Sheina Macadam 
Clinical Associate Professor  
Plastic & Reconstructive Surgery Service 
University of British Columbia 
#1000-777 W. Broadway 
Vancouver, BC V5Z4J7 
Email: drsmacadam@gmail.com 
 
Dr. Katheryn Isaac 
Clinical Assistant Professor 
Plastic & Reconstructive Surgery Service 
University of British Columbia 
#1000-777 W. Broadway 
Vancouver, BC V5Z4J7 
Email: kathryn.isaac@ubc.ca 
 
 
 
 
 
Dr. Esta Bovill 
Clinical Instructor 
Plastic & Reconstructive Surgery Service 
University of British Columbia 
#1000-777 W. Broadway 
Vancouver, BC V5Z4J7 
Email: Esta@drbovill.com 
 
Dr. Peter Lennox 
Clinical Professor  
Plastic & Reconstructive Surgery Service 
University of British Columbia 
#1000-777 W. Broadway 
Vancouver, BC V5Z4J7 
Email: peter.lennox@ubc.ca 
 
First Author:  
 
Dr. Janine Roller 
 
 
 
 
Plastic Surgery Resident 
Plastic & Reconstructive Surgery Service 
University of British Columbia 
#1000-777 W. Broadway 
Vancouver, BC V5Z4J7 
janineroller@gmail.com 
 
 
Second Author: 
 
Dr. Peter Mankowski 

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Plastic Surgery Resident 
Plastic & Reconstructive Surgery Service 
University of British Columbia 
#1000-777 W. Broadway 
Vancouver, BC V5Z4J7 
peter.mankowski@mail.mcgill.ca 
 
Title 
The BREAST Trial: A randomized, non-inferiority, pilot study comparing the 
complication profile of four commercially available acellular dermal matrixes used in 
alloplastic breast reconstruction 
 
Funding 
This trial has received funding from the BC provincial society of Plastic surgeons for 
administrative support as a single bursary through their research support initiative. 
No commercial funding or external funding sources have contributed to the 
development or conduction of this clinical trial. The design, management, analysis 
and reporting of the study are entirely independent of the manufacturers of 
Alloderm, FlexHD, AlloMAX and DermACELL. 
 
Study design 
The BREAST trial is designed as a randomized patient, non-inferiority trial 
with four parallel groups and the primary endpoint of proportion of post-operative 
seromas. Randomization will be performed in block randomization with a 1:1:1:1 
allocation. 
The study will be initially conducted as an internal pilot and then subjected to 
an internal review with preliminary data analysis. Formal protocol modifications will 
be made as needed followed by resubmission to UBC Rise ethics review board. Upon 
ethics approval, the study will be concluded with the goal of recruiting the entire 
desired study population. Our target patient population for the internal pilot study 
will be 40 patients within the study parameters of the protocol outlined below. 
 
Intervention arms of comparison  
Type of ADM:  
• 
AlloDerm (LifeCell Corporation, USA) 
• 
DermACELL (LifeNet Health, USA) 
• 
Flex HD (Ethicon, USA). 
• 
AlloMax (Bard Davol, USA) 
 

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Primary outcome: Proportion of clinically significant seromas 
Time to completion: 1 year as an internal pilot study, 3 years as a formal RCT 
Anticipated start date: 2020 

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Section 1.0: Introduction 
 
Background 
Breast cancer is the most commonly diagnosed female cancer in Canada and 
has a relatively high five-year net survival rate ranging from 84-88% [1]. With 
organized screening programs, the majority of breast cancers are being detected at an 
early stage (Stage I or II), which permits reconstructive opportunities for patients[1]. 
Reconstruction rates are currently rising [2], and between the years of 2000-2017, an 
increase of 35% in the annual rate of these procedures was reported by the American 
Society of Plastic Surgeons[3]. Specifically, alloplastic breast reconstruction is now 
becoming the standard of care as immediate implant-based breast reconstruction 
continues to increase in frequency [4].  
 
The increased rate of alloplastic breast reconstruction can be attributed to the 
expanding utilization of Acellular Dermal Matrices (ADMs). ADMs are donated 
cadaveric dermis that is aseptically processed or sterilized in order to remove cellular 
and immunogenic components to prevent host reactions[5-8]. The use of human 
ADMs in breast surgery was first described in 2001 by Duncan [9] to reduce rippling 
of breast implants and later by Breuing and Warren in 2005 for breast reconstruction 
as a sling to support the lower pole of the breast [10]. ADMs were used in 
approximately 65% of breast reconstructive surgeries in 2017 and this rate continues 
to rise [11]. 
 
Benefits of acellular dermal matrices include facilitating single stage 
immediate direct to implant reconstruction [8, 12, 13] allowing for better coverage at 
the inferior pole of the breast[7, 14] along with: shorter expansion times with TEs [7, 
12, 13, 15], lower capsular contracture rates[8, 12], and improved cosmesis including 
better implant positioning, IMF placement and IMF definition [7, 8, 12-14]. 
Furthermore, there is no associated donor site morbidity associated with ADM use 
[14]. However, the benefits of ADMs must be considered against an increased risk of 
ADM associated post-operative complications. Specifically, ADMs have been linked 
to an increased risk of infection, post-operative seroma [7, 12, 15], and delayed 
healing or mastectomy flap necrosis [14, 15] when compared to breast 
reconstructions without ADM use. Other complications such as implant loss, 
unplanned return to the operating room, or overall complication rate[15] were not 
influenced by the presence of an ADM. Additionally, cost is a commonly reported 
disadvantage to using ADM’s [7, 12] as a single sheet values for multiple thousands of 

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dollars. Recently, Macadam and Lennox performed a cost analysis which, 
demonstrated that direct to implant reconstruction using an ADM is less expensive 
than to a two-staged reconstruction[16]. Similar cost effectiveness was demonstrated 
by de Blacam et al. [17] who noted that potential benefits of minimizing surgical 
stages in breast reconstruction justify the upfront costs associated with ADM use. 
Overall, the proponents of ADM use claim that the benefits outweigh the risks in 
immediate breast reconstruction[7] as ADM associated complication rates have 
generally decreased and stabilized as surgeon experience with these products has 
increased [8].  
 
