Study setting {9}
Cleveland Clinic Center for Abdominal Core Health, part of the Cleveland Clinic Foundation in Cleveland, Ohio is the primary site, with additional participating sites including Cleveland Clinic Hillcrest Hospital, Cleveland Clinic Fairview Hospital, The Ohio State University, University of Florida, Vanderbilt University, and Novant Health.
Eligibility criteria {10}
Inclusion criteria:
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Adults ≥ 18 years old.
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Anticipated hernia defect 2-6cm in width
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Non-emergent case
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Center for Disease Control class I
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Patients who previously underwent primary ventral hernia repair without the use of mesh
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Incisional hernia
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European Hernia Society Classification: M1-M5
Exclusion criteria:
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Emergent cases
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Patients < 18 years old
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Patients who are pregnant
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Patients who previously underwent a prior ventral hernia repair with mesh at the site of the intended repair. Abdominal mesh in separate locations would be allowed.
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Ventral hernia < 2cm or > 6 cm in width
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Non-incisional hernia
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European Hernia Society Classification: L1-L4
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Center for Disease Control wound class II-IV
Who will take informed consent? {26a}
Informed consent
from potential trial participants will be obtained by study investigators or research personnel during the preoperative visit.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable. No additional consent provisions are needed.
Interventions
Explanation for the choice of comparators {6b}
The study will consist of a control and intervention arm: hernia repair with retrorectus mesh and suture only repair using a small bite technique. Retrorectus mesh (control arm) is widely regarded as one of the ideal positions for mesh placement. Small bite technique has been shown to reduce hernia occurrence in primary laparotomy but has not been studied in hernias. Both arms will include a posterior rectus sheath incision and the anterior rectus sheath will be closed using a small bite technique to minimize variation.
Intervention description {11a}
Patients in both arms will undergo the remainder of the operation at the discretion of their surgeon, including the dissection of the hernia sac and reduction of its contents into the abdomen. In both arms, the hernia defect will be measured prior to randomization and the posterior rectus sheath will be incised along the length of the fascial defect bilaterally.
Hernia repair with mesh (Control arm)
Patients will undergo reduction of the viscera and clearing of the anterior abdominal wall. The peritoneum/posterior rectus sheath will be closed to prevent contact between the mesh and bowel. If necessary, a supplementary transversus abdominis release (TAR) can be performed to allow for posterior sheath closure without tension. A polypropylene mesh will be placed posterior to the rectus muscle in the retrorectus position without fixation. Our definition of retrorectus mesh placement includes preperitoneal mesh placement in the setting of a posterior rectus sheath incision or in the retromuscular plane with closure of the posterior rectus sheath. The mesh will be tailored to the defect so that at least 4cm of mesh overlaps the fascia on all sides of the defect. The fascial edges will be closed with the same running stitch as employed in the suture repair group (described below). Closure of the subcutaneous tissue will be performed at the discretion of the surgeon. Surgical drains may be placed at the discretion of the operating surgeon.
Primary closure (Intervention arm): Patients will undergo dissection of the hernia defect with the standard technique at the discretion of their surgeon. After bilateral posterior rectus sheath release, closure of the fascia overlying the hernia defect will be performed using USP 0 Prolene Suture (Ethicon, Somerville, NJ, USA) on either a 31mm or 26 mm needle. The closure will include the small bites technique (5 mm tissue bites, 5mm advancement), and a suture length:wound length of ≥ 4:1 will be maintained. The length of suture used and wound length will recorded intraoperatively as well as the number of bites taken to close the wound. These two techniques are chosen as they have been shown in primary laparotomies to prevent incisional hernia.(3, 16–18) Closure of the subcutaneous tissue will be performed at the discretion of the surgeon (Table 1).
In facilities with access to a tensiometer (both arms)
After reduction of the hernia sac contents into the abdomen, the tension at the midpoint of the incision will be measured using a tensiometer and recorded in pounds. The posterior rectus sheath will be incised along the length of the fascial defect on both sides and the fascial tension will be recorded using a tensiometer in pounds at the midpoint.
