Clinical efficacy and safety of the superpulse thulium fiber laser and holmium laser for ureteroscopic lithotripsy in the treatment of upper urinary tract calculi: a randomized, positive control, blinded, single-center clinical study {1}

Abstract

Background

Kidney stone disease is a common problem. The holmium: yttrium–aluminum–garnet (HO:YAG) laser is currently the gold standard laser for ureterorenoscopic (URS) lithotripsy. Recently, the superpulse thulium fiber laser (SP TFL) has shown potential as a substitute for the HO:YAG laser. We aim to compare and evaluate the clinical efficacy and safety of the HO:YAG laser and SP TFL in the treatment of upper urinary calculi in this trial.

Methods

In this randomized, positive control, blinded management, single-center clinical study, patients with upper urinary calculi will be randomized (1:1) to the experimental group (SP TFL group) or the control group (HO:YAG laser group). Patients in both groups will undergo URS lithotripsy under general anesthesia, and according to the results of randomization, the patients will be treated with an SP TFL (trial group) or a holmium laser (control group). The primary outcome is the stone-free rate at 30 ± 7 days after surgery. The secondary outcomes include the duration of surgery, the duration of laser use, the length of postoperative hospital stay, postoperative clinical indicators, total hospitalization costs, the second-stage stone clearance rate, perioperative complications, the average hemoglobin change, and the mean white blood cell count change.

Discussion

This study aims to evaluate and compare the clinical efficacy and safety of the SP TFL and HO:YAG for URS lithotripsy in the treatment of upper urinary calculi.

Trial registration {2a and 2b}

chictr.org.cn ChiCTR2300076893. Registered on October 24, 2023, with ChiCTR (https://www.chictr.org.cn/bin/project/edit?pid=206827).

Protocol version {3}

August 15, 2023 (V.20230815).

Administrative information

Title	1	Clinical efficacy and safety of superpulse thulium fiber laser ureteroscopic lithotripsy and holmium laser ureteroscopic lithotripsy in the treatment of upper urinary tract calculi: a randomized, positive control, blinded management, single center clinical study
Trial registration	2a	Trial registry name: ChiCTR. Number: ChiCTR2300076893. Date registered: October 24, 2023.
	2b	https://www.chictr.org.cn/bin/project/edit?pid=206827.
Protocol version	3	Version 1.0, August 15, 2023.
Funding	4	This work was supported by the grant (BJ-2023-179) from National High Level Hospital Clinical Research Funding.
Roles and responsibilities	5a	Cheng Pang, MD1*, Weiwei Fang, PhD2*, Fanguo Zhang, MD3, Ming Liu, MD1# 1 Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, P.R. China 2 Department of Blood Transfusion, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 3 Excellence Future International Consulting Co, Ltd, Beijing, 102218, China *These authors contributed equally to this work  CP, WF and ML were involved in the study conception and design. CP obtained funding. CP, WF and FZ implemented the research. FZ was the study statistician. CP and WF conducted the analysis. CP and ML were involved in interpreting the data. WF wrote the first draft. All authors read and approved the final manuscript.  #Corresponding author: Ming Liu, MD, Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 Dahua Road, Dongcheng District, Beijing 100730, China. liumingbjh@126.com
	5b	The trial sponsor is Beijing Hospital. The address is NO.1 Dahua Road, Dongcheng District, Beijing, China. The contact number is +86-010-85136272.
	5c	The sponsor is responsible for financial management, experimental progress tracking and original data review. The funder and the sponsor played no role in the study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.
	5d	The trial is a single site study. The trial steering committee consisted of four members, three senior urologists, and a statistician, who would oversee the trial. The committee is independent of the research team and there are no conflicts of interest. The trial was designed by two senior urologists. A urologist collected clinical data.

