Clinical trial protocol for P-NeLoP: a randomized controlled trial comparing the feasibility and outcomes of robot-assisted partial nephrectomy with low insufflation pressure using AirSeal versus standard insufflation pressure (UroCCR no. 85 study)

Robot-assisted partial nephrectomy (RAPN) is the standard of care for small, localized kidney tumors. This surgery is conducted within a short hospital stay and can even be performed as outpatient surgery in selected patients. In order to allow early rehabilitation of patients, an optimal control of postoperative pain is necessary. High-pressure pneumoperitoneum during surgery seems to be the source of significant pain during the first hours postoperatively. Our study is a prospective, randomized, multicenter, controlled study which aims to compare post-operative pain at 24 h between patients undergoing RAPN at low insufflation pressure (7 mmHg) and those operated on at standard pressure (12 mmHg) using the AirSeal system. This trial is registered in the US National Library of Medicine Trial Registry (NCT number: NCT05404685).


Introduction and hypothesis
Kidney cancer is of increasing incidence in Europe and Worldwide.According to the Global Cancer Observatory, it is the 14th most common malignancy with 431,288 new cases in 2020 including 138,611 in Europe [1].One explanation for this rising incidence is the increasing incidental diagnosis of small renal masses on imaging done for another cause [2,3].For these localized tumors (cT1-T2), conservative surgery (partial nephrectomy) is the standard of care [4], allowing good carcinological results while reducing morbidity.The minimally invasive approach with robotic assistance (robot-assisted partial nephrectomy (RAPN)) is now widely used in many hospitals.It combines a reduced perioperative morbidity and shorter hospital stays without altering the oncological results [5,6].This improvement in the procedure's safety has allowed the development of Enhanced Recovery After Surgery protocols and ambulatory protocols [7][8][9].Nevertheless, in general and in the context of outpatient care in particular, the control of postoperative pain is a crucial issue to allow convalescence and return to activity in the best possible conditions.
Laparoscopic procedures require the generation of a pneumoperitoneum by intra-abdominal insufflation of carbon dioxide (CO 2 ) resulting in an impact on the cardiovascular and respiratory system (reduced venous flow and cardiac output, increased peripheral vascular resistance and blood pressure, increased pulmonary ventilatory resistance and hypercapnia) [10].In order to limit these adverse effects, it is commonly recommended to limit the insufflation pressure to the minimum level necessary to allow sufficient exposure and working space.The commonly used insufflation pressure is 12-15 mmHg [10].In addition to the side effects described above, this abdominal overpressure is also responsible for postoperative pain due to phrenic irritation and residual CO 2 [11], which is, based on our expertise, mainly experienced during the first 48 h postoperatively and is difficult to control with the usual analgesics.The AirSeal ® system consists of an insufflator, a 3-channel tubing set, and a special trocar.It provides active, continuous, and self-regulated insufflation, suction and filtration of CO 2 .This allows the preservation of a stable pneumoperitoneum while ensuring continuous extraction and active filtration of electrocoagulation smoke [12].
This system has been shown to improve intra-operative ventilatory parameters during laparoscopic total cystectomy in a prospective randomized study [13].Shahait et al. also reported a decrease in operative time and postoperative pain during robot-assisted total prostatectomy with the use of AirSeal at standard pressure in a non-randomized comparative study [14], while La Falce et al. demonstrated the feasibility of robot-assisted total prostatectomies at low insufflation pressure (8 mmHg) using the AirSeal ® system [15].Low-pressure insufflation is also being evaluated in other surgical areas.Therefore, Celarier et al. presented evidence of shorter hospital stay and decreased postoperative pain after laparoscopic colonic resection in a phase III randomized controlled trial evaluating the use of AirSeal at low pressure (7 mmHg) versus standard pressure (12 mmHg) [16].Finally, specific data in the literature regarding the use of AirSeal ® in RAPN is limited to the non-randomized prospective study of Annino et al. comparing standard insufflation with Air-Seal ® (at standard pressure of 12 mmHg) and reporting a benefit in terms of operating time, duration of renal ischemia, and rate of procedures without arterial clamping [17].
During the COVID-19 pandemic, the risk of contamination by surgical smoke, which may contain toxic gas but also viral pathogens, has been highlighted [18].Their concentration within the abdominal cavity and the circulating insufflation gas result in a risk of aerosolization [19] and contamination of the operating theater and staff during laparoscopic procedures with or without robotic assistance [20].This is especially significant in renal conservative surgery as SARS-COV-2 appears to have a capacity to bind to proximal convoluted tubules through its affinity for ACE2 receptors [20,21].This risk has led the EAU Robotic Urology Section (ERUS) committee to publish specific practice recommendations [22] advocating for the use of the lowest possible pneumoperitoneum pressure, active aspiration, and filtration of surgical smoke.
In this context, the P-NeLoP (partial nephrectomy in low pressure) trial aims to compare the effectiveness of AirSeal use at low pressure (7 mmHg), in terms of decreasing postoperative pain and therefore allowing fast re-autonomization of the patient, and its safety compared to its use at standard pressure (12 mmHg).

