The goal of this clinical trial is to learn whether the ClearPetra ureteral access sheath (Coloplast) is more effective than the Navigator ureteral access sheath (Boston Scientific) in treating intrarenal kidney stones of 1-3 cm in adult patients undergoing flexible ureteroscopy (RIRS). The main questions it aims to answer are:

Does ClearPetra achieve a higher stone-free rate at 1 month post-intervention compared to Navigator, as assessed by non-contrast abdominal-pelvic CT scan?

Does ClearPetra reduce total surgical time compared to Navigator?

Does ClearPetra lower the retreatment rate at 3 months compared to Navigator?

Does ClearPetra present a rate of clinically significant complications (Clavien-Dindo ≥ II) that is lower than or similar to Navigator?

Researchers will compare flexible ureteroscopy using the ClearPetra vacuum-assisted flexible ureteral access sheath to flexible ureteroscopy using the Navigator standard rigid ureteral access sheath, to see if ClearPetra leads to higher stone clearance rates while maintaining a comparable safety profile.

Participants will:

Undergo flexible ureteroscopy (RIRS) using one of two randomly assigned ureteral access sheaths (ClearPetra or Navigator), determined by computer-generated randomization immediately before surgery

Have a non-contrast abdominal-pelvic CT scan at 1 month post-intervention to assess stone-free status

Have a non-contrast abdominal-pelvic CT scan at 3 months post-intervention to evaluate residual fragments and the need for retreatment

Attend follow-up visits at 1 month and 3 months post-surgery for clinical assessment and complication recording

The study will be conducted at the Urology Department of Hospital Universitario Virgen del Rocío (Seville, Spain), a tertiary reference centre. A total of 156 patients will be randomized in a 1:1 ratio (78 per group), with pre-defined subgroup analyses stratified by stone size (1-2 cm vs. >2 cm). The outcome assessor evaluating CT images for stone-free rate will be blinded to treatment allocation (single-blind).

BACKGROUND AND RATIONALE

Urinary lithiasis (kidney stone disease) affects approximately 10-15% of the population in developed countries and is characterized by high recurrence rates. Among surgical treatment options, retrograde intrarenal surgery (RIRS) using flexible ureteroscopy has become the standard-of-care approach for intrarenal stones measuring 1-3 cm, offering the advantages of a minimally invasive endoscopic approach combined with laser lithotripsy.

Ureteral access sheaths (UAS) are devices placed transurethrally prior to flexible ureteroscopy to facilitate repeated scope insertion, maintain stable ureteral access, and reduce intrapelvic pressure during the procedure. Two fundamentally different UAS designs are currently in clinical use at the study centre: (1) standard rigid sheaths, represented by the Navigator® (Boston Scientific), and (2) a novel vacuum-assisted flexible sheath, the ClearPetra® (Coloplast), which incorporates continuous negative-pressure aspiration to actively evacuate stone fragments and irrigation fluid throughout the procedure.

The theoretical advantages of vacuum-assisted UAS include improved intraoperative visibility due to continuous fluid evacuation, more efficient fragment extraction (particularly smaller dust-like fragments generated by laser pulp), potentially reduced intrapelvic pressure, and lower risk of infectious complications related to high intrarenal pressure. However, despite these mechanistic rationales and promising preliminary data, no randomised controlled trial has yet conclusively established the superiority of ClearPetra® over standard rigid sheaths in terms of stone-free rate for intrarenal lithiasis in the 1-3 cm range.

The current choice between sheath types at most urology departments - including the study centre - is made based on surgeon preference, device availability, or extrapolation from observational studies with significant methodological limitations. This genuine clinical equipoise justifies conducting a prospective randomised trial to generate Level I evidence on this clinically important question.

STUDY DESIGN

This is a prospective, single-centre, randomised controlled superiority trial with parallel groups and single-blind (outcome assessor-blinded) design. Patients are allocated in a 1:1 ratio to one of two treatment arms:

Experimental arm: Flexible ureteroscopy (RIRS) using ClearPetra® ureteral access sheath (Coloplast) - a flexible, vacuum-assisted sheath providing continuous negative-pressure aspiration.