Introduction

Background and rationale {6a}

Kidney stone disease is a common problem that affects approximately 15% of the population [1, 2]. The prevalence of urolithiasis in the general population has increased worldwide in recent decades [3]. In the USA, for example, the prevalence of kidney stones has progressively increased from 3.2% in 1976–1980 to 5.2% in 1988–1994 and 8.8% in 2007–2010 [4,5,6]. Current estimates suggest that the prevalence of kidney stones is 5–10% in Europe, 4% in South America, and 1–19% in Asia [6,7,8]. The recurrence rate of urinary stones is high and is estimated to be approximately 50% at 10 years after surgery [9].

In recent decades, increasing intervention rates for urinary stones have been reported together with a worldwide increase in the prevalence of kidney stone disease [1, 10,11,12]. The HO:YAG laser is currently the gold standard laser for URS lithotripsy and has been used in endourology for over two decades [13]. Recently, another technology has been explored for URS lithotripsy via next-generation lasers: the superpulse thulium fiber laser (SP TFL).

Recently, an increasing number of studies have focused on the application of the SP TFL in the treatment of urinary calculi. A previous study showed that uric acid and calcium oxalate monohydrate stone vaporization rates for the SP TFL were 5–10 times higher on average than those for the HO:YAG laser at 70 mJ pulse energies [14]. In in vitro settings, the SP TFL has been shown to ablate stones with greater volumes with less retropulsion [15]. Furthermore, the SP TFL has been shown to produce significantly greater amounts of stone dust with the ability to use thinner laser fibers without significant heat production [15]. The retropulsion effect of the SP TFL (at 500 W) was 75%, 60%, and 29% of that of the HO:YAG laser for equal pulse energies of 1, 2, and 3 J, respectively [16].

A clinical study conducted in 2018 that included 56 patients who underwent URS lithotripsy via the SP TFL for 68 stones of the upper and lower urinary tracts revealed that the mean duration of stone disintegration was 19 min; at the 4–6-week follow-up after surgery, one patient was found to have a residual symptomatic ureteral stone, which required extracorporeal shortwave lithotripsy [17]. A study conducted by Enikeev et al. in 2020 revealed that both the ablation efficacy and speed were greater in the 200-Hz mode than in the 30-Hz mode (2.7 J/mm³ vs. 3.8 J/mm³ and 5.5 mm³/s vs. 8.0 mm³/s, respectively), and a higher frequency correlated with an increased ablation speed (r = − 0.21, p = 0.019) [18]. However, poor visibility was reported in 2 (5%) patients receiving a 200-Hz regimen [18]. A total of 92.5% of the patients (37 of 40 men) were stone-free at 3 months [18]. The same team published another report the same year. They analyzed a total of 149 ureteroscopy procedures performed with the SP TFL, and the results revealed that the laser was effective and safe for patients with all types of stones regardless of the laser fiber diameter, and the stone-free rate at 3 months was 90% [19]. Moreover, a study retrospectively analyzed 15 patients with a single radiopaque lower pole calculus and reported that the average lithotripsy duration was 12 min (3–30 min); the average “laser” duration was 1.3 min (0.4–2.5 min); the mean hospital stay was 1.1 ± 0.3 days; the complication rate evaluated via the Clavien–Dindo grading system did not exceed the GII (6.6%); and the stone-free rate 30 days after the operation was 86.6% [20]. The SP TFL is highly efficient in the treatment of both ureteral and renal stones even at very low energies. The reported advantages are as follows: an effective clearance rate of stones with diameters up to 3.2 cm; fragmenting at a setting of 0.6–0.8 J at 30 Hz (18–24 W) produced dust and disintegrated stones faster than dusting at a setting of 0.1–0.2 J at 200–240 Hz (20–48 W), even though the latter setting resulted in finer dust; and complete disintegration of 1-cm stones at a setting of 0.6 J at 30 Hz achieved in < 20 min [21]. Stone management with thulium lasers has been reported to be associated with less retropulsion than stone management with holmium lasers, and at 30 days of follow-up, no residual stones were observed in the SP TFL group [22].

