COMPARISON OF THE EFFECTS OF MIRABEGRON AND TAMSULOSIN

COMPARISON OF THE EFFECTS OF MIRABEGRON AND TAMSULOSIN ON THE DEGREE OF BLADDER MUCOSA INFLAMMATION IN PATIENTS WITH URETERAL STENTS

Double J stent (ureteral stent) was introduced in 1978 by Finney et.al., and became the most common installation procedure performed in urology for the treatment of urinary tract stones, overcoming obstruction due to benign or malignant tumors, management of ureteral leaks, and help identify the ureters during surgery. Ureteral stents can cause discomfort to patients, generally due to irritation of the bladder mucosa, especially in the trigone area, smooth muscle spasm, and reflux of urine into the ureter.

Complaints often appear in patients, especially lower urinary tract symptoms (LUTS), pain in the waist when urinating due to reflux of urine, sexual dysfunction, and hematuria. LUTS complaints in the form of frequency and urgency are caused by mechanical stimulation from stent rolls so that the bladder becomes overactive, and nocturia appears due to mechanical stimulation related to activity and awareness of stimuli during the day. Painful urination, especially at the end due to irritation of the bladder trigone, hematuria arising from aerobic torso movement, sexual dysfunction (especially erectile and ejaculatory dysfunction) arising from pain related to ureteral stents.

Complaints experienced after ureteral stent placement are grouped as stent-related symptoms (SRS), in which approximately 80% of patients experience several side effects, particularly lower urinary tract complaints, hematuria, pain, and decreased quality of life. The most effective approach in managing these side effects is to prevent the need for ureteral stent placement, although the majority of patients who undergo ureterorenoscopy and stone lithotripsy continue with ureteral stent placement to maintain patency of the ureteral lumen. When in contact with urine, the ureteral stent will be exposed to calcium phosphate and calcium oxalate which will become a crust that damages the urothelium, causes pain, and triggers infection.

Currently, to assess complaints after ureteral stent placement, the Ureteral Stent Symptom Questionnaire (USSQ) instrument consists of 6 topics: urinary complaints, pain, general health, work, sexual problems, and other things.

Interleukin-6 (IL-6) is an important inflammatory cytokine when irritation occurs after ureteral stent placement which is found more in urine than serum in the first 24 hours. Anti-inflammatory mediators also have a role in determining the course of the inflammatory process. Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that plays a central role in limiting the host's immune response to pathogens, thereby preventing host damage and maintaining normal tissue homeostasis. The profile of these biomarkers has the potential to determine the correct prognosis and therapy.

The first response to injury from a ureteral stent is acute inflammation characterized by vasodilatation and increased vascular permeability, leukocyte migration, and activation of biochemical cascades that release mediators, causing symptoms of bladder mucosal irritation. A mild fever may result from the systemic release of inflammatory mediators.

Prolonged ureteral stent placement can cause non-malignant bladder transitional mucosal tissue changes such as inflammation (89%), squamous metaplasia, cystitis grandularis, cystitis follicular, interstitial metaplasia, and dysplasia.

Mirabegron is a β3 adrenergic receptor agonist that has a dual antioxidant effect that plays a key role in the first step of the antimicrobial response, and early resolution of inflammation so that post-stent complaints similar to OAB complaints can be resolved. Other complaints include bladder irritation, and pain after ureteral stent placement, nocturia, dysuria, and voiding disorders can be significantly reduced.

Apart from Mirabegron, a drug that has been used to treat SRS is tamsulosin (a selective α1A- and α1D-adrenoceptor antagonist) which has a relaxing effect on the smooth muscle in the prostate, bladder neck, and distal ureter thereby reducing the inflammatory reaction and improving oxidative stress by reducing the formation of ROS. and preventing p83 activation, expression of IL-6, TNF-α, and IL-8 at the protein level.

Tamsulosin is commonly used for the treatment of benign prostatic enlargement, but there have been some reports of its use in the treatment of distal ureteral stones. Navanimitkul et al showed that tamsulosin 0.4 mg could improve obstructive and irritative symptoms after ureteral stent placement and improve quality of life.

