Intravesical Injection of Dextrose to Improve Lower Urinary Tract Symptoms Caused by Chronic Cystitis

Study Overview
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Brief Summary
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The pathogenesis of bladder pain syndrome/interstitial cystitis (BPS/IC) is currently unclear. Scholars have put forward different hypotheses, including the function of the extracellular matrix surface of the glycosaminoglycan (GAG) layer, downregulation of tight junction protein, increased urothelial permeability, mast cell activation, neurogenic inflammation, and psychosomatic factors. The symptoms are very similar to severe bladder pain syndrome/interstitial cystitis, and the patients respond to existing medications. In 1956, Dr. George Hackett created a method for treating damaged ligaments and tendons called prolotherapy (proliferation therapy). Prolotherapy is defined as an alternative therapy for musculoskeletal and arthritic pain, including the treatment of irritating substances (such as dextrose, also known as d-glucose) injected into ligaments or tendons to promote the growth of new tissues. There are many clinical trials confirming that proliferation therapy can effectively treat painful musculoskeletal problems. For example, in patients with lateral epicondylitis treated with a solution with a final concentration of 10% dextrose, compared with patients treated with placebo (normal saline), pain and isometric muscle strength improved significantly. A recent literature review also tells that hypertonic glucose proliferation therapy can effectively treat a variety of musculoskeletal diseases. Hence, this research suggests that dextrose prolotherapy is an affordable and effective pain management strategy in dealing with musculoskeletal neuroinflammation pain in BPS/IC. In order to begin to understand prolotherapy and its therapeutic utility, this study should begin to elucidate the immediate response of prolotherapy in the urology field by investigating the impact of dextrose. This project is expected to accommodate subjects with BPS/IC, by injecting 10% dextrose into the bladder lining muscles of IC patients and performing various urodynamic tests and questionnaires to evaluate the patient's urinary voiding symptoms and urinary bladder function recovery. Afterward, the expressions of growth factors and cytokines in the urine samples were investigated in an attempt to reveal the mechanism of dextrose prolotherapy in BPS/IC disease.

Detailed Description
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This project treated 29 male and female subjects (aged over 20 years) with BPS/IC and other chronic inflammation of the bladder. The enrolled subjects were collected from May 2019 to October 2020. The subjects were given intravesical injections of 10% dextrose under intravenous general anesthesia in the operating room: 2 mL of 50% Dextrose (Vitagen Inj., Taiwan Biotech co. ltd., Taipei, Taiwan) was briefly diluted with 10 mL of normal saline and 11 sub urothelial injections (1 mL each site) were performed. The injection needle was inserted into the urothelium at the trigone (1 site), the posterior (6 sites), and the lateral walls (4 sites) of the bladder, using a 23-gauge needle under rigid cystoscopic injection instrument (22-Fr; Knittlingen, Richard Wolf, Germany). No post-injection analgesics were provided to patients. Treatment was repeated based on the patients' condition once every 2 weeks for the first 6 cycles and once every month for the remaining 3 cycles with a maximum of 9 planned therapy cycles up to 6 months. The patients would be followed-up and assessed at each treatment time and up to 1 month after the last treatment. 19 health subjects were also recruited as a healthy control as the comparison.

Official Title
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Intravesical Injection of Dextrose to Improve Lower Urinary Tract Symptoms Caused by Chronic Cystitis

Conditions
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Bladder Pain Syndrome, Interstitial Cystitis