On the basis of preliminary studies, the SP TFL surpasses the HO:YAG laser in many aspects: (1) the SP TFL has higher stone ablation rates and produces smaller stone fragments than the HO:YAG laser does when directly compared with similar laser settings (pulse energy, pulse rate, and average power) [13]; (2) the SP TFL is capable of disintegrating all prevailing urinary stone composition types into particles considerably smaller than 500 µm. These small particles are considered stone dust and have been observed to spontaneously evacuate upon irrigation in an experimental setup, thus validating the SP TFL as a promising new technology for stone disintegration techniques [12]. (3) The additional advantages of longer pulse durations, high frequencies, and low single pulse energies have been shown to deliver promising results, namely, highly efficient fine dusting in conjunction with low retropulsion [23, 24]. Obviously, the SP TFL is the most promising alternative to holmium lasers for lithotripsy owing to its use of a more suitable wavelength, smaller fibers, and potential for using a smaller, less expensive laser system [25].

Objectives {7}

The aim is to evaluate and compare the clinical efficacy and safety of the SP TFL and HO:YAG laser for URS lithotripsy in the treatment of upper urinary calculi by conducting a prospective randomized controlled trial and to provide a new basis for the clinical treatment of patients with upper urinary calculi.

Trial design {8}

This will be a blinded randomized controlled trial. The stratified block randomization method will be used. A statistician will use SAS 9.4 software to generate the subject randomization number. According to a 1:1 random grouping ratio, eligible patients will be divided into an experimental group (SP TFL group) and a control group (HO:YAG laser group).

The patients’ preoperative and postoperative clinical data will be recorded in detail. The stone clearance rate, total operation duration, duration of intraoperative laser use, length of postoperative hospital stay, and incidence of perioperative complications will be compared between the two groups. The specific research process is shown in Fig. 1. The schedule for the clinical study is presented in Table 1.

Fig. 1

Trial flow and study design

Table 1 The schedule for the clinical study

Methods: participants, interventions, and outcomes

Study setting {9}

Patients will be recruited from the Urology Department of Beijing Hospital, a comprehensive tertiary hospital in China. Follow-up will be conducted at the time of screening (− 28 days ~ − 1 day), at baseline (0 day), at 1 day + 1 day, and at 30 days ± 7 days. The procedures and all follow-up visits, including 4 visit points, will be performed at Beijing Hospital.

Eligibility criteria {10}

Inclusion criteria

• 1. Patients aged ≥ 18 years (either sex)

• 2. Patients with upper urinary calculi who met the surgical indications evaluated by color Doppler ultrasound or an abdominal CT scan

• 3. Patients without urinary tract infection or an infection that is controlled before surgery

• 4. Patients without a urinary tract deformity on the surgical side

• 5. Patients who can cooperate with treatment and follow-up

• 6. Patients who can sign an informed consent form

Exclusion criteria

• 1. Patients who do not meet the inclusion criteria

• 2. Patients who are enrolled in other clinical trials

• 3. Pregnant women

• 4. Patients with severe cardiovascular and cerebrovascular diseases or respiratory diseases

• 5. Patients with uncontrolled urinary tract infection before surgery

• 6. Patients with abnormal urinary anatomy

• 7. Patients with a history of mental disorders

• 8. Patients with poor compliance and the inability to complete the treatment and follow-up

Who will provide informed consent? {26a}

Informed consent or assent will be obtained from all potential trial participants or authorized surrogates.

Additional consent provisions for the collection and use of participant data and biological specimens {26b}

Additional consent provisions are not applicable. There are no other provisions except those described in this article.

Interventions

Explanation for the choice of comparators {6b}

Upper urinary calculi are defined as renal or ureteral calculi. Patients with either renal or ureteral calculi or both renal and ureteral calculi ≥ 5 mm in diameter will be enrolled in this study. A total of 120 patients with upper urinary calculi who meet the study criteria will be randomized (1:1) to either the experimental group (SP TFL group) or the control group (HO:YAG laser group).