Protocol overview
This is a two-arm, single blinded, prospective, multicenter randomized controlled trial that evaluates the impact of low insufflation pressure using AirSeal system (7 mmHg) during RAPN on post-operative pain, 24 h after surgery.We hypothesize that the use of AirSeal ® at low pressure (7 mmHg) for RAPN would reduce post-operative pain, decrease the intake of analgesics, and thus facilitate patient re-autonomization.The study design is presented in Fig. 1.

Study population and setting
This trial protocol is supported by the French research network on kidney cancer UroCCR (www.uroccr.fr; NCT03293563).Fifteen hospitals and clinics are involved in this multicentric study.The objective is to include 280 patients divided into two parallel groups: a control group undergoing surgery with a standard insufflation pressure (12 mmHg) and an experimental group undergoing surgery with a low insufflation pressure (7 mmHg), both using the AirSeal system.All adult patients managed for renal tumor and scheduled for transperitoneal RAPN are eligible for inclusion.The inclusion and exclusion criteria are summarized in Table 1.
This study was authorized and approved ethically by the Ouest I Ethics Committee on April 27, 2022 (ID-RCB: 2021-A03136-35), and is prospectively registered in the US National Library of Medicine Trial Registry (NCT number: NCT05404685).

Assessment of baseline and inclusion
Patient characteristics, including medical history, blood work, imaging (including RENAL [24] and PADUA [25] nephrometry scores), and clinical data, will be collected by the investigating physician during diagnostic work-up and included in the web-based shared clinical and biological national database on kidney cancer UroCCR.
During the inclusion consultation, the patient will be fully informed by the investigating physician on the research protocol and given information notes on the P-NeLoP research trial and the UroCCR network.An informed consent form will be signed by each patient participating in the research protocol (Appendix).

Randomization and blinding
Randomization will be performed just before surgery, with the patient being already under anesthesia.It will be conducted directly on the UroCCR database.After validation of the patient's eligibility, the participant's research number and the randomization result from the database, as well as the degree of insufflation, will be immediately communicated to the surgeon.The randomization list will be generated by the statistician at the Methodology and Data Management Center of the promoting hospital.The two groups will be balanced with a 1:1 ratio, and the randomization will be stratified according to the investigating centers.A detailed description of the analgesia habits of each center will be made at the beginning of the study.
A single blind will be applied.Patients will therefore not be informed of the group they have been allocated to.

Procedure
All surgeries will be performed via transperitoneal robotassisted approach with the use of an AirSeal device.The pressure level will be adjusted at the beginning of the surgery, after placement of the ports, according to the randomization result.In the event of technical difficulties experienced by the surgeon that may be induced by low pressure during a procedure performed at 7 mmHg, the pressure can be increased to the standard pressure of 12 mmHg.This information will then be collected as described in the secondary objectives.