Control arm: Flexible ureteroscopy (RIRS) using Navigator® ureteral access sheath (Boston Scientific) - a standard rigid sheath without active aspiration.

Both devices are CE-marked, commercially available, and currently used in routine clinical practice at Hospital Universitario Virgen del Rocío (Seville, Spain).

DEVICES UNDER INVESTIGATION

ClearPetra® (Coloplast): A tip-flexible ureteral access sheath designed for use with flexible ureteroscopes. Its distinctive feature is an integrated vacuum aspiration system that enables continuous active removal of stone fragments and irrigation fluid during the procedure. The sheath flexibility is intended to reduce trauma during insertion and improve conformability within the upper urinary tract.

Navigator® (Boston Scientific): A conventional rigid ureteral access sheath representing the current standard of care. It facilitates ureteroscope passage and provides a working channel for irrigation, but does not incorporate an active aspiration mechanism. Fragment removal depends on passive irrigation and the use of accessory instruments (baskets, stone cones).

Both devices are available in standard sizes compatible with the flexible ureteroscopes used at the study centre.

RANDOMISATION AND ALLOCATION CONCEALMENT

The randomisation sequence will be computer-generated using Randomizer.org (www.randomizer.org) prior to study initiation, producing a list of 156 consecutive assignments in a 1:1 ratio between the two arms. The sequence will be prepared before the first patient is enrolled.

Allocation concealment will be implemented via sequentially numbered, opaque, sealed envelopes prepared by an investigator not involved in patient recruitment or surgical procedures. Envelopes will be stored under lock and key in the principal investigator's office until the moment of use.

At the time of hospital admission for the scheduled surgical procedure, after confirming all eligibility criteria, the principal investigator or designated delegate will open the envelope corresponding to the patient's sequential number, revealing the assigned sheath type. This information will be communicated to the surgical team immediately before the endoscopic procedure begins. The date and time of each envelope opening will be recorded on a separate control sheet to ensure traceability.

BLINDING

Due to the physical nature of the surgical intervention, blinding of the surgeon and patient to treatment allocation is not feasible. However, single-blind design will be implemented at the level of outcome assessment:

CT outcome assessor: The urologist(s) responsible for analysing CT images to determine residual stone volume and stone-free status will be blinded to treatment allocation. Radiological images will be coded with a study number without any identification of the sheath type used.

Complications assessor: The investigator responsible for recording and classifying postoperative complications according to the Clavien-Dindo scale will also be blinded to group assignment.

This assessor-blinding strategy is the recognised standard approach in surgical device trials and is sufficient to ensure validity of the primary outcome, which is based on objective CT measurement.

SURGICAL PROTOCOL

All procedures will be performed by 2-3 urological surgeons at the study centre, each with extensive experience in flexible ureteroscopy (>100 RIRS procedures performed). Both study devices are already part of these surgeons' routine clinical practice, ensuring no learning curve bias.

A standardised intraoperative protocol will be followed by all participating surgeons regardless of the assigned sheath, including:

Criteria for complete stone fragmentation

Systematic use of accessory instruments (retrieval basket, stone cone) according to fragment size

Predefined criteria for procedure completion

Standardised management of intraoperative complications

Randomisation will be performed immediately before the intervention, minimising the time during which the surgeon is aware of the assignment prior to the procedure. The primary outcome variable (CT-assessed SFR at one month) is an objective measure independent of the surgeon's intraoperative assessment.

An intraoperative registration form specific to the study will be completed by the operating surgeon immediately after each procedure, recording: procedure start and end times, active fragmentation time, laser activation time, fluoroscopy time, laser energy type and parameters used, accessory instruments employed, immediate endoscopic and fluoroscopic assessment of stone-free status, ureteral stenting decisions, and any intraoperative complications.

FOLLOW-UP SCHEDULE

Patients will be followed prospectively from the date of the intervention through 3 months post-surgery, with pre-specified evaluation time points:

OUTCOME MEASURES - TECHNICAL DEFINITIONS

Primary outcome - Stone-Free Rate (SFR) at 1 month: Defined as complete absence of residual lithiasis or presence exclusively of fragments ≤2 mm on non-contrast abdomino-pelvic CT performed at 30 ±7 days post-intervention. This is a dichotomous variable (yes/no stone-free). The CT assessor will be blinded to treatment allocation.