Intervention description {11a}

After confirming that there are no surgical contraindications, the two groups of patients will undergo URS lithotripsy under general anesthesia, and according to the results of randomization, the patients will be treated with either the SP TFL (trial group) or HO:YAG laser (control group). The above operations will be performed by the same treatment group with more than 10 years of experience.

Endoscopic lithotripsy

All patients will undergo routine endoscopic lithotripsy (semirigid URS or flexible URS).

Semirigid URS

• 1. After anesthesia, the patient will be placed in the bladder lithotomy position. The semirigid ureteroscope will be placed into the bladder through the urethra and under the action of perfusion water pressure, and the bladder and bilateral ureteral orifice will be evaluated for any abnormalities.

• 2. The guidewire will be inserted into the affected ureter, the perfusion water pressure will be adjusted, and the semirigid ureteroscope will be slowly placed under direct vision to determine whether calculi and stenosis are present throughout the ureter.

• 3. After the calculi are found, the SP TFL (trial group) or HO:YAG (control group) fiber will be inserted, the calculi will be disintegrated to less than 2 mm, the fiber will be removed, some of the stone pieces will be removed from the body via a stone removal basket, and an indwelling double J tube will be placed.

Flexible URS

• 1. In the same way as for the conventional semirigid URS, the ureteroscope was inserted into the ureter to observe whether there were calculi and stenosis throughout the ureter.

• 2. The ureteroscope was withdrawn, the ureteral access sheath (Cook Medical LLC, Bloomington, USA) was inserted under the guidance of a guidewire, and a disposable flexible ureteroscope (Zhuhai Pusheng Medical Technology Co. LTD., Guangdong Province, China) was inserted through the ureteral access sheath.

• 3. After a comprehensive examination of the renal pelvis and calices of the affected kidney to confirm the location and size of the calculi, SP TFL (trial group) or HO:YAG (control group) fibers were inserted, and the calculi were crushed to less than 2 mm.

• 4. For calculi located in the lower calyceal region, stone removal baskets were used to transfer the calculi to the middle or upper calyceal region during surgery.

• 5. For upper ureteral calculi, SP TFL (trial group) or HO:YAG (control group) was used to quickly crush the stone and push it to the renal pelvis, after which the stone was crushed in the renal pelvis.

• 6. The fiber energy was set at 0.1–0.3 J × 100–300 Hz for the thulium laser and 0.2–0.5 J × 15–80 Hz for the holmium laser.

• 7. At the end of URS lithotripsy, stone fragments were grabbed with a stone removal basket.

• 8. An indwelling double J tube guided by a guidewire was used.

Electrocardiography (ECG) was monitored postoperatively, and routine blood tests, C-reactive protein (CRP) tests, and blood biochemistry were performed on postoperative days 1 + 1, and blood culture was performed when necessary to determine whether there was infection.

Criteria for discontinuing or modifying allocated interventions {11b}

• 1. Withdrawal criteria

  • (1) Other circumstances considered by the investigator to require withdraw from the study, such as loss of the ability to freely express one’s wishes due to imprisonment or isolation

  • (2) Patients withdrawing from the study

  • (3) Patients unable to accept long-term follow-up treatment

  • (4) Patients who die from other causes

• 2. Combined medication

Medications that promote stone passage should not be used while patients are receiving treatment.

Strategies to improve adherence to interventions {11c}

We will call the subjects back to the hospital regularly for follow-up, and laboratory tests will be performed.

Relevant concomitant care permitted or prohibited during the trial {11d}

This trial will not impose special requirements for care and interventions.

Provisions for posttrial care {30}

When the trial is complete, the subjects will receive standardized treatment on the basis of the guidelines.

Outcomes {12}

Primary outcome

The stone-free rate at 30 ± 7 days after surgery (number of patients who are completely stone-free/total number of patients treated * 100%).

Secondary outcomes

• 1. Operation duration: the mean time from the placement of the ureteroscope to the end of the operation.

• 2. The mean duration of laser use.

• 3. The mean length of postoperative hospital stay: the number of days from the first postoperative day to discharge. The length of stay will accumulate if the treatment is staged.