Criteria for discontinuing or modifying allocated interventions {11b}
The primary endpoint will be analyzed via intention-to-treat. In the case that a patient is randomized, but the allocated procedure is not completed for technical reasons, they will be analyzed based on randomization. If patients require reoperation with conversion to the alternative treatment arm, all subsequent adverse events will be attributed to the randomized allocation.
Strategies to improve adherence to interventions {11c}
The research coordinator will not randomize until the surgeon confirms the following intraoperative hernia width is 2–6 cm, there was no unexpected contamination, and either repair is technically feasible.
Relevant concomitant care permitted or prohibited during the trial {11d}
Concomitant care is not restricted during this trial.
Provisions for post-trial care {30}
We have no provisions for ancillary or post-trial care, or for compensation to those who suffer harm from trial participation.
Outcomes {12}
Primary outcome: HerQLes summary score(19) at one year postoperatively.
Secondary Outcomes:
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Patient Reported Outcomes at baseline, 30 (± 14 days), 1-year (± 90) days and 2-year (± 6 month) follow-up, and 5-year (± 6 month) follow-up
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Patient guess to allocation at 1-year (± 90) days
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Hernia recurrence using a previously described pragmatic definition(21) that includes clinical, radiographic exam, and Hernia Recurrence Inventory (HRI) at 1-year (± 90) days, 2 years (± 6 month), and 5- year (± 6 month) follow up.
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All complications at 30 (± 14) days, 1-year (± 90) days, 2 years (± 6 month), and 5- year (± 6 month) follow-up postoperatively.
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Wound morbidity
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Surgical site infections (SSI)
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Surgical site occurrences (SSO)
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Surgical site occurrence requiring intervention (SSOPI)
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Readmission
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Hernia-related reoperation
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Mortality
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Perform a formal cost effectiveness analysis utilizing quality adjusted life years and incremental cost effectiveness ratios.
Participant timeline {13}
Estimated patient accrual time is 5 years. Data collection will occur over 5 years from randomization of each patient and includes 30 (± 14) days, 1-year (± 90) days, 2 years (± 6 month), and 5- year (± 6 month) follow ups. Details are shown in the Table 1.
Table 1
Schedule of enrollment, interventions, and assessments
| Screening | Intraoperative | 30-day | 1-Year | 2-Year | 5-Year |
Documentation of Inclusion/Exclusion | x | | | | | |
Informed Consent | x | | | | | |
Randomization | | x | | | | |
Supplemental Data Assessments | | | x | x | x | x |
30-Day Outcomes | | | x | | | |
Long Term Outcomes | | | | x | x | x |
CT Scan | | | | x | +/- | +/- |
Sample size {14}
Based on a retrospective database review at our institution, median HerQLes scores at one year was 80 and 78 for mesh-based repairs and suture repairs respectively (standard deviation of 27 in both groups). Using a one-sided, two-sample equal-variance t-test to detect a margin of a -15 point difference between the two groups (commensurate with the minimal clinically important difference)(22), group sample sizes of 56 and 56 will achieve 90% power, given an alpha of 0.05, to detect non-inferiority. Assuming 25% loss to follow up, we will plan to enroll 154 patients total.
Recruitment {15}
The Cleveland Clinic Center for Abdominal Core Health is a high-volume hernia center, performing approximately 35 hernia repairs meeting inclusion criteria per year. We expect approximately 10 hernia repairs to be completed at the other participating sites per year. We expect to complete enrollment within 4 years.
Assignment of interventions: allocation
Sequence generation {16a}
Intraoperative computer-generated treatment random allocation in REDCap® will randomize participants to suture versus mesh repair.
Concealment mechanism {16b}
The randomization table was generated by a statistician and concealed from the study team within REDCap®
Implementation {16c}
Patients will be enrolled during preoperative consultation. The intraoperative allocation sequence will be generated by the research coordinator in REDCap®.
Assignment of interventions: Blinding
Who will be blinded {17a}
Study participants, those collecting patient reported outcomes, and CT scan assessors will be blinded to repair technique. Operative notes are blinded, and allocation is stored in REDCap®. Operative details are stored in the ACHQC database as standard of care.
Procedure for unblinding if needed {17b}
Participants will be unblinded at 2 years postoperatively. Participants will be unblinded by a study investigator prior to 2 years if they experience complications requiring reoperation.
