PREEMER trial: Study protocol for a randomized controlled trial

Background: Despite the fact that, in itself, emergency midline laparotomy is a factor risk for an incisional hernia, active research on hernia prevention in emergency settings is lacking. Different kinds of meshes and mesh positions have been studied in elective abdominal surgery, but no randomized controlled trials in emergency settings have been published. Methods: The PREEMER trial is a multicenter, double-blinded, randomized controlled trial to be conducted in seven hospitals in Finland (Oulu, Helsinki, Tampere, and Turku university hospitals and Jyväskylä, Lahti, and Seinäjoki non-university hospitals). A total of 244 patients will be randomized at a 1:1 ratio to either the retrorectus mesh group, featuring a self-gripping prophylactic mesh, or to the no mesh (control) group, both closed by small stitch 4:1 closure with continuous slowly absorbable monolament suturing. The primary outcome of the PREEMER trial is the incisional hernia incidence two years after surgery, which will be detected clinically and/or radiologically. Secondary outcomes are the Comprehensive Complication Index score, incidence of surgical site infections and fascial dehiscence within 30 days of surgery; the incisional hernia repair rate and mesh- or hernia-related re-operations within the two- and ve-year follow-ups; the incidence of incisional hernia within the ve-year follow-up; and quality of life measured by RAND-36, the Activities Assessment Scale (AAS), and the PROMIS-questionnaire within 30 days and two and ve years from surgery. Additionally, medico-economic explorative measures are analyzed. Discussion: The PREEMER Trial will provide level 1 evidence on incisional hernia prevention in an emergency setting. Trials


Introduction Background and rationale {6a}
Emergency midline laparotomy is, in itself, a known risk factor of incisional hernia development with up to 33% incisional hernia incidence (1)(2)(3)(4). However, no evidence-based recommendations have been given on the optimal technique for closing midline emergency laparotomy incisions (5,6). A small bite technique with a suture to wound length (SL/WL) ratio of at least 4:1 and a slowly absorbable mono lament suture is the current recommended technique for fascial closure in non-emergency settings (5). The same method can be utilized to close an emergency midline laparotomy as well as to avoid an incisional hernia or fascial dehiscence (4,7) Prophylactic mesh augmentation in a non-emergency midline laparotomy appears both effective and safe in incisional hernia prevention (8). Additionally, there is emerging evidence and research suggesting that synthetic meshes are also safe in contaminated surgery and emergency surgery (9,10).
However, there have only been a few studies on incisional hernia prophylaxis within an emergency setting. In a recent systematic review and meta-analysis, the results of two studies, and altogether 299 patients, were eligible to be analyzed (2). A case-control study from Switzerland reported an incisional hernia rate of 3.2% (2/63) in its intra-abdominal mesh group and 28.6% (20/70) in its sutured control group after emergency midline laparotomy for peritonitis (11). A Spanish group exhibited similar results in their retrospective cohort study including patients with emergency midline laparotomies: an incisional hernia rate of 5.9% (3/50) in the onlay mesh group and 33.3% (33/100) in the control group (12). There was no statistically signi cant difference in the incidence of surgical site infection or other complications when the prophylactic mesh group was compared to the standard closure group.
As an emergency laparotomy is a signi cant risk factor for incisional hernia, a mesh augmented closure should be considered. Therefore, our study group has designed a randomized controlled trial (RCT) comparing prophylactic mesh with the best standard suturing technique within this challenging setting.

Objectives {7}
The objective of this study is to evaluate whether the rectorectus placement of a self-gripping popypropylene mesh (Progrip TM , Medtronic) is safe and prevents an incisional hernia after emergency midline laparotomy. The results of mesh augmented closure are compared with controls operated with no mesh. In both groups, the fascia will be closed using the best standard 4:1 small stitch closing technique with a continuous slowly absorbable mono lament suture.

Trial design {8}
Enrolled subjects will undergo assessments at the following intervals: pre-operative, operative, discharge, and 30 days, two-, and ve years post-surgery.
All study patients are evaluated both clinically and radiologically two years after their emergency midline laparotomies in order to detect clinical and radiological incisional hernias. The follow-up will continue until ve years after surgery in order to assess the long-term results and safety.
Ultrasounds with and without the Valsalva maneuver will be performed on all patients two years after surgery. The extent of any fascial defect and the hernia sac volume (i.e., the volume of the incisional hernia) are measured and graded according to the European Hernia Society criteria of incisional hernias (13).
Quality of life will be measured using RAND-36, the Activities Assessment Scale (AAS), and the PROMIS questionnaire at all follow-up visits of 30 days, two years, and ve years as well as when a hernia is diagnosed. Patients ful lling the inclusion criteria and not meeting the exclusion criteria will be offered the opportunity to participate by investigator when a decision of an emergency laparotomy is achieved. To control selection bias, a prospective database of patients not participating in the study will be maintained at each attending hospital during the study period.
Additional consent provisions for collection and use of participant data and biological specimens {26b} Not applicable.