AlloDerm (LifeCell Corporation, USA) was the first ADM’s to be described in 
literature and was one of the first ADM to be available in Canada in 2009 [18]. As a 
result, there is extensive literature regarding its use and safety in breast 
reconstruction[5, 7, 8, 13, 14, 19]. Since the introduction of AlloDerm, alternative 
products have been introduced including AlloMax (Bard Davol, USA)  in 2010 [18], 
DermaACELL (LifeNet Health, USA) and Flex HD (Ethicon, USA). However, the 
benefits and risk of alternatives are less well described.  
 
Flex HD was first compared to AlloDerm by Liu et al. where a multivariate 
analysis suggested that Flex HD may be an independent risk factor for implant loss 
but acknowledged their study was small and retrospective in that its reliability is only 
as accurate as its medical records. Additionally, the complication rates, including 
return to the OR, were similar between groups. Overall, they suggest a randomized 
controlled study should be conducted to clarify the risk and benefits [14]. In a study 
done by Ranganathan, Flex HD was found to be at increased risk of both minor and 
major infections when compared to AlloDerm. However, this study has been 
criticized for its low volume over a 15 year period and failure to state which Flex HD 
product was used – structural or pliable – of which Flex HD pliable is indicated for 
breast reconstruction[7]. Similarly, to Liu et al, they did not find any difference in 
return to OR rates[7, 14]. Other studies have since shown that there is no difference 
in complication rates between AlloDerm and Flex HD[8, 19] with one demonstrating 
that Flex HD has significantly lower post-operative implant extrusion and a higher 
cosmetic score[19].  
 
DermACELL was found to be appropriate acellular dermal matrix option 
elucidated by Bullocks in 2014 [20]. It’s decellularization process removes more than 
97% of donor DNA with a sterility assurance level of 10-6 to reduce host reactions [5, 

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20, 21]. In a recent study comparing DermACELL to AlloDerm, there was statistically 
significant decrease in time to drain removal with DermACELL (regardless of 
immediate reconstruction or tissue expander placement) and higher incidence of Red 
Breast Syndrome in AlloDerm (26% vs. 0%)[5]. Other non-statistically significant 
differences included lower rates of hematoma, seroma, wound healing, infection and 
thus lower total implant failures[5]. However, this study is criticized as it was not 
used as per manufacturers guidelines and performed ‘off-label’ meshing of products. 
A small 9 patient clinical study using DermACELL was performed by Vashi and found 
low rates of seroma, infection and hematoma. However, the study involved a small 
sample size and may have been biased by the authors as they received compensation 
for data collection and analysis of the case series[21]. 
 
AlloMax, previously known as NeoForm, is a non-orientation specific [12] ADM 
that reports sterile processing techniques in contrast to aseptic methods. As a result, 
lower inflammatory reactions as seen in rat studies, may lead to lower complication 
rates[22]. Lower complication rates have been seen by Rundell et al. [13] and was 
demonstrated in a prospective study that examined tissue expander-based breast 
reconstructions over a 1 year period with 65 breasts. However, this study was 
criticized as there were 14 different breast surgeons performing mastectomies with 
variable flap thickness and different TE were used.  
 
It is important to note that there are numerous ADM products available. 
Fenestrated ADMs are currently not part of the study design as the selected 4 
products are based on surgeon familiarity and similarity of product characteristics to 
minimize potential confounding features. Minimizing the differences in products also 
preserves the external generalizability of our study results. However, should one of 
the products be found to have significantly different seroma outcomes early on 
(within the pilot study), there is the possibility to include a fenestrated product at 
that time to maximize study comparisons and study conclusions. Based on surgeon 
experience and literature support, contour fenestrated AlloDerm would be the 
fenestrated product chosen. Furthermore, this product could be incorporated into the 
study if one of the four products is deemed as being inferior to work with by the 
research team (ie. The surgeons develop a majority bias against one of the four 
products). 
 
 
 

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Rationale 
At the present time, there is no high-quality evidence in the literature to aid in 
the decision-making process as to which ADM should be chosen based on patient 
clinical information. The results of this study may revolutionize the use of ADM’s in 
breast reconstruction by improving both surgeon and patient knowledge of the post-
surgical outcomes associated with the individual ADM types and improve subsequent 
informed decision making.  
Given the increasing popularity of breast reconstruction with ADMs, medical 
companies have produced similar competing products. No large-scale randomized 
study has been conducted to directly compare the outcomes four ADM’s in two-
staged breast reconstruction. Therefore, there is no high-quality evidence elucidating 
safety and non-inferiority among products. This study aims to identify outcomes, 
complications, aesthetic results and patient satisfaction of four comparable ADM 
products. This will ultimately lead to the ability to directly compare ADM products 
and improved informed decision making for surgeons with respect to their use and 
anticipated outcomes.  Given the significance of ADM associated complications and 
variability in the high cost of these products, a prospective direct head to head trial is 
justified.   
 