Data collection and management
Plans for assessment and collection of outcomes {18a}
HerQLes, a validated 12 question survey with an MCID of 15.6, will be collected at baseline and each time point to assess abdominal wall-specific quality of life.(19, 22) PROMIS 3a Pain Intensity Surveys will be collected at all timepoints to assess pain.(20) EQ-5D-5L with visual assessment score will be collected at all timepoints to assess overall quality of life.(23) Hernia recurrence will be measured using a pragmatic definition.(21) Cross sectional imaging will be assessed by three surgeons blinded to the operating surgeon and randomization with recurrence defined by consensus of at least two. In the absence of imaging, a clinical exam will be used to assess recurrence. In the absence of either imaging or clinical exam, the patient response to the presence of a bulge on the Hernia Recurrence Inventory (HRI).(24) Patients will also be asked to guess their intervention allocation at 1 year postoperatively.
Plans to promote participant retention and complete follow-up {18b}
Patients are scheduled for standard of care clinic appointments at 30 days and 1 year and 5 years postoperatively. Patients will be contacted by the research team for patient reported outcomes in the 2-year follow-up window and scheduled for a CT and clinical visit if they report a bulge on the HRI, which is considered standard of care. We will promote complete follow up through multiple approaches. The 30-day follow-up period will extend from 16 to 44 days postoperatively, the 1-year follow-up period will extend from
9 to 15 months postoperatively, the 2-year follow-up period will extend from
18 to 30 months postoperatively, and the 5-year follow-up period will extend from 54 to 66 months postoperatively. Appointment reminders will be sent via patient online portals and nursing phone calls. Virtual follow-up visits can be accommodated, and patients can complete imaging at their local institutions. For patients who have missed follow-up appointments, the dedicated study coordinator, research fellow, and/or surgeon will call patients to reschedule and/or collect patient reported outcomes over the phone. This will increase convenience for patients and protocol adherence. Appropriate statistical analyses will be conducted to account for missing data.
Data management {19}
Patient characteristics and operative details will be captured in the ACHQC database, accessed using an assigned username and password. Treatment arm allocation, postoperative complications, CT results, and patient-reported quality of life scores will be collected in REDCap®, a secure electronic database accessed by the investigator and designated study team members using an assigned login and password. Only the principal investigator, research coordinators, and biostatisticians will have access to patient data for routine data quality assessments and data analyses. All electronic records pertaining to the clinical study will be password-protected, and only approved study members listed in the Institutional Review Board (IRB) protocol will have password access.
Confidentiality {27}
Anonymity and confidentiality of subjects participating in this study will be maintained before, during, and after the trial period. Every effort will be made to maintain the confidentiality of documents that identify the subject by name (e.g., signed informed consents or clinic charts), except when necessary to allow monitoring by the Office of Research Compliance at the Cleveland Clinic or other regulatory authorities. All data will be stored in secure databases. Written consent forms will be stored in study binders in a locked office at Cleveland Clinic or at the respective participating sites.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable. No biologic specimens will be collected as part of this trial.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
All analyses will be conducted on intention to treat basis (ITT). An ACHQC statistician will perform analyses from all participating centers and will require access to identifiable data. A DUA will be executed prior to sharing of PHI. Patient characteristics and operative comparisons will be summarized by the treatment group. Any departures from ITT will be documented and reported.
Participants’ clinical and demographic characteristics will be summarized by suture repairs and mesh repairs. Differences between two groups will be assessed using Wilcoxon rank sum tests for continuous variables and Chi-square or Fisher’s exact tests for dichotomous variables. One-sided p-values less than or equal to 0.05 will be considered statistically significant.
Primary Outcome
The primary outcome is the HerQLes summary score at 1 year. To demonstrate the suture repair is clinically non-inferior to mesh repair, a two-sample one-sided t test of the hypotheses H0: µm ≥ µs + d verses H1: µm < µs + d, will be conducted, where µm and µs denote the summary scores at 1 year in mesh repairs and suture repairs groups, respectively, and d is the non-inferior margin, d = 15.
Secondary outcomes
The secondary outcomes of the change score from baseline to 2 years and 5 years in HerQLes summary score as well as the change score of PROMIS scores from baseline to 30 days, 1 year, 2 year and at 5 years will be assessed by two-sided Wilcoxon rank sum tests between two groups at each time point.