Explanation for the choice of comparators {6b}
The fascia in the control group of the study will be closed using the best standard 4:1 small stitch suturing via continuous slowly absorbable mono lament suture bene cial also in the emergency setting (4). Self-gripping mesh (Progrip TM , Medtronic) in the rectorectus position was chosen to avoid need for separate attachment method of the mesh and to diminish the risk of seromas associated with onlay mesh (10,15).

Intervention description {11a}
At the end of the operation, the abdomen will be closed according to the patients' randomized group, if applicable.
In the mesh group, the posterior layer of the rectus sheath is opened as close to the midline as possible without interrupting the midline. The space behind the rectus muscle is created mainly using a blunt dissection. At each ends of the incision, opening of the retrorectus space is achieved both cranially and caudally over the ends of the wound, if applicable. The posterior layer is closed using USP 0 or 2-0 slowly absorbable mono lament 4:1 small stitch technique. The stitch bites are 5 mm with a 5. mm inter-stitch space. The length of the wound is measured as well as the length of the suturing material used. The aim is to close the fascia using a suture material at least four times the length of the wound (4:1) using the small stitch technique. After securing that there will be no contact with the mesh and abdominal cavity, In the control group, the rectus aponeurosis is closed in a single aponeurotic layer using slowly absorbable mono lament USP 2-0 or 0 sutures via the 4:1 small stitch technique. Both the length of the wound and the length of the suture material used are measured.
Cataloguing of the operative technique will be sent to all participating surgeons to standardize the procedure.

Criteria for discontinuing or modifying allocated interventions {11b}
If the mesh cannot be safely kept outside of the abdominal cavity, or the fascia cannot be securely closed in either randomization group, the patient is intra-operatively excluded.

Strategies to improve adherence to interventions {11c}
Not applicable.

Relevant concomitant care permitted or prohibited during the trial {11d}
Not applicable. Study patients will be treated according to standard of care.

Provisions for post-trial care {30}
Not applicable. Study patients will be treated according to standard of care.

Primary Outcomes
The primary endpoint of this study is the incidence of incisional hernia, either symptomatic or asymptomatic, detected clinically and/or radiologically within two years after surgery.
The de nition and classi cation of an incisional hernia provided by the European Hernia Society will be used to classify the primary outcome (13) .
In the case of inconsistencies between the clinical and radiological evaluations, or either clinical evaluation or imaging is missing for any reason, the following de nitions of the primary endpoint will be used: All related costs are analyzed in detail. The direct costs, such as the meshes, resources, and hospital stay costs, are monitored, and the indirect costs from productivity losses of a patient are estimated.

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The following costs of treatment for both groups will be analyzed in detail: Mesh and other materials used to close the abdomen The following data will be recorded prospectively using speci c electronic case report forms (eCRF). Two-year follow-up Patient-related recovery outcomes and QoL questionnaires (RAND-36, AAS, PROMIS) will be completed, and any complications, clinical signs, and abdominal ultrasound ndings of an incisional hernia or protocol deviations will be reported. Both the patient and surgeon assessing recovery and well-being of the patient will be blinded to the randomized groups.
The ultrasound ndings will all be analyzed by a single independent radiologist at each study site who will be blinded to the randomized groups. Possible hernia opening, size, location, and incisional sack volume will be de ned both at rest and with the Valsalva maneuver. If the ndings are inconclusive or there is a discrepancy between the clinical assessment and imaging, or a patient has a symptomatic incisional hernia and operative treatment is indicated, an abdominal CT scan will be done to verify the hernia diagnosis or plan an operative technique.
Five-year follow-up Patient-related functional outcomes and QoL will be completed and any complications, clinical signs of an incisional hernia, or protocol deviations will be reported. Additionally, ultrasound scans will be done following the same protocol as described for the two-year control if there is any suspicion of incisional hernia.
All exceptions to the protocol are recorded and explained in detail at each point of follow-up schedule. To calculate the sample size required to compare these two groups, we estimated a 10 % rate of incisional hernia in the mesh group and a 25% incisional hernia incidence in the control group upon clinical assessment and ultrasound examination. Assuming α = 0.05 and power = 90%, we would need 97 patients per group. Furthermore, assuming a two-year dropout rate of 20%, 122 patients per group are needed (244 patients in total). The sample size is calculated only for the primary outcome, and the secondary outcomes will be interpreted for hypothesis-generating only. If the estimated 20% dropout rate is exceeded, the sample size may be recalculated.
All analyses will be performed by or under the guidance of a professional statistician and following the CONSORT guidelines (14).