Objectives 
The objective of this study is to compare the safety and outcomes of four 
different acellular dermal matrices used in alloplastic breast reconstruction. The 
primary outcome will be: proportion of clinically significant seromas. Secondary 
outcomes will include: mean drain duration, mean aspirations per seroma, 
hematoma incidence, infection incidence, implant failure/loss, red breast syndrome, 
unplanned surgical care, rates of mastectomy flap necrosis, capsular contracture, 
ADM integration and cosmetic outcome. Additionally, using the BREAST-Q, patient 
satisfaction will be evaluated. 
 
Hypothesis 
1. There will be no difference in the proportion of clinically significant 
seromas (ie. requiring drainage/intervention) between the four acellular 
dermal matrix assisted breast reconstruction treatment groups. 
2. Secondarily, there will be no difference in safety, complications, cosmetic, 
or patient reported outcomes when comparing four different human 
derived acellular dermal matrices. 

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Significance 
Alloplastic breast reconstruction has shown a significant increase in 
popularity over the last 10 years. This is thought to be due to multiple factors 
including long term silicone implant safety data, increase in the frequency of bilateral 
mastectomies and improved cosmetic outcomes. Acellular dermal matrices (ADMs) 
were introduced in 2009 in Canada and have become increasingly popular as a 
critical component of alloplastic breast reconstruction following mastectomy. 
Currently, there is widespread data profiling the safety of ADMs, and numerous ADM 
alternatives to the original AlloDerm have been introduced. However, few high-
quality comparative studies have been conducted to ensure the similar outcomes are 
obtained with ADMs other than AlloDerm. Clinical equipoise is thought to exist 
between four ADM subtypes: AlloDerm, FlexHD, DermaCell and Allomax, however 
this has yet to be effectively supported within the scientific literature. To date, there 
are no studies that compare four products in a randomized control trial fashion. 
Therefore, the purpose of this study is to identify product non-inferiority between 
ADM types.  
 
 
Study Design 
This study is a randomized control trial to be conducted in Canada from 2020 
until 2 years post completion of recruitment. This study will include all patients who 
are agreeable and deemed appropriate for alloplastic breast reconstruction involving 
the use of an ADM with two stage tissue expander (TE) reconstruction. The ADM 
used will be determined by random assignment to one of four available products 
being utilized within the study: AlloDerm, AlloMax, DermACELL and FlexHD. Each 
ADM product will comprise of an individual treatment arm. Those undergoing 
bilateral reconstruction will have the same ADM used in each side. The four 
treatment arms will be compared to assess their impact on our primary outcome: 
proportion of clinically significant post-operative seroma requiring intervention. 
Analysis will be performed per surgeon to prevent post-operative outcomes from 
being confounded by the principle operator. 
The trial will initially be conducted as an internal pilot study. We will 
initially target a study population of 40 patients for recruitment as a means to assess 
the feasibility of the study. In doing this, we will be able to establish the necessary 
protocol and administrative infrastructure that is needed to complete the trial in its 
entirety. We will also be able to create a sample population for initial outcomes 

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assessment in support of our selected outcome metrics. The initial data collection and 
review will be used to validate our study power calculation and ensure the 
appropriate study population sized is targeted for when the study transitions into a 
formal RCT. 
 
Section 2.0: Methods Participants, Interventions and outcomes  
 
Study Setting 
The study will take place at four health centers affiliated with the University of 
British Columbia and the UBC breast program: the Vancouver general hospital 
(VGH), Mount Saint Joseph’s hospital (MSJ), Saint Paul’s Hospital (SPH) and the 
University of British Columbia Hospital (UBC). 
Study patients will be initially recruited through the outpatient clinics from 
one of the above listed hospitals. They will complete their surgical procedures 
through the operative sites of one of the listed hospitals. Standard scheduled 
ambulatory follow ups will continue for two year post-operatively at the site of initial 
contact with their designated surgeon. 
 
Patient recruitment 
The UBC Breast Reconstruction program involves several plastic surgeons 
whom in conjunction with general surgeons perform a number of mastectomy and 
alloplastic breast reconstructions. These operations are carried out primarily in four 
hospitals in the central Vancouver area as listed above (study site).  The senior author 
performs over 100-150 breast reconstructions per year and therefore we would 
anticipate recruitment over 2 year period to allow for adequate sample size. Patient 
recruitment will occur until all four treatment arms have received their targeted 
participant populations or clinical equipoise is no longer maintained. 
Patient recruitment will be conducted at the time of initial consultation for 
breast reconstruction. Currently, patients are referred by their surgical oncologists to 
the four participating surgeons within this study. These patients are then presented 
with a plan for breast reconstruction based on their demographic and oncological 
characteristics. Patients who seek out alloplastic breast reconstruction and are 
appropriate surgical candidates are then consented for this process in office and 
scheduled for an appropriate surgical date based on OR availability and the schedule 
of the treating surgical team (Surgical oncologist and Plastic surgeon). 
Patients who are successfully scheduled for breast reconstruction will 
simultaneously be screened by a trained research assistant affiliated with the 

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BREAST trial to evaluate if these patients are appropriate study candidates based on 
the defined study inclusion and exclusion criteria. The assistant will then introduce 
the trial to the potential study candidate and explain the study in entirety with the aid 
of information sheets and resources made available to the patient. Agreeable patients 
will then sign a consent form that is provided to them by the in person medical office 
assistant who will then register the patient in the randomization process for the 
study. All documents will be stored in a confidential manner in locked cabinets at the 
study site of original recruitment. Patients will be provided a two-week period to 
decide if they would like to enroll in the study. Should a patient agree to join the 
study while out of office, the consent process would be coordinated at their next in-
person follow up. 
 
Study subjects 
Inclusion criteria 
All woman aged 21 years or older but less that 65 undergoing unilateral or 
bilateral mastectomy with alloplastic breast reconstruction using ADM will be invited 
to participate. Breast reconstruction must be done by means of a two staged process 
using tissue expanders and ADM-based reconstruction followed by tissue expander to 
implant exchange.  
 
