Study setting {9}
Data will be collected from patients treated mainly in Spanish hospitals but also in Chile and Italy, giving this study an international approach. Participant hospitals are: Maresme Health Consortium (Mataró Hospital), Moisès Broggi Sant Joan Despí Hospital, University Hospital Mútua de Terrassa, Corporació de Salut del Maresme i la Selva, Fondazione Istituto G.Giglio in Cefalù, University Hospital Vic, Can Ruti University Hospital, Corporación Sanitaria Parc Tauli, Hospital University d’Igualada, Granollers General Hospital, Santa Creu i Sant Pau University Hospital, Joan XXIII University Hospital, Consorci Sanitari of Terrassa Hospital, Parc Salut Mar University Hospital, General de Catalunya University Hospital, Barbastro Hospital, Van Buren Hospital of Valparaíso Chile, Vega Baja Hospital, CHUIMI Hospital, Bologna Metropolitana Bellaria Hospital, Severo Ochoa Hospital, Palencia University Assistance Complex, Istituto Nazionale Tumori, IRCCS, Fondazione Pascale, Napoli.
Eligibility Criteria {10}
Inclusion criteria
Exclusion criteria
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Need for mastectomy
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History of ipsilateral axillary radiotherapy
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ASA 4 patients. (Selected ASA 3 patients)
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Lack of adequate cognitive capacity and/or failure to sign the informed consent
In all the cases surgeons (general surgeon or a gynaecologist) will perform the intervention during breast cancer surgery.
Who Will Take Informed Consent? {26a}
During the standard preoperative clinical assessment, all BC patients who are candidates for surgery meeting the inclusion criteria, will be informed of the possibility to participate in the present study by the surgeon. The patient will give their authorization by signing an informed consent document during the base-line visit.
Additional Consent Provisions For Collection And Use Of Participant Data And Biological Specimens {26b}
Patients enrolling this study gave informed consent to be followed-up during the study period and to allow the use of their medical records according to the trial’s objectives, for academic purpose. This trial does not include biological specimens.
Interventions
Explanation for the choice of comparators {6b}
Symptomatic seroma is the comparator chosen to prove if a sealant has an effect after AL in patients without drain. All patients are treated following current breast cancer guidelines, therefore the criteria for performing AL are uniform among participating hospitals. Pain is a usual symptom after axillary surgery, however, we wanted to evaluate if there is the use of a sealant agent has any role in pain control in this patients. We chose the QoL EQ-5D-5L questionnaire because it also allows to check the upper extremity mobility.
Intervention Description {11a}
The AL will be performed in all cases with a sealing device such as LigaSure®, Harmonic Focus® or similar. The incision may be chosen by the surgeon at each of the participating centers. AL will be performed according to standard technique, including Berg levels I, II and level III if necessary.
After AL is performed, Glubran 2® will be placed in the axillary hollow in the study group. The product will be applied homogeneously in all participating centers. For this purpose, training lessons have been held in each hospital, with both visual material and the presence of a product expert on the field. After washing the armpit with physiological saline, assuring it is completely dry and caring for an exhaustive control of hemostasis, the product should be applied using its specific applicator (yellow). It has to be distributed over the entire lymphadenectomy area including: the area above the axillary vein, the area below the axillary vein, around the latissimus dorsi bundle, the lateral costal wall including the vascular-nerve bundle, the serratus muscle and the subcutaneous cellular tissue. The closure of the subcutaneous cellular tissue and the skin will be led to the standard in each participating center, although the most common technique is the closure of the subcutaneous cellular tissue with simple stitches of resorbable multifilament suture and the closure of the skin with a continuous intradermal suture of resorbable monofilament thread.
Hospitalization Regime And Analgesic Regimen
Patients will be operated on an outpatient or conventional inpatient basis, according
to the criteria of each hospital participating in the study.
The recommended analgesia at discharge will consist of paracetamol 1g/8h alternating
with metamizole 575mg/8h for the first 7 postoperative days in all patients. The need
to extend this regimen will be assessed at the different clinical follow-up visits. In case
of allergy or intolerance, the regimen will be adapted with two alternating analgesics
The performance of a neurological block prior to surgery will be recorded.
Criteria For Discontinuing Or Modifying Allocated Interventions {11b}
In accordance with the Declaration of Helsinki, participants can withdraw from the trial at any time and for any reason.
Withdrawal criteria
Patients will be excluded from the study in any of the following scenarios: (a) the patient expresses their willingness to leave the study, (b) the patient is not able to accomplish the established clinical controls, (c) continuation of the study procedures may be detrimental to the patient's health or well-being, (d) there is a concurrent illness that prevents compliance with patient monitoring and assessment procedures.