• 4. Postoperative examination indicators: the mean changes in the peripheral blood hemoglobin level and white blood cell count.

• 5. Total hospitalization costs: the sum of the costs of outpatient reexamination, adjuvant therapy (ESWL), cystoscopy, ureteral stent removal, and emergency treatment during hospitalization and after the operation.

• 6. The stone clearance rate of the second stage.

• 7. Perioperative complication rate: the percentage of patients with complications. According to the modified Clavien–Dindo score, minor complications are defined as complications that are self-limiting, complications that require only minor support or Clavien–Dindo grade I complications, such as self-limited hematuria, urinary tract infection requiring antibiotic treatment, or pain relief requiring analgesic medication; major complications are defined as the need for further surgical management or close postoperative monitoring or complications with a Clavien–Dindo grade of II or higher, such as ureteral perforation, subcapsular or perirenal hematoma formation, severe intraoperative or postoperative blood loss requiring blood transfusion, or renal artery embolization.

• 8. The mean hemoglobin change: the difference in the hemoglobin level between preoperative and postoperative day 1 + 1 day.

• 9. The mean white blood cell count change: the difference in the white blood cell count between preoperative and postoperative day 1 + 1 day.

Participant timeline {13}

See Table 1.

Sample size {14}

Taking the stone-free rate of CT reexamination at 30 days after the operation as the primary outcome, the sample size needed for the unilateral difference test of the clinical efficacy of the SP TFL and the HO:YAG laser for URS lithotripsy in the treatment of upper urinary tract stones was calculated. According to the literature [26], the stone-free rate of the ultra-pulsed thulium laser for URS lithotripsy was estimated to be 90.0% when CT was reviewed 30 days after surgery, and the stone-free rate of the HO:YAG laser for traditional URS lithotripsy was 67%. A one-sided α = 0.025 and β = 0.2 will be set, and the experimental group and the control group will be randomly grouped at a 1:1 ratio. At least 47 patients in each group will be analyzed via PASS 15.0 software. After accounting for a dropout rate below 20% and block factors, we increased the sample size from the original calculation to 60 patients per group. The total sample size for the trial will be 120, with 60 patients in each group.

Recruitment {15}

Study subjects will be recruited from outpatient and inpatient departments by advertising on the social media platforms of the hospital departments and hanging posters in public areas of the hospital. Interested subjects will be welcome to contact the investigator by phone or in person for initial screening. Potential participants will be enrolled, and an appointment with the designated physician will be made to review the inclusion and exclusion criteria. We will invite eligible patients to participate in this study and provide details of the trial protocol.

Assignment of interventions: allocation

Sequence generation {16a}

A statistician will use SAS 9.4 software to generate the subject randomization number.

Concealment mechanism {16b}

A research assistant who does not take part in enrolling patients will generate the allocation sequence, which will involve sequentially numbered, opaque, sealed envelopes, and can be reproduced if needed.

Implementation {16c}

A research assistant will generate the allocation sequence, radiologists or urologists will evaluate and enroll participants, and the urologists with more than 10 years of experience will perform the surgical interventions.

Assignment of interventions: blinding

Who will be blinded {17a}

A total of 120 eligible subjects will be randomly assigned to two parallel groups. Stratified block randomization will be performed with the following two randomization stratification factors: stone size (≤ 2 cm or > 2 cm) and the maximum CT value of the stone (≤ 1000 HU or > 1000 HU). The patients will be randomly divided into an experimental group (SP TFL group) and a control group (HO:YAG laser group) at a 1:1 ratio. Special personnel will be responsible for case allocation. Clinical trial observation tables for independent and complete prospective randomized controlled studies will be established. Randomization will be completed before surgery, and participants and surgeons will be informed of the results of randomization. All operations will be performed by the same treatment group with more than 10 years of experience to eliminate relevant technical differences.