Exclusion criteria to participation of the study 
1. Patients undergoing autologous reconstruction either at the time of mastectomy or 
in a delayed fashion. 
2. Patients with a history of previous breast reconstruction procedures. 
3. Patients with prior radiation treatment to the breast or with prior mantle radiation 
4. Any patient with a contraindication to breast reconstruction 
5. Patients undergoing an axillary node dissection with clearance 
6. Patients with an allergy to Polysporin or any of its ingredients. 
7. Patients with contraindications to any of the acellular dermal matrices: 
• 
DermACELL: Allergy to Gentamicin, Vancomycin[12] 
8. The surgeon performing the breast reconstruction may also deem a patient 
ineligible if intraoperatively, there is evidence of significant mastectomy flap 
ischemia prior to the initiation of the breast reconstruction procedure. 
 
Randomization 
Prospective breast reconstruction candidates will be identified at the initial 
consultation. Once the decision has been taken to perform alloplastic reconstruction, 

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the study will be discussed with the potential participant but a trained research 
assistant who will facilitate the consenting process. Patients that consent to proceed 
as study participants will then be registered into the centralized study database and 
randomization process. 
Randomization will be performed in blocks at a ratio of 1:1:1:1. A web-based 
randomization program (REDCap) will assign a patient to one of four potential ADM 
groups (AlloDerm, AlloMax, DermACELL and Flex HD). This information will be 
non-blinded to the surgical staff who will then proceed to order the appropriate ADM 
product to be available at the time of the study participants scheduled breast 
reconstruction. Additionally, randomization will occur independently for each 
surgeon prevent bias from arising as a result of the surgeon performing the 
reconstruction.  
 
Blinding 
All patients will be blinded to the type of ADM selected upon by the 
randomization process. The surgeon performing the procedure as well as the 
operating team however will be aware of the ADM being used as the preparation of 
each ADM are different. Additionally, the operating team will remain unblinded to 
the selected ADM to ensure accurate documentation and to facilitate appropriate 
communication during the process of ADM transfer to the sterile operating field and 
subsequent implantation. Patients will be informed of the ADM product they received 
on the completion of the study. 
 
Interventions 
Surgical procedure 
Patients involved in the study will present to the operating room having been 
previously randomized to one of four treatment arms: AlloDerm, AlloMax, 
DermACELL, or FlexHD. The surgeon will be aware of which ADM product that the 
patient has been randomized to and this will be reviewed at the initiation of the 
surgery at the surgical time out to ensure the correct product is available within the 
room and appropriately ready for use. The surgeon will have also ordered the product 
in advance as per the randomization process. Patients will firstly undergo either a 
bilateral or unilateral skin or nipple sparing mastectomy by a surgical oncologist. In 
addition, they may perform nodal sampling or axillary clearance if deemed necessary, 
as per standard of care. If axillary dissection and clearance is performed, the patient 
will be excluded from the study. The plastic surgeon will then perform alloplastic 
breast reconstruction raising a sub-pectoral pocket as per standard practice. All two 

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stage breast reconstructions will place smooth tissue expanders during the first stage 
of reconstruction. The inframammary crease will be recreated with a sling of acellular 
dermal matrix using the assigned ADM product. The standard size of ADM of 6 x 
16cm will be used and will not be subjected to fenestration. Two drains will be placed, 
one in the mastectomy pocket superficial to the ADM and pectoralis muscle and one 
laterally. All patients will receive preoperative antibiotic therapy with Ancef as per 
standard elective indications f0r surgical site infection prophylaxis. All patients 
undergoing an alloplastic 2-stage reconstruction with tissue expander will have the 
subsequent second stage implant exchange after a minimum of 3 months following 
the first stage tissue expander insertion.  
 
Radiation status 
The patient’s oncology team will deem if radiation treatment is necessary for 
an enrolled patient. Patients who are subjected to radiation during their breast 
oncology care will not be excluded from the study. If radiation is required after they 
have completed their stage I procedure, their implant exchange will be delayed a 
minimum of 6 months (standard practice of care) following insertion of the tissue 
expander. 
 
Patient who require radiation will be analyzed within a subgroup analysis to 
ensure that this oncologic treatment factor is accounted for and to minimize the 
impact of this variable on study conclusions. Presence of radiation treatment will be 
included in the study as this treatment composes a large element of breast 
oncological care and outcomes specific to this population are of interest. The study 
analysis will be appropriately conducted to minimize confounding outcomes and the 
study statistician will be principally involved in this process. Furthermore, we suspect 
that patients who receive radiation may have unique aesthetic outcomes and 
satisfaction scores. This data be compared to non-radiated patients and compared 
amongst ADM products within this radiated population. 
 
Post-operative treatment 
Patients will be transferred to the post anesthesia care unit and then to the 
inpatient ward until they meet the usual discharge criteria. After discharge, all 
patients will receive a course of oral antibiotics until drains removed. Follow up will 
be performed in plastic surgery offices where progress will be documented using 
study affiliated data collection forms with defined relevant outcome details and post-
operative course. 