Strategies To Improve Adherence To Interventions {11c}
A breast cancer nurse in each center will be the responsible to check that the clinical visits and ultrasound sessions are met and in the adequate timing. They will also be the contact person for patients in case of doubts about their condition or any questions related to the study.
Relevant Concomitant Care Permitted Or Prohibited During The Trial {11d}
All aspects of clinical care will be permitted as long as they are registered in the medical records
Provisions For Post-trial Care {30}
If any side effect occurs due to the use of Glubran 2® or any other action concerting the study, it will be covered by the hospital’s insurance
Outcomes {12}
Primary outcome
Percentage of patients with symptomatic seroma, defined as a seroma requiring its puncture-aspiration.
Seroma puncture-aspiration is indicated in the following scenarios during follow up:
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Tension seroma causing uncontrollable pain (VAS = 5) even though taking the recommended oral analgesia (paracetamol 1g/8h alternating with metamizole 575mg/8h).
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Seroma volume not allowing a full adduction of the upper limb and causing discomfort as a result.
Secondary endpoints
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Number of seroma aspiration-punctures required.
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Pain (measured by Visual Analogue Scale, VAS).
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Axillary seroma volume (measured by axillary ultrasound in cm3)
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Number of post-operative emergency room visits
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Need for hospital readmission
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Presence of lymphoedema in the arm
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QoL after the intervention (measured by the EQ-5D-5L questionnaire, Spanish version).
Main Safety Measures:
Adverse events and post-surgical complications such as suture failure, surgical wound infection, etc.
Other study variables:
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Surgical wound infection: defined as the presence of inflammatory signs - heat, redness, increased temperature and/or pain - requiring antibiotic treatment with or without surgical or percutaneous drainage.
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Surgical regimen: major outpatient surgery (MOS) or short-stay hospitalization (first 24–48 hours post-operatively).
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Anesthetic technique performed. Use of neuromuscular blockade prior to surgery.
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Definitive pathological anatomy (number of axillary lymph nodes)
Participant Timeline {13}
After surgery, all patients in the study will follow the same clinical assessments, which
will be at days 7, 14 and 30 post-surgery. Patients will also be evaluated in the long term, at 6 and 12 months after surgery (Table 1). Clinical visits outside those that are established will be made at the discretion of the surgeon at each participating center.
During clinical assessments, data on the level of pain (VAS), adherence to prescribed analgesic medication, presence of symptomatic seroma, need for puncture-evacuation of the seroma as well as QoL will be collected.
Sample Size {14}
Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a bilateral contrast, 67 subjects in each study arm are required to detect a statistically significant difference in the percentage of patients with symptomatic seroma (which is expected to be 25% for the control group and 7% for the study group). A loss to follow-up rate of 10% has been estimated.
For the calculation of “n” and due to the large extent of seroma described in the literature, reference values of 25% described in the study by Jan et al (9) have been taken.
Recruitment {15}
All the hospitals participating in this trial have a Breast Cancer Unit, all of them treating more than 100 BC patients a year. Hospitals without a Breast Cancer Unit are not included.
Assignment Of Interventions: Allocation
Sequence generation {16a}
The allocation of participants to the different groups has been carried by means of a computer-generated randomisation stratified by center.
Concealment Mechanism {16b}
Randomisation lists have been prepared using the REDCap (Research Electronic Data Capture) program. At the time of recruitment, each participant is assigned a personal and non-transferable study identification number.
Implementation {16c}
After randomization, the surgeon will create the allocation sequence by REDCap program. The surgeon will be the only person to know the group in which the patient is allocated.
Assignment Of Interventions: Blinding
Who will be blinded {17a}
Patients, trial statistians and postoperative care nurses will be blinded after assigning the intervention.
Procedure For Unblinding If Needed {17b}
In case of withdrawal from the trial, the patient will be able to know in with arm of treatment was allocated.
Data Collection And Management
Plans for assessment and collection of outcomes {18a}
For each patient included in the study, a patient case report form (CRF) will be filled in. This also applies to patients who do not complete the full follow-up foreseen in the trial. Subjects will not be identified by name or initials in the CRF or in any trial document. The only acceptable identification that will appear on the CRF or other documents is the subject's unique subject identification number. The investigator will retain the contact details of all participants, so that they can be contacted quickly if necessary.