CT measurements will follow a standardised imaging protocol: multiplanar reconstruction (axial, coronal, sagittal), identification of all stone/fragment foci, measurement of maximum diameter in any plane, manual volumetric calculation, and density measurement at the point of maximum attenuation in Hounsfield Units (HU). All volumetric and dimensional measurements will be performed by a single experienced urological radiologist/assessor who is blinded to the assigned sheath type.

Sensitivity analysis for the primary outcome: A pre-specified sensitivity analysis will apply a stricter stone-free definition (complete absence of any residual fragment, 0 mm threshold) to evaluate consistency of results.

Secondary efficacy outcomes include:

Stone volume reduction rate at 1 month: calculated as [1 - (residual postoperative volume / preoperative volume)] × 100 (%)

Pre- and post-operative stone volumes (mm³) measured by CT volumetric software

Immediate endoscopic SFR (surgeon's qualitative assessment at end of procedure)

Immediate fluoroscopic SFR (fluoroscopic assessment at end of procedure)

SFR at 3 months (CT-assessed, same definition)

Retreatment rate at 3 months: need for a second therapeutic procedure (repeat RIRS or extracorporeal shockwave lithotripsy, ESWL) due to clinically significant residual fragments

Secondary operative parameters include:

Total surgical time (ureteroscope introduction to final withdrawal, in minutes)

Active stone fragmentation time (chronometric, in minutes)

Laser activation time (from device log, in minutes)

Fluoroscopy time (from fluoroscopy equipment log, in minutes)

Laser energy type used (Holmium:YAG / Thulium / other)

Accessory instruments used (retrieval basket / stone cone / both / none)

Need for pre-stenting and procedure deferral due to failed sheath passage on first attempt

Safety outcomes include:

Immediate postoperative complications (≤30 days): classified by Clavien-Dindo scale (Grade 0-V), with specification of complication type (fever/sepsis, haematuria, ureteral injury, other)

Late postoperative complications (>30 days to 3 months): Clavien-Dindo classification

Hospital length of stay (days from admission to discharge)

Type of postoperative urinary drainage placed (double-J stent / percutaneous nephrostomy / both / none)

Complications will be recorded by an investigator with experience in Clavien-Dindo classification who is blinded to group assignment. All complications will be registered, differentiating immediate (≤30 days) from late (>30 days to 3 months post-intervention).

COVARIATES AND CONFOUNDERS RECORDED

The following baseline and stone-related variables will be recorded for descriptive analysis and multivariate adjustment:

Sociodemographic: Age (years), sex, BMI (kg/m²).

Stone characteristics (from pre-operative CT): Maximum stone diameter (cm), stone location (renal pelvis / upper calyx / middle calyx / lower calyx / multiple), number of stones (single / multiple ≥2), stone density (maximum HU), known stone composition from prior lithoanalysis (calcium oxalate monohydrate/dihydrate / calcium phosphate / uric acid / struvite / cystine / mixed).

Stone composition from current episode (post-hoc): Lithoanalysis of fragments recovered during the procedure, when available.

Clinical history: Date of current stone diagnosis, date of surgery, waiting list time (days), prior surgical treatments for the same stone (ESWL / previous RIRS / percutaneous nephrolithotomy / other), preoperative medical expulsive therapy with tamsulosin (yes/no), underlying stone-predisposing conditions (primary hyperparathyroidism / renal tubular acidosis / gout / inflammatory bowel disease / cystinuria / other), prior urinary diversion (yes/no), preoperative urine culture result (negative / positive - specifying microorganism / not performed).

SAMPLE SIZE CALCULATION

The sample size was calculated to detect differences in the primary outcome (SFR at 1 month) based on the following statistical assumptions:

Study design: Bilateral superiority trial, parallel groups

Significance level (α): 0.05 (bilateral)

Statistical power (1-β): 80%

Allocation ratio: 1:1

Expected SFR for Navigator® (weighted average): 73.4%

Expected SFR for ClearPetra® (weighted average): 91.0%

Expected difference: +17.6 percentage points

The expected SFR values were estimated from prior literature on vacuum-assisted UAS in flexible ureteroscopy, stratified by stone size: for stones <2 cm, 77% (Navigator®) vs. 95% (ClearPetra®); for stones ≥2 cm, 68% (Navigator®) vs. 85% (ClearPetra®), weighted by the expected proportion of each subgroup in the study population (60% and 40%, respectively).