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Sample size: 
As there are four treatment arms within this study, a power calculation was 
conducted to identify the anticipated participant recruitment required to 
demonstrate a meaningful difference between study groups using our primary 
outcome. Power calculation was supported by a consulting epidemiologist (P.B.).  
Our primary outcome is the proportion of patients that develop a clinically 
significant seroma requiring intervention. A clinically significant seroma is defined as 
one that necessitates drainage, either due to symptomatic concerns or clinical 
judgement by the evaluating surgeon. Drainage is achieved either through office-
based aspiration or by ultrasound guided aspiration through radiology referral. Post-
operative seromas occur in approximately than 10% of breast reconstruction cases 
when an ADM is utilized. We believe that incidence of seroma formation is an 
appropriate primary endpoint due to the clinical implication that the rate of seroma 
occurrence has on ADM selection. If an ADM product is associated with a higher 
incidence of post-operative seromas, surgeons would be dissuaded from utilizing this 
product even when cost differences are present.  
For comparison between the ADM subtypes, we have chosen a difference of 
10% in the proportion of clinically significant seromas.  This is a clinically relevant 
difference that would guide the choice of product by surgeons. Therefore, for the 
power calculation, a mean of 0.10 with a margin of 0.10 will be utilized. Additionally, 
we will require an 80% probability (Beta=0.80) for 90% confidence (alpha = o.10) for 
our statistical comparison. Using these parameters, a minimum of 82 patients per 
intervention arm is required to effectively power the study (328 total). A p-value of 
0.10 allows for an attainable and reasonable target sample size for the purposes of the 
study. A p-value of 0.05 would require a significantly larger target population to 
ensure the study is appropriately powered which may become challenging given the 
number of study arms (4 ADMs). However, after completion of the internal pilot 
study this will be subjected to internal review with consultation from our team 
statistician and modified as needed. 
As the trial will be initially conducted as an internal pilot study, only 40 
patients will be recruited during this phase of the study. These patients will formally 
enter the study and receive their breast reconstruction within the parameters of the 
study protocol. An interim study analysis will then be performed on this initial 
sample population prior to proceeding out of the pilot phase of the study. Changes to 
the target study size will be made if the interim analysis suggests that this is 

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necessary to appropriately power our study using our primary outcome of proportion 
of seromas.  
 
Section 3.0: Methods Data collection, management and analysis  
 
Data Collection and Measured outcomes 
All clinical data will be obtained prospectively. Clinicopathological factors and 
identified metrics associated with patient outcomes will be recorded at each follow up 
visit. Follow up for patients during the first stage of the two staged tissue expander 
reconstruction will occur at: 1 week, 2 weeks, and then in two week intervals until the 
final expansion volume has been reached. Following the second stage where the 
tissue expander is exchanged for the final implant, follow up will occur at: 1 week, 2 
weeks, 4 weeks, 3 months, 6 months, 1 year and 2 years.  The scheduled follow ups 
are not study specific and are consistent with routine post-operative care. 
 
Patient demographics and relevant risk factors will be recorded including age, 
comorbidities, past surgical history, smoking status, current medications, allergies, 
alcohol consumption, radiation history, chemotherapies, BMI, type of mastectomy, 
cancer type and cancer stage.  
 
Reconstruction associated parameters will also be collecting including 
mastectomy weight, and permanent implant volume. The primary outcome and 
secondary outcomes of the study are summarized below. 
 
Summary Table of Primary and secondary outcomes 
Primary Outcome Measure:  
Seroma incidence  
Incidence of seroma formation requiring 
intervention including aspiration in-office or 
ultrasound-guided drainage [Time Frame: within 
6 months of stage I or stage II surgery] 
Secondary Outcome Measures:  
Mean drain duration (Days) 
Postoperative duration of drain placements [Time 
Frame: within 1 month of stage I or stage II 
surgery]  
Mean drain output (ml) 
Total volume of drain output until drain removal 
[Time Frame: length of time the post-operative 
drain remains in-situ] 

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Mean seroma volume (ml) 
Total volume of seroma fluid aspirated until 
resolution of seroma 
Time Frame: within 6 months of stage I or stage II 
surgery] 
Mean aspirations per seroma 
Number of aspirations required for seroma 
resolution 
[Time Frame: within 6 months of stage I or stage 
II surgery]  
Hematoma incidence  
Incidence of hematoma requiring evacuation or 
aspiration 
[Time Frame: within 1 month of stage I or stage II 
surgery] 
Surgical site infection 
Incidence of surgical site infection requiring 
antibiotics or operative management [Time 
Frame: within 6 months of stage I or II surgery] 
Implant loss 
Loss of Implant for any reason (wound 
dehiscence, exposure, periprosthetic infection) 
[Time Frame: within 2 year of stage II surgery] 
Red breast syndrome 
Noninfectious erythema localized to the area of 
ADM reconstruction [Time Frame: within 1 month 
of stage I surgery]  
Unplanned surgical care 
Unexpected return to the operating room that was 
not planned at the initial visit for any reason 
[Time Frame: within 2 year of stage I or stage II 
surgery] 
Mastectomy flap necrosis 
Mastectomy flap necrosis and associated 
management: expectant, office debridement, or 
return to the operating room [Time Frame: within 
1 month of stage I surgery] 
Capsular contracture 
Incidence of capsular contracture (as identified by 
the plastic surgeon, grouped by Baker’s 
classification of severity)  
[Time Frame: within 1 years after stage II 
procedure] 
ADM integration 
Clinical assessment of ADM integration into the 
breast pocket at the time of the second stage 

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procedure. 
[Time Frame: Specimen obtained at the stage II 
exchange to implant procedure] 
Post-operative aesthetic 
assessment (patient and 
surgeon) 
Subjective assessment of cosmetic outcome by the 
patient and blinded assessors using post-operative 
aesthetic breast survey assessment  
[Time Frame: within 2 years of stage II surgery] 
Patient satisfaction 
Evaluation of the satisfaction and quality of life of 
patients undergoing breast surgery using the 
BREAST-Q 
[Time Frame: within 2 years of stage II surgery] 
 
 
Primary outcome: 
Seroma formation occurs when serous fluid accumulates in the breast 
reconstruction surgical site post operatively resulting in a clinically appreciable 
pocket of fluid. The primary outcome measure of our study is: proportion of post-
operative seroma requiring clinical intervention.  
 
