Low Energy HoLEP on IPSS
Low Energy HoLEP on IPSS
The purpose of this study is to prove that low-energy (30W) Holmium laser prostatectomy
 (Holeb) is not inferior to high-energy (100W) Holmium laser prostatectomy (safety and
 effectiveness)
1. Overview of the study Research design: prospective, single-arm blind randomized control
 study, non-inferiority study Study Period: 12 months since IRB approval date Subject:
 Patients with benign prostatic hyperplasia Number of study subjects: 90 Vulnerable
 Subjects: None

 2. Background and purpose of the study

 1) Research background

 1. Overview and main symptoms of prostatic hyperplasia (BPH)

 -The prostate is a male reproductive organ located in the lower bladder. Benign
 prostatic hyperplasia (BPH) causes lower urinary tract symptoms (LUTS) due to bladder
 outlet obstruction.

 -  The prevalence of prostatic hyperplasia is known to reach 37% in the 50s, 49% in
 the 60s, and 70% in the 70s; a disease with a very high incidence in long-aged men.

 -  BPH is a disease directly related to the quality of life that interferes with the
 patient's social life, sexual life, and daily life. If it persists for a long time,
 it may cause bladder stones, hematuria, and even renal dysfunction, so timely
 treatment is absolutely necessary.

 2. Surgical Treatment of BPH

 -Surgical treatment is recommended for an enlarged prostate that is not treated with
 drugs, and transurethral surgery using an endoscope is recommended for standard surgery
 for an enlarged prostate.

 -  Transurethral surgery for BPH varies from traditional transurethral resection of
 the prostate (TURP) to holmium laser enucleation of the prostate (HoLEP).

 -  HoLEP has a sharp increase in the number of surgeries worldwide due to its low
 recurrence rate, high efficiency, and high patient satisfaction;

 -  Since its first introduction in 2008 in Korea, the number and rate of surgeries
 have been steadily increasing. The total number of surgery for BPH is equivalent to
 about 10,000 cases per year. TUR-P and KTP laser surgery are on a decreasing trend,
 while HoLEP is on an increasing trend.

 3. The importance of HoLEP

 -HoLEP is a surgery to completely remove prostate tumors using a Holmium-YAG Laser of
 2100nm wavelength.

 -The tissue penetration depth of the Holmium laser is less than 0.44mm, enabling sharp
 incisions, and has the advantage of less bleeding than traditional transurethral
 prostatectomy.

 -The surgery principle of HoLEP is fundamentally different from TUR-P and KTP laser
 prostate vaporization. TUR-P and KTP laser prostatectomy aim to remove part of the
 prostate tumor, whereas HoLEP performs complete removal of the prostate tumor according
 to the anatomical structure.

 -HoLEP consists of two steps, and the first step consists of an enucleation step in
 which the prostate tumor is completely removed and placed in the bladder, and a
 morcellation step in which the enucleated adenoma tissue is morcellated and removed.

 -  HoLEP is relatively safe compared to other transurethral surgery and can completely
 remove prostate adenoma, so it has a low recurrence rate and the patient's
 satisfaction with surgery is over 90%, making it the next-generation standard
 treatment for BPH.

 4. Low energy HoLEP related research and clinical status -HoLEP is mainly applied to
 treatment with 80-100 Watt high energy equipment. High-energy HoLEP has the advantage of
 removing prostate tumors in a short time, but there are problems of frequent laser fiber
 damage, device shutdown problems, and possible bladder damage due to scattered lasers.

 -  In 2008, Rassweiller et al. proposed the possibility of clinical application of low
 energy HoLEP by applying a 40 Watt Holmium laser. Since then, prospective studies
 have been published sporadically. In 2018, a prospective randomized study that
 compared and analyzed the prostate removal efficiency of 50 Watt laser and 100 Watt
 laser in a total of 121 patients was the latest and largest study and confirmed
 that low-energy prostatectomy is not inferior to the high-energy procedure. And
 proved its clinical safety.

 -  In theory, low-energy HoLEP reduces dysuria immediately after surgery and storage
 symptoms after surgery. It is estimated to be advantageous in preserving erectile
 function.

 -  The research team is the first in the world to compare the safety and usefulness of
 30 Watt HoLEP with 100 Watt HoLEP through prospective, non-inferiority studies.

 2) Research goal The final purpose of the study: To prove that the low-energy
 (30Watt) HoLEP is not inferior to the high-energy (100Watt) HoLEP in short-term and
 mid-term surgical results (safety and effectiveness).

 Detailed research objectives:

 1. Compare short-term (2 weeks-1 months) surgical outcomes/surgical complications of low
 energy HoLEP with high energy HoLEP.

 2. Compare the mid-term (3, 6 months) surgical outcomes/surgical complications of
 low-energy HoLEP with high-energy HoLEP.

 3) Selection criteria, exclusion criteria, the target number of subjects and basis for
 calculation

 -  Selection criteria Men over 50 Patients receiving HoLEP due to an enlarged prostate
 Patients who fully understood and agreed to the study

 -  Exclusion criteria Patients with neuropathy that may adversely affect the urination
 function (Parkinson's disease, dementia, etc.) Patients with acute urinary retention
 within the last month Patients with symptomatic urinary tract infection In case there
 are other factors that can significantly affect treatment results at the discretion of
 the researcher

 (2) Number of research subjects About 90 patients

 -  The basis for calculating the number of subjects This study aims to prospectively enroll
 and randomize prostatectomy patients, and then compare the results of the treatment at 6
 months after the maximum operation to confirm non-inferiority.