Applying the formula for comparison of two independent proportions yields 70 patients per group. After accounting for an expected 10% loss to follow-up rate (patients who do not complete the 1-month CT scan), the adjusted sample size is 78 patients per group, for a total of 156 patients.

STATISTICAL ANALYSIS PLAN

The primary analysis will follow the intention-to-treat (ITT) principle, including all randomised patients in the group to which they were assigned regardless of the treatment actually received. A per-protocol (PP) analysis will additionally be performed, including only patients who completed the assigned treatment and the 1-month follow-up assessment according to protocol.

Statistical significance threshold: p <0.05 (bilateral) for all hypothesis tests. Statistical software: IBM SPSS Statistics version 29.0.

Descriptive analysis: Categorical variables expressed as absolute and relative frequencies; continuous variables as mean ± standard deviation or median (interquartile range) according to normality (Kolmogorov-Smirnov test).

Baseline comparability: Baseline characteristics will be compared between treatment groups to verify homogeneity achieved by randomisation.

Primary outcome analysis: Comparison of stone-free rates between groups by Pearson chi-squared test (or Fisher's exact test if any expected cell count <5). Effect size will be expressed as relative risk (RR) with 95% confidence interval, and absolute risk reduction (ARR) with number needed to treat (NNT) where applicable.

Secondary continuous outcomes: Student's t-test (normal distribution) or Mann-Whitney U test (non-normal distribution), with mean differences or median comparisons and 95% CI.

Secondary dichotomous outcomes: Chi-squared or Fisher's exact test, with RR or odds ratio (OR) and 95% CI.

Ordinal outcomes (Clavien-Dindo): Mann-Whitney U test for ordinal distribution comparison; additionally dichotomised as no significant complication vs. Clavien-Dindo ≥II for chi-squared analysis.

Pre-specified subgroup analyses: SFR will be compared between treatment arms within two pre-defined stone size subgroups: Subgroup 1 (stones 1-2 cm maximum diameter) and Subgroup 2 (stones ≥2 cm maximum diameter). An interaction term (sheath type × stone size) will be included in a logistic regression model to formally evaluate whether the effect of ClearPetra® differs significantly by stone size.

Multivariate analysis: Logistic regression analysis with SFR at 1 month as the dependent variable and sheath type as the primary independent variable, adjusting for potential confounders: stone size, stone density (HU), stone location (lower calyx vs. other), number of stones, prior surgical treatments, age, and BMI. Variables will be selected for the final model based on clinical relevance and p <0.20 in bivariate analysis. Collinearity will be assessed using the variance inflation factor (VIF), excluding variables with VIF >10. Results will be presented as adjusted odds ratios (aOR) with 95% CI. Goodness-of-fit will be evaluated by the Hosmer-Lemeshow test; discriminative ability by the area under the ROC curve.

Where appropriate, multivariate linear regression will be performed for secondary continuous outcomes (e.g., surgical time, stone volume reduction rate) adjusting for the same covariables.

Handling of missing data and losses to follow-up: The number and percentage of losses will be described per group. Baseline characteristics of patients lost to follow-up vs. completers will be compared to assess whether losses are random. In the ITT analysis, patients lost to follow-up will be classified as "not stone-free" (conservative worst-case scenario). No imputation of missing covariate data will be performed given an expected rate of <5%.

PREDEFINED SENSITIVITY ANALYSES

Stricter stone-free definition (0 mm, complete absence of any residual fragment)

Per-protocol analysis restricted to protocol-adherent patients

Subgroup analysis stratified by operating surgeon (to assess inter-surgeon consistency if relevant baseline differences are observed)

DATA COLLECTION SYSTEM

Data will be collected using a purpose-designed Case Report Form (CRF) structured into six sections: (1) baseline data form (pre-operative visit), (2) intraoperative registration form, (3) in-hospital follow-up form, (4) 1-month follow-up form, (5) 3-month follow-up form, and (6) lithoanalysis form (when available).