The seromas themselves are detected clinically when patients present for 
post-operative evaluation that includes a clinical exam, which facilitate the 
seroma diagnosis. After the seroma diagnosis,  they are commonly managed by 
percutaneous aspiration that can be performed in a clinic setting by the surgeon with 
local anesthetic. In the case of larger seromas, aspiration and drainage can be 
performed under ultrasound guidance. Rarely, seroma’s that do not resolve by repeat 
aspiration require operative evacuation and re-closure of the surgical site.  
 
The use of ADMs has been linked to an increase incidence in post-operative 
seroma formation in breast reconstruction patients [14, 23]. However, ADM use is 
also associated with a reduction in the risk of capsular contracture, a complication 
associated with scar tissue accumulation around the implant that distorts the 
aesthetics of the breast and can be painful for the patient. Therefore, this benefit of 
utilizing ADMs in breast reconstruction is weighted against the increased risk of 
seroma formation.  
 
The incidence of seroma formation after breast reconstruction with ADMs 
remains low at less than 10%. Evaluating if ADM type is associated with different 

Protocol, Version 2.0, April 29, 2020 
 
 
18
rates of seroma formation is necessary to identify if these products can be used 
interchangeability. Surgeons have a low threshold for selecting a specific ADM 
product should there be variation in their complication profile. Even an increase in 
seroma incidence by as little as 5% may deter surgeons from selecting a product due 
to the negative impact seroma formation has on patient care and wellbeing.  
 
 
A seroma will be defined as a collection of serous fluid that develops under the 
breast skin flaps following surgery. In the outpatient clinic, if patients express 
discomfort or present with a clinically significant seroma within their breast pocket, 
they will receive ultrasound-based or surgeon conducted aspiration. The secondary 
outcomes include mean aspirations per seroma until resolution, seroma aspiration 
volume measurements, and time to drain removal. These secondary outcomes 
provide additional information and statistics that can be used to profile the primary 
outcome.  
 
If the gross estimation is less than 30 ml, or does not necessitate aspiration, 
the patient will be managed conservatively and monitored as per standard of care. 
Seromas that occur within 6 months post a surgical procedure will contribute to the 
primary endpoint analysis. 
As the primary endpoint, the proportion of seromas that occur will then be 
subjected to statistical comparison between ADM subtypes. All statistical analysis 
will be conducted after being stratified by surgeon to ensure that the principle 
operator does not confound the association between ADM type and seroma 
incidence. 
 
In conclusion, the decision to select the proportion of post-operative seroma 
requiring clinical intervention as the primary endpoint of the study is multifactorial. 
The first is that seromas themselves are clinically significant outcomes that influence 
post-operative care and their occurrence rate is directly increased by the presence of 
an ADM. Therefore, understanding the relationship between seroma occurrence and 
the different ADM products will influence product selection and outline complication 
profiles of these products. Seromas’ and their associated interventional management 
are associated with elevated health care costs. Most importantly the presence of a 
seroma that require an invasive physician supervised procedure in order to establish 
resolution affects a patient’s post-operative course. Associating ADM products to 
clinically significant seroma outcomes will help profile which ADM that have the 
largest impact on health care resources and patient care. Finally, one of the earliest 

Protocol, Version 2.0, April 29, 2020 
 
 
19
symptoms of a ALCL presentation is a delayed large volume seroma. Therefore, 
understanding seroma incidence and outcomes tied to breast reconstruction with 
ADMs is of paramount importance for long term implant associated care.  
The pilot study again will be concluded by an internal review and should 
proportion of clinically significant seromas be deemed an inadequate primary 
outcome measure this will be subjected to reassessment and modification as needed. 
 
Secondary outcomes: 
Secondary endpoints that will be collected and incorporated into the study 
analysis include time to mean number of aspirations per seroma until resolution, 
seroma aspiration volume measurements, hematoma incidence, incidence of surgical 
site infections, implant loss, red breast syndrome, unplanned surgical care, incidence 
of mastectomy flap necrosis, incidence of capsular contracture, ADM integration, 
cosmetic evaluation and patient satisfaction.  
 
The time to drain removal between the 4 treatment arms will be compared. 
Time to drain removal will be collected and recorded per breast. Patients will be 
instructed on how to empty and record their drain volumes. Drains will be left in situ 
until producing <30mls every 24 hours to a maximum of 2 weeks, or otherwise 
advised by the surgeon. Patients who require prolonged drain placement will be 
recorded for data monitoring purposes tied to the secondary outcome of drain 
management. Reasons for prolonged drain placement will be categorized as 
scheduling conflicts/missed appointments or as clinically indicated. The duration of 
the drain is to profile clinical practices around drain use.  
 
 
The total volume of seroma fluid aspirated will be calculated for each seroma 
by the summation of aspirated volumes performed either through clinic aspiration of 
US guided aspirations. The total seroma volume will be recorded in milliliters within 
6 months of each stage of the surgical procedure. 
 
The total number of aspirations until seroma resolution for each seroma will 
be calculated by the summation of aspirations performed either in clinic or by US 
guidance. The total number of seroma aspiration will be recorded within 6 months of 
each stage of the surgical procedure. 
 
Hematoma will be defined as an expanding mass of blood requiring 
evacuation in the OR or significant bruising noted at the 1st post-operative visit. The 

Protocol, Version 2.0, April 29, 2020 
 
 
20
volume will be quantified by operative evaluation or by ultrasound when possible if 
the hematoma is investigated by imaging. The total hematoma volume will be 
recorded in milliliters within 1 month of either surgical procedure. 
 