Study Overview

• Status: Completed
• Conditions: Kidney Stones; Ureteral Stone; Ureteral Stenosis
• Intervention / Treatment: Drug: Mirabegron 50 MG

Detailed Description

The research design used was experimental with randomized sampling, double-blinded, in men and women with ureteral stents. The patient signed informed consent regarding blood and urine sampling, bladder mucosal biopsy, placement and removal of ureteral stents, drug administration, and side effects of therapy. The history and physical examination of the patient were recorded including age, height, weight, and body mass index (BMI). Investigation procedures for urinalysis, routine blood, SGOT/SGPT, urea/creatinine, blood sugar during, ultrasonography, plain abdominal photos, and CT scan urography were performed on patients before surgery. The patient's largest stone size is used as a benchmark to record the patient's stone size.

All patients who underwent routine post-ureterorenoscopy lithotripsy (URSL) ureteral stent procedures and met the inclusion and exclusion criteria were included in the study evaluation. The ureteral stent used was 4.7 Fr in size with a length of 24-26 cm, made from polyurethane used in all patients.

Blood and urine samples will be taken before drug administration begins, and when the ureteral stent is removed or replaced. Bladder mucosal biopsy was performed in the trigone vesicae around the contralateral ureteral opening during cystoscopy before ureteral stent placement, and on the ipsilateral side when the ureteral stent was to be removed or replaced in the 6th week after ureteral stent placement.

A plain photo of the abdomen or ultrasound is done postoperatively to see the remaining stone fragments and the position of the ureteral stent. Urethral catheters were removed on the 2nd postoperative day in all patients before the patients were discharged and given oral antibiotics (cefadroxil) for 5 days. During the observation phase, the patient was given the same analgesic (paracetamol 500 mg every 8 hours/24 hours and if needed can be given every 6 hours/24 hours). The total amount of analgesics consumed by the patient will be recorded in filling out the final questionnaire.

Patients were asked to come to the urology clinic at the hospital for control on the seventh day. The patient will be given a questionnaire format that will measure the presence or absence and severity of side effects experienced by the patient for 7 days after ureteral stent placement.

Patients will be divided into 3 groups of drug administration. The double-blinded method is used to minimize bias. All medicines were placed in the same 3 boxes, which were held by the paramedics so that the patients and researchers did not know the allocation of the types of drugs given. All patients have been informed about the side effects of the drug.

Administration of mirabegron 50 mg/day compared to tamsulosin 0.4 mg and placebo began on the third day before insertion of the ureteral stent. Completion of the questionnaire began on the seventh day after ureteral stent insertion, then it was measured every 7 days (7th, 14th, 21st, 28th, 35th, and 42nd day) after ureteral stent insertion. Filling out the questionnaire can be done by in-person interview at the clinic or by telephone.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• Indonesia
  • South Sulawesi
    • Makassar, South Sulawesi, Indonesia, 90245
      • DR Wahidin Sudirohusodo Hospital, Hasanuddin University Hospital, and Akademis Jaury Jusuf Putra Hospital.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18 years
• Patient with first ureterorenoscopy and ureteral stent placement
• Using a semi-rigid (rigid) retrograde or flexible (flexible) ureteroscope
• Stent placement on one side
• Stent installation size 4.7 Fr, length 24-26cm hydrophilic coated ureteric stent
• Patients who can read and understand Indonesia language (Bahasa Indonesia)

Exclusion Criteria:

• Patients with or who have a history of malignancy of the urinary tract
• Patients with LUTS caused by benign prostatic enlargement, bladder stones, or urethral strictures
• Catheterized patients or on self-catheter therapy regularly and patients with urinary diversion
• Patients with Post void residual volume > 350 mL
• Patients with neurogenic bladder and/or OAB syndrome, stress incontinence, or mixed stress/urge incontinence
• Patients with chronic pain that is not controlled or on therapy to manage chronic pain
• Patients with symptomatic UTI
• Patients with a prior history of sexual dysfunction
• Have or are currently undergoing radiation therapy/hormonal therapy and/or surgical procedures in the minor pelvis, ureteral reconstructive surgery.
• Patients with primary neurological disorders, such as multiple sclerosis, Parkinson's disease, diabetic nephropathy, or other neurological diseases that affect bladder function.
• Patients who are hypersensitive to mirabegron and tamsulosin or their derivatives and patients with mirabegron and tamsulosin contraindications.
• The patient could not follow the research protocol due to an organic brain disorder or psychiatric disorder
• Patients with autoimmune diseases and other inflammatory diseases, as well as patients taking immunosuppressant drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Mirabegron; The participants were given mirabegron 50 mirabegron/day started 3 days before DJ stent insertion and until 6 weeks after the DJ stent insertion and filled in USSQ every week until 6 weeks after the DJ stent insertion(filled in directly when the patient arrived or by telephone)	Drug: Mirabegron 50 MG; The participants were given mirabegron 50 mg or tamsulosin 0.4 mg and filled in the Ureteral Stent Symptom Questionnaire (USSQ), filled in directly when the patient arrived or by telephone.; Other Names: Placebo; Tamsulosin 0.4 mg
Active Comparator: Tamsulosin; The participants were given tamsulosin 0.4 mg that was started 3 days before DJ stent insertion and until 6 weeks after the DJ stent insertion and filled in USSQ every week until 6 weeks after the DJ stent insertion(filled in directly when the patient arrived or by telephone)	Drug: Mirabegron 50 MG; The participants were given mirabegron 50 mg or tamsulosin 0.4 mg and filled in the Ureteral Stent Symptom Questionnaire (USSQ), filled in directly when the patient arrived or by telephone.; Other Names: Placebo; Tamsulosin 0.4 mg
Placebo Comparator: Placebo; The participants were given a placebo that was started 3 days before DJ stent insertion and until 6 weeks after the DJ stent insertion and filled in USSQ every week until 6 weeks after the DJ stent insertion(filled in directly when the patient arrives or by telephone)	Drug: Mirabegron 50 MG; The participants were given mirabegron 50 mg or tamsulosin 0.4 mg and filled in the Ureteral Stent Symptom Questionnaire (USSQ), filled in directly when the patient arrived or by telephone.; Other Names: Placebo; Tamsulosin 0.4 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
serum and urine Interleukin-6 serum level (ELISA)	Interleukin-6 serum level	Pre-intervention and immediately after the intervention
serum and urine Interleukin-10 serum level (ELISA)	Interleukin-10 serum level	Pre-intervention and immediately after the intervention
Histopathology	The severity of the mucosal inflammatory reaction was graded using a semiquantitative scale where 0=none, 1 = focal lymphocytic infiltration, 2 =diffuse predominantly lymphocytic infiltration, 3 =diffuse predominantly eosinophil polymorphonuclear infiltration and 4 = grade 3 changes in combination with intra-epithelial eosinophilic micro-abscesses.	Pre-intervention and immediately after the intervention
Urinary symptoms in the Ureteral Stent Symptom Questionnaire (USSQ) parameter	Minimum values 2 and maximum values 47	Pre-intervention, immediately after the interventio, and up to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Basis data	Characteristic data participants	pre-intervention

Collaborators and Investigators

• Sponsor: Hasanuddin University

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): October 30, 2022

Study Registration Dates

• First Submitted: September 2, 2023
• First Submitted That Met QC Criteria: November 3, 2023
• First Posted (Estimated): November 9, 2023

Study Record Updates

• Last Update Posted (Estimated): November 9, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Mirabegron; Tamsulosin; Interleukin-6; Interleukin-10; lower urinary tract symptoms; Double J stent
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Pathological Conditions, Anatomical; Ureteral Diseases; Urolithiasis; Urinary Calculi; Calculi; Nephrolithiasis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Calculi; Ureteral Calculi; Ureterolithiasis; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adrenergic beta-3 Receptor Agonists; Tamsulosin; Mirabegron
• Other Study ID Numbers: 583/UN4.6.4.5.37/PP36/2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The data supporting this study's findings are available on request from the corresponding author (Muhammad Asykar Palinrung).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No