 The current standard is a method using a high-energy holmium laser, and the treatment results
 for 6 months after surgery have been published through many studies. The research team wants
 to confirm the surgical outcome as a decrease in the International Prostate Symptom Score
 (IPSS). After 6 months of predicted high-energy HoLEP, IPSS in other literature (5.1 ± 5.0),
 6 months after the expected of low-energy HoLEP. IPSS is estimated from the most recently
 published academic paper (5.0 ± 5.0).

 Alpha (0.15) and Beta (0.8) were calculated, and the non-inferior margin was set to 3. The
 estimated number of subjects is calculated by considering the 20% drop-out rate. Statistics
 for calculating the number of subjects are calculated using PASS 2019.

 Considering drop-out 20%, it is necessary to recruit 25-114 patients (total 50-114) per group
 to conduct the study.

 This organization is an organization that implements about 20-30 HoLEP cases per month, and a
 follow-up period of up to 6 months is required to announce short-term and mid-term results.
 Therefore, the actual patient enroll period is estimated to be up to 6 months. It is expected
 that 120-180 patients can undergo surgery during the recruitment period of up to 6 months,
 and assuming that only 60% of patients will participate in the study based on the median of
 about 150, a total of 90 patients, about 45 for each group. It is judged realistic to conduct
 a study with 3 patients.

 4. Research method

 1. Specific research method Since the researchers have already published dozens of studies
 related to HoLEP surgery, we are securing a systematic preoperative
 examination/postoperative follow-up process. The preoperative examination/postoperative
 follow-up protocol of high energy HoLEP surgery, which was previously performed, will be
 used as it is, but the study will be conducted by adding only the preoperative
 randomization process.

 -Pre-screening: After making operation in the outpatient clinic, before hospitalization,
 it is checked whether it is subject to enroll according to the patient record.

 -Random allocation: Using R package (RandomizeR), low energy HoLEP, and high energy
 HoLEP is randomly assigned.

 -Pre-Op work-up & Operation: This item is irrelevant to Randomization and is a situation
 where you do not know who will undergo surgery, so it is considered a normal treatment
 process and proceeds according to the existing process.

 -  Monitoring: It is planned to perform research ethics, safety, and monitoring work
 independently from the researcher by requesting the Medical Device Innovation
 Center.

 -  Clinical trial insurance: In case of adverse side effects to patients, the company
 plans to subscribe to clinical trial liability insurance through the Medical Device
 Innovation Center to notify the patient of the procedures and details of the
 clinical trial damage relief.

 -  Compensation: There is no monetary incentive for research participants, and the
 research team will pay 30,000 won of transportation and inspection costs (160,000
 won) per visit during the participation period of visit #1-#3.

 2. Test drug administration/dosage, administration/use method, combination therapy, reasons
 for selection when using a reference drug None

 3. Observation items, clinical test items and observation test methods Primary endpoint:
 3-6 month questionnaire (International Prostate Symptom Score, IPSS) total score

 Secondary endpoint:

 1) Surgery day: surgery time, total energy, resected prostate volume, immediate complication

 1) 2 weeks after surgery: questionnaire (IPSS-subscore, IPSS-QoL, OABSS total score), Qmax,
 2) post voided residual urine volume, Clavian-Dindo complication classification 3) 3, 6
 months after surgery: questionnaire (IPSS-total, IPSS subscore, IPSS-QoL, OABSS total score),
 Qmax, post voided residual urine volume, Clavian-Dindo complication classification, urine
 test (urinalysis, urine microscopy), serum PSA level

 4) Effect evaluation criteria, evaluation method Efficacy

 1. Statistical analysis of low-power HoLEP is not inferior in short-term (2wk/1month) and
 mid-term (3-6 months) IPSS.

 2. Uroflowmetry (UFM) and non-inferiority of post voided residual (PVR) were verified in
 urinalysis.

 3. 3 months/6 months U/A, micro, 6 months PSA

 4. Non-inferiority was verified in terms of improving the patient's QoL.

 5. To verify the non-inferiority of the storage symptom subscore after the patient's
 surgery.

 Safety:

 1. The safety of HoLEP has been revealed to some extent through overseas research results,
 so animal testing is not required. For the safety, all safety issues that occurred using
 the Clavian-Dindo grade, which are commonly used clinically in human studies, were
 recorded and compared and analyzed.

 2. If adverse events that occurred immediately after surgery and during up to 3 visits were
 recorded and there was a statistically significant difference in complications of Grade
 III-IV, it was judged that there was a safety problem.

 4) The difference between existing treatment and research Existing studies comparing low
 energy HoLEP surgery and high energy HoLEP are mostly retrospective studies, and two
 prospective studies have been performed.

 One of the two prospective studies involved 54 patients and had no active control group.

 The most recent study was RCT with 121 subjects, but it was a study comparing 50W laser and
 100W laser.

 This study is the first in the world to compare 30W laser and 100W laser, and it is a
 prospective, RCT that recruits 90 patients, and it is judged that the results of the study
 can provide important medical evidence for the safety and effectiveness of low-energy HoLEP
 surgery.
-  Selection criteria Men over 50 Patients receiving HoLEP due to an enlarged prostate
 Patients who fully understood and agreed to the study

 -  Exclusion criteria Patients with neuropathy that may adversely affect the urination
 function (Parkinson's disease, dementia, etc.) Patients with acute urinary lung
 disease within the last month Patients with symptomatic urinary tract infection In
 case there are other factors that can significantly affect treatment results at the
 discretion of the researcher