Surgical site infections will be identified based on patient post-operative 
clinical status including signs of erythema, pyrexia, local tenderness or presence of 
purulent discharge on return to operating room[5]. These will be managed with 
wound culturing, appropriately selected antibiotics and return to the operating room 
if indicated. Cellulitis is defined as whole breast erythema, edema, local tenderness 
that resolves with oral antibiotics. A surgical site infection will be defined as peri-
incisional erythema, pyrexia, local tenderness beyond cellulitis [5], requiring IV 
antibiotics with either a positive aseptically obtained culture or the presence of 
purulent discharge on exam or upon return to the operating room. Post-operative 
infections will be recorded within 6 months of both surgical procedures. 
 
Implant failure or implant loss will be recorded when the removal of 
implant(s) in the operating room [5] occurs for pathological reasons, or findings of a 
ruptured implant. This will be confirmed intraoperatively or by imaging evaluation 
including MRI or US. 
 
Red Breast syndrome, which is described as a delayed type hypersensitivity 
which is idiopathic, and self-limiting erythema, in the absence of other signs of 
symptoms of infection, in an otherwise asymptomatic patient. It is isolated to the 
lower pole of the breast in the distribution of the underlying acellular matrix, and is 
refractory to oral antibiotics and resolved without further complications[5, 24]. 
 
Any unanticipated to return to the OR will be noted. This will include the 
following indications: Seroma, Hematoma, Soft Tissue Infection, Mastectomy Flap 
Necrosis, exposed implant, capsular contracture, or animation that requires 
intervention. Unplanned surgical procedures will also include implant loss or rupture 
as defined above.  
 
Mastectomy flap necrosis (MFN) is defined as vascular compromised skin 
flaps that require intervention. It will be record and quantified by size of surface area 
involved measured in centimeter units. The location will be documented by 
quadrant localization (UMQ, ULQ, LMQ, LLQ) and will be assessed for depth 
involvement 
(superficial, 
full 
thickness, 
indeterminate, 
exposed 
implant). 

Protocol, Version 2.0, April 29, 2020 
 
 
21
Photographs will be taken of identified necrosis and the subsequent surgical 
management will be recorded: conservative (with dressings and/or antibiotics) or 
debridement either in the office or operating room. If conservative management fails, 
and the patient requires debridement, their management status will be changed to 
the intervention given. To differentiate delayed wound healing from MFN, delayed 
wound healing is wound disruption that does not require surgical intervention, where 
MFN beyond superficial depth, requires sharp debridement and closure of skin [5]. 
MFN will be recorded within 1 month of the stage I breast reconstruction procedure. 
 
Capsular contracture which is progressive hardening and thickening around 
the implant, will be recorded and classified according to Baker’s classification. Grade 
I include breast that are soft without significant scar tissue. Grade II includes breasts 
with palpable scar tissue around the implant, however the capsule is not visible. 
Grade III includes visible and palpable hardening around the breast leading to a 
deformed breast shape. Grade IV includes breasts that are often cold, hard, and very 
painful to palpation. There are visible and palpable capsular deformities.  
 
ADM integration will be evaluated clinically during the second stage 
procedure. The operating surgeon will inspect the ADM previously placed in both 
breast pockets and score the degree of integration on a 4-point scale. This scale has 
been adapted from Mendenhall et al., with 1 = 100% integration, 2=greater than 50% 
integration, 3= less than 50% integration and 4= 0% integration[27]. Additionally, 
punch biopsies will also be obtained from the ADM and subjected to pathological 
evaluation for angiogenesis and lymphogenic infiltration.  
 
ADM biopsy specimens will be sent to pathology for microscopy assessment 
and to evaluate ADM integration. These specimens will be stored within the routine 
practices of the pathology department for oncological specimens (2 years for paraffin 
blocks). The study specimens will be disposed of by standard tissue disposal. Should 
the study be terminated early, the specimens will be disposed of. There is no future 
plan for utilization of these specimens. 
 
An evaluation of the aesthetic outcomes of the four treatment arms will be 
performed. All patients will have 5 standardized photographs of the breasts between 
the levels of the shoulder and umbilicus in front of a uniform background with 
patients standing with their hands on their buttocks from 1 m away. The photographs 
will be taken at 5 angles: a frontal view, a view from each lateral side, and at 45˚ to 

Protocol, Version 2.0, April 29, 2020 
 
 
22
each lateral side. All photos utilized for aesthetic evaluation will be obtained 24 
months postoperatively after the second stage reconstruction. The surgeons will be 
asked to score the aesthetic appearance using the Aesthetics items scale, which is a 
validated and reliable tool for assessing outcomes after breast reconstruction 
surgery[28], including volume, shape, symmetry, scars, and nipple (when 
applicable). All images will be viewed through an EMR system and not be sent off-
site. Concurrently, the patient will also be asked to complete an aesthetic evaluation. 
Additionally, a sample of the last 5% of patients enrolled will have deidentified 
photos from each ADM group obtained and will be presented to a panel of blinded 
plastic surgeons. This evaluation will be performed as a single analysis after 
completion of the trial. 
 
Patient satisfaction will be assessed to complete a BREAST-Q assessment 
prior to reconstruction and 24 months after the second stage reconstruction for 
patients with tissue expanders. This previously validated patient reported outcome 
measure that will allow for the ability to evaluate patient satisfaction, well-being and 
the impact of the breast reconstruction [29-31]. These outcomes will be collected for 
all treatment groups. 
 
Statistical methods 
Firstly, the patient demographic variables previously listed will be 
summarized for each treatment are and summarized to describe the study patient 
population. Continuous variables will be reported by mean  standard error. All 
outcomes evaluated by this RCT will be done so using an intention to treat analysis. A 
stratified analysis will be done by surgeon between ADM subgroups. 
 