A complete double-blind design could not be achieved for this study. To reduce evaluation bias, the primary outcome, the stone-free rate at CT review 30 ± 7 days after surgery, will be reviewed by an independent reviewer via the following procedure:

• 1. The imaging evaluation team for the CT-based stone-free rate will be composed of three independent radiologists or urologists with at least 3 years of experience. The doctors involved in the evaluation of the primary end point will not be involved in the randomization, surgical procedures, or patient follow-up during the study.

• 2. CT results, which include patients’ personal information, will need to be desensitized. CT data will be independently evaluated by two assessors on the evaluation team, and when the results are consistent, the results will be recorded in the medical records of the participants. When the results are inconsistent, a third evaluator will act as the “referee” and make the final judgment.

• 3. Two independent readers will read the films immediately or retrospectively.

Procedure for unblinding if needed {17b}

If an emergency requiring knowledge of surgical allocation occurs, we will provide a separate surgical allocation for each patient. The password will be provided in a site-sealed envelope that is stored in a locked and secure area and accessible only to personnel authorized by the investigator. This procedure will allow individual subjects to be unblinded without revealing the code of the entire study. Investigators can determine which procedure has been performed by opening sealed envelopes with the corresponding randomization number. The investigator must explain why the code on the envelope was broken and sign and date the envelope. At the end of the study, all sealed and unsealed envelopes will be reported.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Case report forms (CRFs) will be used for the assessment of data, collection of outcome data, and collection of baseline data. In addition, the clinical trial database will be constructed by designated data managers who are responsible for the regular management and maintenance of the database.

Plans to promote participant retention and complete follow-up {18b}

• 1. All patients will undergo follow-up examinations on postoperative days 1 + 1 day and 30 ± 7 days to assess the stone-free rates.

• 2. The pain visual analog score (PVAS) (range: 1–10 points) will be measured on postoperative day 1 + 1 day to assess the severity of each patient’s pain.

• 3. The patients will come to the hospital for CT or KUB reexamination 30 ± 7 days after the operation to determine the postoperative stone clearance rate. Patients with no residual stones will be evaluated via the PVAS score to assess pain severity. Cystoscopy will be performed to remove the ureteral stent in the outpatient operating room. Patients with residual stones will receive follow-up diagnosis and treatment plans according to their condition.

Data management {19}

Baseline data collection (perioperative preparation)

• 1. Medical history: duration of present illness, previous medical conditions, smoking and drinking history, allergy history, bleeding-related disease history, surgery history, and family history.

• 2. Physical examination: general physical examination.

• 3. Laboratory tests: routine blood, blood biochemistry, coagulation function, and urine routine tests.

• 4. Imaging examination: chest X-ray (or chest CT scan), abdominal and pelvic CT scan, and electrocardiogram.

• 5. Quality of life assessment: PVAS score before the operation, 1 + 1 day after the operation, and 30 ± 7 days after the operation (PVAS score range: 1–10 points).

• 6. All patients will be treated with prophylactic broad-spectrum antibiotics 30 min before surgery.

• 7. For patients with urinary tract infection combined with obstruction, a ureteral stent can be placed first if necessary, and URS lithotripsy can be performed after the infection is controlled.

Data management

The process of data collection, transmission, and use in this study will strictly follow the Measures for the Management of Population Health Information (Trial) (National Health and Family Planning Commission, 2014), the Service Guidelines for the Collection, Sale, Export and Exit Approval of Human Genetic Resources (Ministry of Science and Technology, 2015), the Regulations of the People’s Republic of China on the Management of Human Genetic Resources (State Council, 2019), and other relevant regulations to strictly control data quality and data security.

• 1. Data validity management

  • (1) Variables will be uniformly formatted, and the option data dictionary and variable value range will be standardized via MedDRA 25.0.

  • (2) The CRF of each subject will be verified by monitoring for at least 2 rounds.

  • (3) A data processing plan will be formulated, and the personal private information of the subjects will not be exported or processed. Data export and preanalysis verification will be carried out within 1 month after enrollment.