Data sources include: electronic health records, the Radiology Information System and PACS (for CT measurements and fluoroscopy times), intraoperative surgical records and anaesthesia sheets, and clinical follow-up appointments. Volumetric CT measurements will be performed using dedicated imaging workstation software with multiplanar reconstruction capabilities.

Each patient will be assigned a unique alphanumeric study code at the time of randomisation (format: NAVCP-001, NAVCP-002...). The identification sheet linking patient codes to personal data will be stored under lock and key in the principal investigator's office. The study database will contain only coded, non-identifiable data.

Data will be entered into a purpose-built electronic database compliant with the European General Data Protection Regulation (GDPR, EU Regulation 2016/679) and Spanish Law 3/2018 on Personal Data Protection. Data will be retained for 5 years after study completion, after which they will be securely destroyed.

STUDY TEAM

Principal Investigator (PI): Dr.ª Paula Rodríguez Marcos - Staff Urologist, HUVR; >200 RIRS procedures performed; dedicated to endourological stone management.

Co-Principal Investigator: Dr. Rafael Antonio Medina López - Head, Department of Urology and Clinical Management Unit of Urology-Nephrology, Hospital Universitario Virgen del Rocío. Coordinator of the Advanced Urology Surgery research group (IBiS). Extensive experience in directing clinical trials and publishing in high-impact indexed journals.

Collaborating Investigators:

Dr. Enrique Argüelles Salido - Coordinator, Lithiasis Unit, Hospital Universitario Virgen del Rocío. Over 15 years of experience in the management of urolithiasis, flexible ureteroscopy, and percutaneous nephrolithotomy.

Dr. Pedro Campoy Martínez - Staff Urologist, Lithiasis Unit, HUVR; >20 years of experience in percutaneous and endoscopic stone procedures.

Dr. Miguel Ángel Gómez Luque - Urologist and postMIR research fellow (FISEVI); training in clinical research methodology and statistical analysis; will serve as data manager and statistician.

The study is conducted within the institutional framework of Hospital Universitario Virgen del Rocío (third-level university hospital, regional referral centre for complex urological pathology), with support from the Instituto de Biomedicina de Sevilla (IBiS) and the Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI).

STUDY TIMELINE

The total estimated study duration is 30 months, structured in five sequential and partially overlapping phases:

Phase 1 - Preparation and start-up (Months 1-3): Ethics Committee submission and approval, protocol finalisation, CRF design, randomisation sequence generation, envelope preparation, team training, coordination with Radiology and Supply departments.

Phase 2 - Recruitment and interventions (Months 4-25): Consecutive enrolment of 156 patients at an estimated rate of 7 patients/month (range 6-8/month). Surgical procedures and 1-month follow-up for each patient.

Phase 3 - 3-month follow-up (Months 7-28, overlapping with recruitment): CT assessments at 3 months, retreatment recording, late complication documentation.

Phase 4 - Data analysis and results (Months 26-29): Database closure, blinded CT measurements, complete statistical analysis, results interpretation.

Phase 5 - Dissemination (Months 29-30+): Manuscript preparation, submission to an international peer-reviewed urology journal (open-access preferred), congress presentations, final Ethics Committee report.

Contingency provisions include: allowance for Ethics Committee revision requests (+1-2 months), and an extended recruitment period of up to +6 months if enrolment rates fall below 80% of target after 6 months (with potential expansion to a multicentre design if required).

LIMITATIONS AND MITIGATION STRATEGIES

The main study limitations are inherent to the nature of a surgical device trial:

Incomplete blinding: Surgeon and patient cannot be blinded to sheath type. Mitigated by assessor-blinding for the primary outcome, standardised surgical protocol, and selection of experienced surgeons with no learning curve for either device.

Performance bias: Surgeon awareness of device assignment may unconsciously influence technique. Mitigated by standardised protocol and experienced, homogeneous surgical team.

Inter-surgeon variability: 2-3 surgeons participating. Mitigated by standardised protocol; surgeon will be included as adjustment variable in multivariate analysis if relevant baseline differences are observed.