To compare the primary outcome, the number of seromas for each ADM 
subtype will be tabulated. The number of seromas will be calculated per breast for 
each ADM treatment arm. An analysis of variance test (or Kruskal-Wallis) will be 
used to determine if a difference is detected within the treatment groups. Individual 
pair wise Wilcoxon rank-sum tests will then use used to compare between sets of 
ADMs and ultimately identify which ADM is associated lowest seroma rate. A p-value 
of less than 0.10 will be deemed statistically significant. A similar analysis will be 
conducted to additionally compare the output volumes from the drains between the 
treatment arms and the frequency of aspirations required for seroma management in 
the post-operative course. 
 

Protocol, Version 2.0, April 29, 2020 
 
 
23
The secondary outcomes outlined to be evaluated by the study comprise of the 
complication profiles of each ADM group and will be recorded by frequency and 
percent occurrence. Chi squared or Fisher’s exact tests will be used when appropriate 
to compare categorical data between the treatment arms. 
 
Analysis of the aesthetic evaluation using the Aesthetic item scale will be 
performed using a non-parametric test (Wilcoxon rank-sum) to compare Likert scale 
scores for each metric between the four treatment arms. This will include analysis of 
the overall scores assessed by the scale for each patient. Finally, the scores produced 
from each metric of the BREAST-Q assessment will be subjected to a similar 
comparison based statistical analysis between ADM groups. 
 
Data Storage 
As this study will be initially conducted as an internal pilot study, all patient 
associated data will be recorded using the appropriate data collection forms. These 
forms include a consultation form, pre-operative exam, post-operative follow up, 
surgical record form and a procedure log. These forms will be maintained within each 
surgeon’s office in paper format so that they can be easy accessed by study personal. 
Studied affiliated charts will be stored in locked cabinets with the office space to 
ensure confidentiality. Individual surgeons will only have access to the study charts 
of the patients that they are directly involved in caring for. Our appointed research 
administer will be responsible to manually entering the data into REDcap which will 
be used for electronic storage and facilitating data analysis. 
 
After completion of the internal pilot study, the study will be subjected to an 
internal review process to determine feasibility and likelihood of successfully 
obtaining of target study population size within our institution. If this review is 
successful we will transition the record collection process to be conducted entirely 
electronically using REDCap. 
 
Harms and potential risks 
In general, acellular dermal matrices have shown a trend for increased risk of 
infection and seroma but have also demonstrated a potential reduced risk of capsular 
contracture [7, 12, 14, 15]. The vascularity of the mastectomy flap in most cases has a 
significant effect on complications[6]. This is dictated by the general surgeon’s ability 
to safely resect the pathology, whilst leaving behind a vascular skin flap. 
 

Protocol, Version 2.0, April 29, 2020 
 
 
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Some of the acellular dermal matrices have been associated with an 
inflammatory reaction named red breast syndrome. This does not constitute and 
infection as the erythema is well demarcated and presents in a well-defined line 
overlying the acellular dermal matrix. This is self-limiting and does not require any 
change in management but higher rates have been noted in ready to use AlloDerm [5, 
24].  
 
These risks will be mitigated by the fact that the use of acellular dermal 
matrixes has been standard practice in alloplastic breast reconstruction. Currently all 
four surgeons participating in this study utilize ADM as the basis of their alloplastic 
treatment algorithm to improve the long-term outcomes of their patients and 
decrease the likelihood of capsular contracture. Only if patients have increased risk of 
mastectomy flap necrosis is the use of an ADM avoided. These principles will be 
maintained within this study. If at any time, the surgeon’s preference is to not 
incorporate the use of an ADM into the patient’s surgical plan, that patient will be 
removed from the study to facilitate their new care plan. 
 
To ensure that clinical equipoise is not lost during the study, a blinded 
statistician will perform preliminary data analysis at designated time intervals. If at 
any point, one ADM demonstrates a difference in surgical outcomes compared to the 
others, the clinical trial will be abandoned. 
 
Monitoring committee 
 
The preliminary analysis of the 40 patients involved in the pilot study will 
occur by the Data and Safety Monitoring Board. This will determine feasibility for the 
full study. 
Once the full study is initiated, there will be interim analysis performed every 
6 months to ensure early identification of any safety concerns. If there is a notable 
difference in early outcomes and a loss of clinical equipoise, the trial may be 
terminated prematurely.  
 
Section 4.0: Ethics and Consent 
 
Confidentiality and Consent 
All study information will be store at the study site of collection. Participant 
information will be stored in locked cabinets with restricted access. Data collection 
forms and associated study files will de-identified by assigning a participant code to 

Protocol, Version 2.0, April 29, 2020 
 
 
25
each study participants. A master file will be maintained solely by the research 
administrator of the study which will be password protected, encrypted and stored 
separately but would allow for decoding of the study participants should this be 
required for any reason. 
Participant’s study information will not be released outside of the study 
without the written permission of the participant. 
 
Declarations of interests 
JR, PM, TS: Have no discourses or conflict of interests to state. The remaining 
declarations of interests to be reviewed with all affiliated study members. 
 
Research and ethics approval 
The study protocol and all associated forms (e.g. data collection forms, 
consent forms and consultation forms) will be sent for review and approval by the 
IRB (institutional review board) of UBC under the human ethics committee. 
After the initial review and approval by the IRB, annual review of the study 
protocol and auditing of study progression will additionally be performed. This 
process is maintained for ensuring ethics approval through the entire study duration. 
Completion of the study will be submitted to the UBC IRB within 3 months of study 
termination. 

Protocol, Version 2.0, April 29, 2020 
 
 
26
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