• 2. Data quality

  • (1) In the process of data collection, the roles will be divided into investigators and monitors. The former will be responsible for data entry, and the latter will be responsible for data quality review. Investigators and monitors will not be authorized to disclose subjects’ personal privacy information (mobile phone number, address, etc.), and relevant personnel will sign a data confidentiality agreement.

  • (2) All modification records of the data will be checked and signed by relevant investigators and monitoring personnel.

  • (3) Electronic data will be backed up offline after monthly verification.

  • (4) A data verification mechanism will be developed.

  • (5) All relevant patient clinical data will be traceable in the clinical data system of our hospital.

  • (6) After the end of the study, the data will be backed up with multimedia to ensure availability for no less than 10 years. Data summary and team summary meetings will be conducted every quarter to ensure that the data are true and valid.

Confidentiality {27}

The results of this study may be published in a medical journal. Subject information will be represented by unique numbers, and coded information will be stored in the Urology Department of Beijing Hospital. Subject information will be kept confidential as required by law. However, to ensure that the study complies with applicable laws and regulations, subjects’ records may be reviewed.

Plans for the collection, laboratory evaluation, and storage of biological samples for genetic or molecular analysis in this trial/future use {33}

The clinical data of the patients, including age, sex, body mass index (BMI), stone shape, stone location, longest diameter of stones, average CT value of stones, degree of preoperative hydronephrosis, blood test indicators, total operation duration, intraoperative laser use duration, postoperative electrocardiogram monitoring indicators, postoperative hospital stay, and hospitalization expenses, will be collected. Missing data will be imputed via multiple imputation. All patients will come to the hospital 30 ± 7 days after surgery to determine the stone clearance rate. According to the results of the postoperative plain CT scan, a maximum diameter of residual stones < 4 mm is defined as complete stone clearance.

The stone-free rate will be calculated as follows: the stone-free rate = the number of patients who are completely stone-free/the total number of surgical patients * 100%.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

SPSS 26.0 statistical software will be used to analyze the data. The count data will be expressed as numbers or percentages (%), and comparisons between groups will be performed via the chi2 test or Fisher’s exact test. The normally distributed measurement data will be represented as $\overline{\text{x} }$ ± s, and the comparisons between groups will be performed by independent sample t-tests. The measurement data that are not normally distributed will be described by the mean (P25, P75), and the Wilcoxon rank sum test will be used for comparisons between groups. p < 0.05 will be considered to indicate statistical significance.

Interim analyses {21b}

Interim analysis will not be performed in this study.

Methods for additional analyses (e.g., subgroup analyses) {20b}

Additional analyses will not be performed. No subgroups will be set, and subgroup analyses will not performed in this study.

Methods in the analysis to handle protocol nonadherence and any statistical methods to handle missing data {20c}

Multiple imputation will be used to manage missing values.

Plans to give access to the full protocol, participant-level data, and statistical code {31c}

The data will be available upon reasonable request. For inquiries about data sharing, please send a request to liumingbjh@126.com.

Oversight and monitoring composition of the coordinating center and trial steering committee {5d}

The trial steering committee consists of four members, three senior urologists and a statistician who will oversee the trial. The committee is independent of the research team, and there are no conflicts of interest. The trial was designed by two senior urologists. A urologist will collect the clinical data.

Composition of the data monitoring committee, its role, and reporting structure {21a}

The data monitoring committee will provide regular oversight, hold monthly meetings, and organize site visits every 2 months to ensure smooth and ethical conduct of the trial. In addition, supervisors will ensure the authenticity and completeness of the data. During the visit, a committee member will interview investigators and review original study documents. Any noncompliance with the protocol will be fully documented via a violation report form.

Adverse event reporting and harms {22}

Adverse events (AEs) refer to all adverse medical events that occur after a subject has received the study URS lithotripsy treatment; these events can manifest as symptoms and signs, diseases, or laboratory abnormalities but may not be causally related to the investigational drug.