Recruitment {15}
Eligible patients will be recruited at the approved participating sites. All patients who are eligible, will be offered enrolment in the study at each study site. A screening log of all abdominal emergency midline laparotomies throughout the study period will be maintained for the further assessment of selection biases.
After receiving the proper information on the possible advantages and disadvantages of the intervention as well as signing the voluntarily informed consent form, the subject will be enrolled in the PREEMER trial.
Participating centers and investigators are quali ed colorectal or general surgeons experienced in the surgical management of patients with abdominal emergencies and emergency midline laparotomies. Each hospital's contribution to the study will be limited to no less than 20 cases per hospital.

Assignment of interventions: allocation
Sequence generation {16a} The allocation will be strati ed according to patient BMI (< 30 and ≥ 30kg/m 2 ), previous laparotomy history, and age (< 65 and ≥ 65 years). A separate randomization list will be created for each participating center.

Concealment mechanism {16b}
A dedicated electronic database and randomization software will be used to host the clinical trial data for this study.

Implementation {16c}
Patients are randomly assigned (1:1 ratio) to either an intervention group or control group according to a computer-generated list compiled by a biostatistician otherwise uninvolved in the clinical care of the trial patients. Patients undergoing emergency midline laparotomy for any abdominal indication and ful lling the inclusion criteria will be randomized by investigator into the groups prior to surgery after the decision to perform a midline laparotomy is made and the informed consent form is signed. Participating centers and investigators are quali ed colorectal or general surgeons experienced in the surgical management of patients with abdominal emergencies and emergency midline laparotomies. Each hospital's contribution to the study will be limited to no less than 20 cases per hospital.

Assignment of interventions: Blinding
Who will be blinded {17a} Study patients will be blinded of the randomized group during the whole follow-up period. Both the surgeon evaluating the outcome at 30 days, two years, and ve years follow-ups as well as the radiologist will be blinded to the randomized groups. In both groups, the following sentence will be written in the medical records instead of revealing the randomized group: "Fascial closure was performed according to randomized group".

Procedure for unblinding if needed {17b}
Patients' randomization number will be available in the medical records. Envelopes marked with the randomization numbers and containing the allocated group information will be accessible at all times in the case of complications etc. A record of unsuccessful blinding will be maintained and published.

Data collection and management
Plans for assessment and collection of outcomes {18a} A dedicated electronic database and randomization software will be used to host the clinical trial data for this study. All eCRFs are handled with a special trial ID and date of birth. Access to the database is limited to the main investigators, and all data requested on the eCRFs will be recorded. Any missing data will be explained. The data collection will be the responsibility of the principal investigator at each study site and will be reviewed by the study group.

Plans to promote participant retention and complete follow-up {18b}
The reasons for withdrawal are documented carefully. The investigator attempts to contact the subjects at least three times prior to designating them as lost to follow-up. The investigator documents the date and type of attempted communication. If a subject cannot be reached during the visit window, a missed visit is recorded; after three (3) consecutive missed visits, a subject will be considered lost to follow-up and a study exit form will be completed on the electronic database. Any data on a subject's participation and procedures prior to withdrawal will be analyzed within the research.

Data management {19}
A dedicated electronic database and randomization software will be used to host the clinical trial data for this study. All eCRFs are handled with a special trial ID and date of birth of the patient. Access to the database is limited to the main investigators, and all data requested on the eCRFs will be recorded. Any missing data will be explained.
The data collection will be the responsibility of the principal investigator at each study site and will be reviewed by the study group.
Con dentiality {27} Patient con dentiality will be strictly maintained. Patients will be assigned a study ID, and all data will be managed without names or personal social security numbers. Access to patient records is limited to the study group and the investigator-delegated study coordinator.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable.

Statistical methods for primary and secondary outcomes {20a}
The linear mixed model (LMM) or generalized linear mixed model (GLMM) will be used for repeatedly measured data, the previous for continuous data and the latter for categorical data. If there are signi cantly more serious complications in either group compared to other at 30 days or 2 years control, the trial will be discontinued.