Data will be collected via a study-specific electronic case report form (eCRF) by using REDCap program. This eCRF include the necessary fields to fill in during every visit (7, 14, 30 days and 6, 12 months). Final data will be cheeked by an independent data monitoring committee which will verify the veracity of the data and the absence of duplications. The database will only be locked for the final analysis, after all data management and statistical data validation checks have been satisfactorily resolved.
QoL will be measured by EQ-5D-5L questionnaire (Spanish version). This questionnaire has been validated by EuroQol in 2009. EQ-5D-5L measures mobility, self-care, usual activities, pain/discomfort and anxiety/depression; with Four levels of severity in each dimension: no problem, some problems, serious problems or disability.
Pain is measured by the Visual Analogue Scale (VAS), ranging from 0 to 10.
Plans To Promote Participant Retention And Complete Follow-up {18b}
The nurses of each Breast Cancer Unit will be the ones checking that the patients have the appointments established according to the trial
Data Management {19}
Data registered in the eCRF will be filled in by the surgeon in charge of each patient. An independent data monitoring committee will, at the end, check all data to make sure there are no duplications or other errors. The main investigator of the trial will also validate data periodically. Data discrepancies will be flagged to the study site, and any data changes will be recorded to maintain a complete audit trail (reason for change, date when the change was made and who made change).
Confidentiality {27}
The patient's clinical data shall be completely dissociated from any information that would allow identification of the patient. In all reports and communications relating to trial subjects, the subject will be identified only by case number. The Main investigator of each hospital (surgeon) will be the one to registered all data in the eCRF, besides him no one else will have access to it. All data will be registered in fields in REDCap program with a single password so that no one apart from main investigator can open it.
This file will be treated strictly according to professional standards of confidentiality and will be archived under appropriate security measures and restricted access, in the terms provided for in Regulation (11) 2016/679 of the European Parliament and of the Council of 27 April 2016 on Data Protection (RGPD), as well as in the Organic Law 03/2018, of 5 December.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
This trial does not include biological specimens
Statistical Methods
Statistical methods for primary and secondary outcomes {20a}
The Statistical Analysis Plan (SAP) will be based on intention to treat principles in line with Consolidated Standards of Reporting Trials (CONSORT) guidelines.
Descriptive analysis of the study sample: as quantitative variables, the mean, median, range and standard deviation will be analyzed. Absolute values and percentages will be used for qualitative variables. The frequency measures used will be prevalence, analysis of the homogeneity or comparability of study groups. Quantitative variables will be assessed for normal distribution using the Kolmogorov- Smirnov or Shapiro-Wilk test.
Bivariate analysis of quantitative variables will be performed using Student's t-test or Mann Whitney U-test as appropriate.
For the analysis of qualitative variables, the Chi square test or Fisher's test will be used as appropriate. The OR (odds ratio) is considered as a measure of effect calculated by logistic regression.
In the multivariate survival analysis, the Cox regression method will be used, while for the multivariate analysis of risk factors, the logistic regression method will be used; introducing in the statistical model those variables that show statistical significance in the univariate analysis and/or those that in the bibliography and theoretical framework are prognostic factors.
Clinical lymphoedema-free survival will be analyzed using the Kaplan-Meier method and survival curves will be compared using the Long-Range test and Cox regression. The safety analysis will be performed per protocol and will use the same statistical tests mentioned above. The level of significance is set at p < 0.05. The statistical analysis will be carried out with the Statistical Package for the Social Sciences (SPSS) version 21.
Interim Analyses {21b}
No interim analysis is planned in the current study.
Methods For Additional Analyses (E.g. Subgroup Analyses) {20b}
Analyses of the primary and secondary outcome will be done in relation to subgrouping variables including age, sex, type of tumor, neoadjuvant treatment and pathological history.
For each subgroup analysis, we will undertake a Cox proportional hazards model assessing each primary outcome incorporating a subgroup interaction term to provide the basis for evaluating subgroup effects. We will consider the possibility that a subgroup effect is present if the interaction term of treatment and subgroup is statistically significant at a p-value < 0.05. We will also consider other credibility criteria to judge the reliability of a subgroup effect
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Patients who are included in the study but who do not meet the inclusion or exclusion criteria will be withdrawn from the analysis. Missing data will be excluded for the primary and secondary outcome analyses. Further analyses based on multiple imputation methods will be considered if appropriate. Analyses will be carried out based on the intention to treat principle.