Intra-and post-operative follow-up
The follow-up does not differ from the standard followup after RAPN.Four post-operative follow-up time points will be set to collect the data needed for evaluation (Fig. 2).
During surgery, complications, type of clamping, operative time, volume of blood loss, changes in insufflation pressure, and duration as well as the plateau pressure and PETCO 2 60 min after incision will be collected.
Post-operatively, we will record adverse events (according to Clavien-Dindo classification), presence of pain (according to the numeric rating scale (NRS)), and the use of analgesics (according to the Medication Quantification Scale Version III [23]), at H+6, H+24, and H+48.The return to eating, walking, and transit should also be noted.Finally, a first follow-up consultation is planned at day 30 (± 15 days) with collection of adverse events during the postoperative period.

Calculation of the study size
We hypothesize that the average pain level measured at 24 h post-operatively by NRS will be 4.8 in the Air-Seal ® standard pressure group of 12 mmHg [11].We also believe that the use of the AirSeal ® device at a low pressure of 7 mmHg will decrease the mean pain by at least 0.8 points to 4.0 or less.With a common standard deviation of 2 [11], a power of 90%, an alpha risk of 5%, and a proportion of 5% missing or uninterpretable data, a total of 280 patients (140 patients per group) should be included (SAS ® version 9.4, "Proc power" with a twosided t-test on the difference in mean).

Table 1 Inclusion and exclusion criteria
RAPN Robot-assisted partial nephrectomy

Inclusion criteria Exclusion criteria
Male or female aged of 18 and over Daily chronic painkillers intake for another indication than the kidney tumor and intended to be maintained at the time of surgery

Data analysis
The data will be analyzed by the biostatistician of the promoting hospital.The analyses will be performed with the SAS ® software (version 9.4 or later).The main analysis will be performed on an intention-to-treat basis (any missing value of the primary endpoint will be replaced by the value corresponding to the failure of management, i.e., the maximum NRS value for all groups combined).Secondary objectives will be analyzed on available data.A descriptive analysis will be performed overall and by group.The primary endpoint (NRS at H+24 postoperative) will be compared between the two randomization groups without adjustment and then after adjustment for the center and the level of analgesia prescribed (1, 2, or 3) using a linear regression model.Tests on the primary endpoint will be performed with an α risk of 5%.

Conclusion
In recent years, we have witnessed an increase in cases of small renal tumors for which RAPN is now the standard of care.This surgery allows a shortening of hospital stay and is even performed on an outpatient basis for selected patients.Post-operative pain management is essential to the completion of these care paths and to the early rehabilitation of the patient.The AirSeal system allows the reduction of the insufflation pressure of the pneumoperitoneum during these surgeries which could lead to a significant decrease in postoperative pain.The P-NeLoP trial will evaluate the efficacy and safety of this low insufflation pressure device on a prospective basis.