Serious adverse events (SAEs) or reactions/experiences refer to medical events that occur during the clinical trial, such as hospitalization, prolonged hospitalization, disability, affected work ability, life-threatening events or death, or congenital malformation. AEs and laboratory tests will be graded according to the NCI-CTCAE, version 5.0. All AEs occurring within 30 days after the last procedure will be recorded. AEs are listed and summarized descriptively. Serious adverse events that persist after treatment, recovery to baseline status, steady state, or loss to follow-up will be recorded.

Common adverse reactions of ureteroscopic lithotripsy: The overall complication rate of ureteroscopic lithotripsy is only 3.5%, including ureteral perforation (0–4%), ureteral stricture (3–6%), submucosal stones and stone loss (2%), and ureteral avulsion (0.06–0.5%). Ureteral injury, hematuria, and infection are common complications, but most cases are mild and do not require special treatment.

All treatment-related AEs will be managed according to clinical practice.

Conditions that are present before the index treatment (e.g., elevated laboratory values) will not be reported as AEs. If the severity of an AE increases, the investigator must reassess the event to determine whether it must be reported.

Frequency and plans for auditing trial conduct {23}

We will audit the trial conduct every 6 months.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

The committee will identify problems in the trial and recommend changes to the trial protocol. If a decision to modify the protocol is needed, a written request will be submitted to the Institutional Medical Ethics Committee, and after approval, the investigator will be notified in writing. The protocol will be updated in the system immediately.

Dissemination plans {31a}

Any data undermining blinding will not be released until the results are published. The main findings will be published in the article.

Discussion

Currently, the HO:YAG laser is the gold standard for stone management. However, several limitations still exist, which lead to prolonged operation durations: (1) Worsening of the endoscope view during laser operation due to the so-called snowstorm effect. (2) A lower energy could be passed through the smallest fiber, which results in a prolonged operation time and limited efficacy. (3) Nevertheless, retropulsion can sometimes be clinically significant [22]. The SP TFL promotes the development of novel miniature fiber-optic delivery systems, including tapered, ball tip, hollow steel tip fibers, and muzzle brake fiber-optic tips, which can reduce both fiber burnback or degradation and stone retropulsion without sacrificing laser ablation rates [25]. However, the research and clinical application of the thulium laser in the treatment of urinary calculi in China are still in the exploratory stage. Therefore, this clinical trial aims to evaluate and compare the clinical efficacy and safety of the SP TFL and traditional HO:YAG laser for URS lithotripsy in the treatment of upper urinary calculi. However, the SP TFL also has some shortcomings, and few clinical studies exist at present. Theoretically, the power of the SP TFL can reach more than 2000 Hz; however, an SP TFL power > 300 Hz will cause great thermal damage to the tissue in the actual use process [27,28,29]. The SP TFL is highly efficient for fine dusting, but it is difficult to collect large stones for stone analysis. In addition, research on the cost of SP TFL procedures is still lacking. More clinical studies are needed to better understand the indications for this novel technology and clarify its position in the urologic endoscopy armamentarium.

Nevertheless, this trial has several limitations. First, the generalizability of the results of the trial to the sample population and the research centers involved is limited. For the successful completion of this clinical trial, local residents in Beijing will be selected to ensure their participation throughout the treatment process. Second, because this study is a single-center trial, the generalizability of the results to other medical facilities is unknown. At the end of this trial, we hope that the results will provide more reliable evidence for the clinical treatment of patients with upper urinary calculi.

Trial status

The revised version of this protocol published on April 23, 2023, was approved by the Institutional Medical Ethics Committee of Beijing Hospital. Recruitment began on July 1, 2023; the approximate end of recruitment will be in August 2024, and this study will be completed on December 31, 2024.

Name and contact information for the trial sponsor {5b}

Trial sponsor: Beijing Hospital.

Address: No. 1 Dahua Road, Dongcheng District, Beijing 100,730, China.

Role of sponsor {5c}

The sponsor is responsible for financial management, experimental progress tracking, and original data review.