Plans To Give Access To The Full Protocol, Participant Level-data And Statistical Code {31c}
Every main investigator will receive a full protocol copy and could also visualize it in REDCap program. In case that a patient would like to consult it, the surgeon will be the one in charge to provide such information. Data will not be publicly available, only main investigator of each hospital, statistician and data monitoring committee could visualize it.
The use of data and statistical code is subject to the main investigator decision after signing a written agreement.
Oversight And Monitoring
Composition of the coordinating center and trial steering committee {5d}
The trial steering committee will meet weekly initially. The coordinating center and the trial steering committee will check periodically the evolution of the research, revising the data included by each center and contact to them in case of needs. Main investigator will actualize the information about the trial to the research unit of the coordinating center every 4 months. Main investigator will communicate the evolution of the trial to the research unit of the coordinating center.
Composition Of The Data Monitoring Committee, Its Role And Reporting Structure {21a}
An independent Data Monitoring Committee (iDMC) will be created with independent members (clinical, statistical and methodological expertise). iDMC meets every 6 months or more frequently if required. The iDMC is independent from the sponsors and depends from the coordinating center.
Adverse Event Reporting And Harms {22}
Throughout the study, every effort should be made to detect and evaluate adverse
events or harmful findings. If adverse events occur, the primary concern is for the safety and well-being of the subject. Appropriate medical intervention will be undertaken. This includes all adverse events or complications observed by the investigator or reported by the subject, whether or not caused by the surgery under study. The relationship of the adverse event to the surgery will be assessed by the investigator and documented in the Case Report Form (CRF). The investigator should complete the entire CRF and notify the Sponsor for review, including a description of the event, the date of onset, an assessment of its relationship to the surgery, a medical assessment of its severity, the actions taken, whether the study surgery had to be discontinued, and the resolution of the event. Serious adverse events that continue to exist at the end of the study period should be followed up to determine the final outcome. Any adverse event that occurs after the study period and is considered possibly related to the study surgery or study participation should be recorded and reported immediately. A pre-existing condition, i.e. one that was present at the start of the study, should be recorded as an adverse event if its frequency, intensity or nature worsens during the study period.
The Sponsor is responsible for adverse event classification and ongoing safety assessment of the clinical investigation and shall:
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Review the investigator's assessment of all adverse events and document in writing their severity and relationship to the experimental intervention. In case of disagreement between the Sponsor and the Principal Investigator, the Sponsor shall communicate both opinions to the Investigation Ethics Committee (IEC) and to the national competent authorities, if necessary.
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Report, or ensure that the Principal Investigator reports, all serious adverse events to the IEC. The Investigator should report any serious adverse events to the Sponsor and the local IRB as soon as he/she becomes aware of them, by fax/telephone.
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Report all serious adverse events to the competent authorities within the required time period, if required by national laws.
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Inform all local principal investigators, in writing, of all serious adverse events reported to the Sponsor and ensure that they report them to their IECs if required by national law. This information should be sent to all principal investigators within a time period established on the basis of potential risk.
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Ensure that any new information on the clinical investigation is communicated to the competent authorities.
Frequency And Plans For Auditing Trial Conduct {23}
Trial monitor aspects are described in 21a before. The trial will be monitored and audited by main investigators and sponsor.
Plans For Communicating Important Protocol Amendments To Relevant Parties (E.g. Trial Participants, Ethical Committees) {25}
In case of trial modification, it will need to be approved by the IEC of the coordinating center and modify in ClinicalTrials.gov. Main investigator of the coordinating center will inform about the changes to the rest of the hospitals involved. All changes will be modified in the protocol, adapting the version and date.
Dissemination Plans {31a}
The Principal Investigator declares his commitment to publish the final results of the
study in a scientific publication and the results will we showed in scientific conferences.
The ICMJE's recommendations regarding authorship according to the following four
criteria shall be taken into account:
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Substantial contribution to the conception or design of the work; or to the acquisition, analysis or interpretation of data for the work.
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Drafting of the paper or critical revision of its important intellectual content
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Final approval of the version to be published.
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Commitment to be responsible for all aspects of the work by ensuring that all questions concerning the accuracy or honesty of any part of the work have been properly investigated and resolved.
All persons qualifying as authors according to the ICMJE will be asked to sign an authorship contract
The inclusion of a minimum of 5 patients per center is required. In case of including 10 patients, the name of the collaborating author in that center will appear in the title of the future scientific publication (as long as they meet the criteria of ICMJE’s recommendation). The order of authors in the scientific publication will depend on the inclusion contribution of each one. If there happens to exist a limit on the number of authors in the scientific journal, the inclusion of the remaining authors will be assessed as "Breast Cancer Research Group”