Stone-free threshold arbitrariness: ≤2 mm threshold, while widely accepted, is not universal. Addressed by pre-specified sensitivity analysis with 0 mm (complete clearance) threshold.

Follow-up duration: 3-month follow-up may not capture late complications such as ureteral strictures. Justified as the standard follow-up period for RIRS efficacy studies and the clinical decision point for retreatment; patients will continue routine service follow-up beyond the study period.

Loss to follow-up: Addressed by 10% oversizing of sample, flexible time windows (±7 days at 1 month, ±14 days at 3 months), and conservative ITT analysis classifying losses as treatment failures.

Key methodological strengths include: randomised design, assessor-blinding, objective CT-based primary outcome, prospectively calculated sample size, dual ITT and per-protocol analyses, experienced surgical team without learning curve, protocolised follow-up, and planned multivariate adjustment for confounders.

ETHICAL AND REGULATORY FRAMEWORK

The study will be conducted in accordance with the Declaration of Helsinki (Fortaleza 2013 revision), the Oviedo Convention, ICH Good Clinical Practice (GCP) guidelines, Royal Decree 1090/2015 on clinical trials (applied by analogy to medical device studies), Spanish Law 14/2007 on Biomedical Research, and GDPR (EU) 2016/679 and Spanish Law 3/2018 on Personal Data Protection.

Protocol, informed consent documents, and all study-related materials will be submitted to the Ethics Committee for Clinical Research with Medicines (CEIm) of Hospital Universitario Virgen del Rocío for evaluation and approval prior to initiating recruitment. No patient will be enrolled until formal Ethics Committee approval is obtained. Any substantial protocol modifications during the study will be submitted for Ethics Committee review and approval before implementation.

No economic compensation will be offered to participants. Patients will remain covered by public health insurance for all treatment and follow-up. Study participation does not impose significant additional burden, as both compared treatments are part of routine clinical practice and follow-up CT scans coincide with standard post-RIRS monitoring

Inclusion Criteria:

• Age ≥18 years
• Diagnosis of intrarenal lithiasis with maximum stone diameter of 1-3 cm on preoperative non-contrast abdomino-pelvic CT scan
• Candidate for treatment by flexible ureteroscopy (RIRS) as indicated by the treating urologist
• Attended at the Department of Urology, Hospital Universitario Virgen del Rocío (Seville, Spain)
• Willing and able to provide written informed consent
• Able to comply with the study follow-up schedule (CT scan at 1 and 3 months post-intervention)

Exclusion Criteria:

• Active urinary tract infection or urosepsis at the time of the planned intervention
• Known ureteral stricture precluding passage of a ureteral access sheath
• Pregnancy
• Prior urinary diversion incompatible with transurethral access (e.g., urinary conduit, neobladder)
• Bleeding disorder or anticoagulant/antiplatelet therapy that cannot be safely interrupted perioperatively
• Stone diameter <1 cm or >3 cm on preoperative CT
• Inability to provide informed consent (cognitive impairment, language barrier without interpreter availability)
• Simultaneous participation in another clinical trial that could interfere with the outcomes of this study

Individual participant data (IPD) that underlie the results reported in the primary publication will be shared, after de-identification (text, tables, figures, and appendices). This includes data for the primary outcome (stone-free rate at 1 month) and all pre-specified secondary outcomes. Data will be shared upon reasonable request to the principal investigator, subject to a data sharing agreement ensuring compliance with GDPR (EU Regulation 2016/679) and Spanish Law 3/2018 on Personal Data Protection.

IPD and supporting information will be available beginning 6 months after publication of the primary results article and will remain available for a minimum of 5 years following initial data availability. Requests submitted after this period will be considered on a case-by-case basis.

Access to IPD will be granted to researchers who provide a methodologically sound research proposal, approved by their institutional review board where applicable. Requests must be submitted to the principal investigator (Dr. Enrique Argüelles Salido, Hospital Universitario Virgen del Rocío, Seville, Spain) via institutional email. Data will be transferred via a secure, password-protected platform under a signed data sharing agreement. Data will not be used for commercial purposes.