Methods for additional analyses (e.g. subgroup analyses) {20b}
The prospectively planned subgroup analyses are as follows: BMI > 30 and previous hernia and contamination class 4. However, sample size calculation will be done only for the primary end point, and subgroup analyses are hypothesis-generating only.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Multiple imputations of missing outcome data will be used for sensitivity analyses.
Plans to give access to the full protocol, participant level-data and statistical code {31c} There will be no public access to the full protocol, participant-level dataset, and statistical code.

Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d} Not applicable.
Composition of the data monitoring committee, its role and reporting structure {21a} There will be no data monitoring committee. If there are signi cantly more serious complications in either group compared to other at 30 days or 2 years control, the trial will be discontinued.
Adverse event reporting and harms {22} All adverse events are reported by eCRF and published. A separate electronic Complication form will be lled for any complication Clavien-Dindo 3B or more serious. Interim analysis of adverse events will be accomplished once 30 patients in both groups have reached both 1 month and 2 years follow-ups.

Dissemination plans {31a}
The protocol of the trial will be published at the beginning of the trial. The results concerning the primary end point and results of secondary endpoints within 2 years follow up will be published once included patients have reached 2 years follow-up. The results of 5 years follow up will be published.

Discussion
The aim of this study is to, in a randomized, double-blinded, multicenter setting, assess the safety and e ciency of preventive self-gripping mesh in incisional hernia prevention for emergency abdominal midline laparotomies. The mesh closure group is compared to a control group without a mesh closed via a standard small stitch closure with a continuous slowly absorbable mono lament suture. The hypothesis is that a signi cant number of symptomatic incisional hernias and further operations due to the incisional hernia can be prevented with a prophylactic mesh. Quality of life is measured throughout the study in both groups to analyze the effect of the prophylactic mesh.
Prophylactic meshes signi cantly reduce the incidence of incisional hernia in high-risk patient groups (5,15). As the risk of incisional hernia after abdominal midline laparotomy increases to above 30% (12), a signi cant number of hernias could be prevented using a prophylactic mesh in the emergency setting.
Onlay mesh has been associated with an increased risk of seroma (10,15). As an emergency laparotomy, especially one at a contaminated surgical site, is prone to infections and seromas (12), a retrorectus position was chosen for this study. This position also enables the skin to be left open in the cases of contamination level IV.
The use of synthetic materials in contaminated surgical sites has been increasing. However, there are concerns over its potential mesh-related complications, such as infection, chronic pain, seromas, and bowel stulas, especially in emergency situations like peritonitis and intestinal obstruction (10). Therefore, it is crucial to evaluate the potential bene ts, hernia risk groups, costs, quality of life, and longterm results in a randomized setting before adapting preventive meshes on a large scale.
If a signi cant number of incisional hernias can be safely prevented by using a mesh, not only will patients bene t from a better quality of life, but major health care cost savings can be achieved. Each year, there are about 1,650 patients operated upon in Finland due to symptomatic incisional hernias.
According to a French study, the estimated cost for an incisional hernia surgery is 6,450 euros (16). The corresponding costs in Sweden are even higher, reaching 9,060 euros per treatment (17). Extrapolating this to Finland, this means that the operative treatment of incisional hernias cause more than 10 million Euros in expenses for the Finnish health care sector in a year. A majority of these costs may be avoided by using the prophylactic mesh during the closure of midline emergency laparotomies in patients presenting with incisional hernia risk factors.
In the two previous studies on this topic, the SSI rate in a Swiss study was 60% and, respectively, only 17% in a Spanish study (11,12) .This re ects differences in their patient selection, as there were only subjects with peritonitis in the rst study, while all kinds of emergency laparotomies were included in the latter. Neither of the studies included in the only meta-analysis on the topic were randomized controlled trials (2). There were also many methodological differences in both the mesh itself and the mesh placement in these two studies. Thus, the conclusion of the only systematic review paper published on the topic was that there is a limited amount of data available for assessing the effect and safety of the use of prophylactic mesh in an emergency laparotomy setting (2). Thus, randomized control trials are required to address this important clinical question. Moreover, the EHS guideline group came to the same conclusion in their recommendation report for preventing incisional hernias (13).

Trial Status
Ethics Committee approval in Oulu University Hospital was received February 25 th 2020 for protocol version 1.0 dated January 2 nd 2020. The recruitment will begin in April 2020 and is anticipated to be complete in 2022. Availability of data and material

Abbreviations
The datasets generated and/or analyzed during the current study are not publicly available due to Finnish laws on privacy protection but are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate The Ethical Committee at Oulu University Hospital has approved the PREEMER Trial February 25 th 2020 (3/2020) and its consent to participate.

Consent for publication
Not applicable. Other authors have nothing to declare.