SSI, SSO, and SSOPI, will be determined with binary measures at each time point. Differences between suture repairs and mesh repairs will be assessed by Chi-square tests at each time point. Hernia recurrence will be analyzed as a binary outcome (yes or no) at 1 year, 2 years, and 5 years after surgery. Time-to-hernia recurrence will be assessed with a log-rank test and the Cox proportional hazard model with pre-specified covariates described by Kaplan-Meier curves, tested by proportional hazard models, and reported as hazard ratios (HR). Pre-specified covariates include: hernia width, BMI, active smoking at the time of surgery, history of previous abdominal wall SSI, and measured fascial tension. Cluster effect of surgeon will be adjusted in the regression model. Costs will be compared as continuous variables using a student’s t-test. Additionally quality adjusted life years and incremental cost effectiveness ratios will be analyzed between groups. The EQ-5D-5L with VAS surveys (which will be collected from the patients at baseline and each time point as detailed above) multiplied by the number of years will be used in the calculation of the quality adjusted life years. Cost data will be obtained from the Cleveland Clinic eResearch department and will include direct costs. Direct costs for the index operation will include operating room supply and time, intensive care unit, anesthesia, floor care, laboratory tests, radiology and endoscopy, pharmacy, and in-hospital rehabilitation therapies.
Interim analyses {21b}
Two interim analyses will be conducted. The first interim analysis will be conducted after 52 patients have been enrolled and will consider p-value < alpha 0.0015 as an efficacy stop or predictive power < 0.1055 as a futility stop. The second interim analysis will be conducted after 103 patients have been enrolled and will consider p-value < alpha 0.0172 as an efficacy stop or predictive power < 0.5240 as a futility stop. The final analysis will be conducted after 154 patients have been enrolled.
Methods for additional analyses (e.g. subgroup analyses) {20b}
No additional subgroup analysis will be considered.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
All analyses will be conducted on intention to treat basis (ITT). When patients experience complications requiring reoperation and conversion to the alternative treatment arm, all subsequent adverse events will be attributed to the randomized repair technique. Missing data is anticipated to reflect a pattern of missing at random. Multiple imputation will be used to impute missing data at baseline only and provide the missing at random assumption holds. Multiple imputation of follow-up measures will not be performed. If non-random missing data patterns are observed, alternate methods, such as pattern mixture models, will be considered.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
We do not have plans for granting public access to the full protocol, participant-level dataset, or statistical code.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The study principal investigator, co-investigators, and research coordinators at the Cleveland Clinic Center for Abdominal Core Health meet weekly to discuss trial enrollment, randomization, and follow-up. Screening and enrollment logs should be maintained at each study site by study coordinators. Each site will maintain a weekly log of screen failures and patients who met inclusion criteria but were not included with explanation for exclusion. De-identified lists of enrolled patients, completed surgeries, and completed follow ups will be shared with the Cleveland Clinic sponsor and study coordinator every 3 months. The trial investigators capture patient characteristics and operative details in the ACHQC registry, and the research coordinators are responsible for collecting intraoperative randomization and postoperative outcomes in REDCap®.
Composition of the data monitoring committee, its role and reporting structure {21a}
A Data Safety Monitoring Board (DSMB) meets for this trial after specific numbers of randomized patients complete 30-day follow-up as follows: 25, 52, 75, 103, and 125 patients. The DSMB is comprised of two surgeons and a statistician who are external to the trial.
Adverse event reporting and harms {22}
All adverse events are captured by the research coordinator and reported annually to the IRB per institutional requirements and to the DSMB each time it meets. All serious adverse events (e.g., return to the operating room within 30 days or mesh-related complication) are reported to the DSMB within 24 hours.
Frequency and plans for auditing trial conduct {23}
Research regulatory officers from the Digestive Disease Institute at the Cleveland Clinic Foundation will audit trials to ensure regulatory compliance.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Protocol modifications will be added to the study on the Cleveland Clinic IRB website and communicated to other sites within 10 days for modification to their institutional IRBs.
Dissemination plans {31a}
The investigators plan to publish their results in a scientific journal within 6 months of the primary endpoint.