Patient consent form UROCCR 85 -P-NELOP -CHUBX 2020/62
Research sponsor: CHU de Bordeaux  I am aware of the possibility of interrupting my participation in research at any time without having to justify my decision and I will do my best to inform the who is monitoring me in the research.This will of course not affect the quality of subsequent care.
I have been assured that the decisions that are necessary for my health will be made at any time, in accordance with the current state of medical knowledge.
I have been informed that this research has received a favorable opinion from the Committee for the Protection of Persons (CPP) and has been reported to the ANSM.
The Bordeaux University Hospital has signed a commitment to comply with the "Reference Methodology" (MR-001) in application of the provisions of article 54 paragraph 5 of the law of 6 January 1978 relating to information technology, files and freedoms, modified by the law no.2018-493 of 20 June 2018 on the protection of personal data.
The Sponsor of the research (CHU de Bordeaux, 12 rue Dubernat, 33404 Talence Cedex) has taken out insurance for liability insurance in case of damage with the company LLOYD'S INSURANCE COMPANY SA through the brokerage company BEAH SAS whose address is 16-18 rue de Londres, 75009 Paris (tel: 04 82 25 01 62).
I agree that the persons who collaborate in this research or who are mandated by the Promoter, as well as possibly the representative of the Health Authorities, may have access to the information in strict confidentiality.
I agree that the data recorded during this research, in pseudonymized (coded) form, may be subject to computerized processing under the responsibility of the Promoter.I am informed that, at the end of this research, these data may be used for other research purposes (new statistical analyses) and I have been informed of my right to object to this.
I have noted that, in accordance with the General Data Protection Regulation (RGPD) and the provisions of the law relating to data processing, files and freedoms, I have a right of access, rectification, deletion, limitation of processing, portability of data, opposition and withdrawal.These rights can be exercised with the investigator who is following me in this research and who knows my identity or via the UroCCR website www.uroccr.fr.
My consent does not relieve the investigator and the Sponsor of the research of their responsibilities to me.I retain all rights guaranteed by law.
The results of the study will be communicated directly via the UroCCR website www.uroccr.fr, in accordance with the law of 4 March 2002 on the rights of patients and the quality of the health system.
Having had sufficient time to consider my decision, I freely and voluntarily agree to participate in P-NeLoP research.

Patient public involvement
The French patients' association A. R. Tu.R is a member of the UroCCR scientific committee and was involved in the design of the protocol.The research project was also presented at scientific conferences attended by patients from this association

Trial steering committee
It is composed of the coordinating investigator (a surgeon), the project manager, the data manager, and the clinical research assistants from the coordinating center.The committee is running the trial day to day and provide organizational support for the participating centers.They meet every month and additional meetings can be scheduled if necessary.

Audit and inspection
Subject to notification within a suitable period of time, an audit may be carried out at any time by persons mandated by the sponsor and independent of those conducting the research.The purpose of the audit is to verify the safety of the participants and respect for their rights, compliance with the applicable regulations, and the reliability of the data.An inspection could also be carried out by a competent authority.Both audit and inspection may apply to all stages of the research, from the development of the protocol to the publication of results and the classification of data used or generated in the research.Investigators agree to comply with the requirements of the sponsor for an audit and the competent authority for an inspection of the research.Management of adverse events/adverse reactions/incident Adverse events/incidents should be reported to the relevant health vigilance circuits for each product or practice concerned in accordance with the regulations.The notifiers must specify that the participant is included in a clinical trial and identify precisely the clinical trial concerned.If the investigator becomes aware of a breach of safety in the context of the research, he/she must inform the sponsor without delay.

Fig. 2
Fig. 2 Timeline.NRS, numeric rating scale agree that my clinical data may be stored and used for other research purposes (new statistical analyses).….Yes … No Done at ………... On: Done at ………….. On: Name of investigator: Signature of participant: Signature of investigator: Dr. Caroline Lacoste-Roussillon (physician in charge of the Clinical Trials Safety and Vigilance Unit), and Aline Doublet (representative of the promoter).The scientific committee meets according to the needs of the research.It is responsible for taking all important decisions at the request of the coordinating investigator concerning the proper conduct of the research and compliance with the protocol.It verifies compliance with ethical standards.It keeps the Methodology and Data Management Centre and the coordinating investigator informed of the progress of the research, any problems, and the results available.It decides on any relevant changes to the protocol necessary for the continuation of the research, including measures to facilitate recruitment into the research, changes to the research documents, decisions to open or close research sites, measures that ensure the best possible safety for research participants, discussion of the results, and the strategy for publishing them.The Scientific Council may propose to extend or interrupt the research if the inclusion's rate is too slow, if too many people are lost to follow-up, if there are major violations of the protocol, or for medical and/or administrative reasons.It specifies the possible modalities for the prolonged follow-up of the participants included in the research