Intervention / Treatment
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* Drug: Dextrose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject is aged over 20 years old. The subject was diagnosed as bladder pain syndrome/interstitial cystitis subject with lower urinary tract symptoms, such as frequent urination, urgent urination, bladder pain, etc. Exclusion Criteria: The subject is aged under 20 years old. Pregnant women. The subject with congenital disorders of the urinary tract. The subject with a urinary tract infection or tumor.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>Healthy participant | |
| Experimental: Dextrose treatment<br>IC/PBS patients had been treated by intravesical instillations of hyaluronic acid and/or botox for more than 6 months | Drug: Dextrose<br>* 10% dextrose: 2 mL of 50% dextrose in 10 mL normal saline and injected by 11 sub urothelial injections<br>* Other names: Vitagen Inj., Taiwan Biotech Co., Ltd., Taipei, Taiwan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary Voiding Symptoms Analysis | Patients were asked to provide a three-day voiding frequency volume chart prior the treatment to record episodes of urinary voiding symptoms including urinary frequency, urgency, and nocturia. | 3 days | 
| Global Response Assessment (GRA) | GRA examined the overall response to treatment. Patients were requested to rate symptoms on a seven-point centered scale from markedly-, moderately-, and slightly- worse, no change, slightly-, moderately-, and markedly-improved. | Up to 7 months | 
| International Prostate Symptom Score (IPSS) | The severity of voiding symptoms was evaluated by using the International Prostate Symptom Score (IPSS-TOTAL), and the IPSS-voiding (IPSS-V) and IPSS-storage (IPSS-S) sub-scores were also recorded. There were 7 questions including questions of IPSS-V and IPSS-S. The IPSS-V is the sum of the answers to question 1 (incomplete emptying), question 3 (intermittency), question 5 (weak stream), and question 6 (straining to void). Oppositely, the IPSS-S is the sum of the answers to question 2 (frequency), question 4 (urgency), and question 7 (nocturia). The IPSS subscore can be used to evaluate symptom severity or the results of treatment. IPSS-TOTAL then took into account the total score from the answers of the questions that can therefore range from 0 to 35 (0-7 mild symptomatic; 8-19 moderately symptomatic; 20-35 severely symptomatic). | Up to 7 months | 
| Visual Analogue Scale (VAS) | VAS is a pain rating scale which its scores are based on patient self-assessment measures of symptoms that are recorded with a single handwritten mark placed at one point of 10-point along the length of a 10-cm line. The line represents the pain condition, the left end of line scale (0 cm) represents no pain and the right end of the scale (10 cm) shows the worst pain. | Up to 7 months | 
| O'Leary-Sant Score (OSS) | OSS indexes have eight questions assessing pain and voiding symptoms. OSS is obtained from O'Leary Sant instrument which evaluates a Symptom Index (ICSI with range: 0-20 points) and a Problem Index (ICPI with range: 0-16 points), each of which contains four questions related to urinary and pain symptoms. For each index, the score is calculated by summing the points for each item. A maximal index score of 36 reflects maximal symptom and problem severity. The Symptom Index covers various areas, including whether the patient feels the need to urinate with little or no warning, has to urinate more frequently than every 2 hours, needs to get up during the night to urinate, and has pain in the bladder. The Problem Index evaluates other aspects, such as urinary frequency during the day, the urinary frequency at night, the need to urinate with little or no warning, and burning, pain, discomfort, or pressure on the bladder. Both indices evaluate the situation over the previous month. | Up to 7 months | 
| 5-Item Brief Symptom Rating Scale (BSRS-5) | BSRS-5 evaluated the quality of life of patients. It contained five items of a self-administered questionnaire that is derived from the 50-item brief symptom rating scale. The score for each item ranges from 0 to 4 (from not at all to extremely). A total score on the BSRS-5 above 14, between 10 and 14, and between 6 and 9 indicated severe, moderate, and mild symptoms, respectively. | Up to 7 months | 
| 5-item Female Sexual Function Index (FSFI-5) | FSFI-5 was performed to assess the sexual dysfunction possibility of female patients. FSFI-5 contained item-by-item combinations of the 5 domains of sexual desire, arousal, lubrication, orgasm, and satisfaction. The 5 items were derived from 19 items of FSFI questionnaire. | Up to 7 months | 
| Luminex Assay of Growth Factors | Urine samples were collected and stored at 4°C until analysis. Samples were analyzed for the presences of 4 analytes: epidermal growth factor (EGF), hepatocyte growth factor (HGF), placental growth factor-1 (PIGF-1), and vascular endothelial growth factor-D (VEGF-D). Their concentration was measured using a Growth Factor 11-Plex Human ProcartaPlex™ Panel assay kit with magnetic beads (EPX110-12170-901, Thermo Fisher Scientific, MA, USA) and examined with an automated immunoassay analyzer (Luminex™ 100 IS System, Luminex, TX, USA) and the accompanying ProcartaPlex Analyst Software 1.0 (Thermo Fisher Scientific, MA, USA) according to the manufacturer's instructions. | Up to 7 months | 
| Luminex Assay of Cytokine Assay | The levels of serum cytokines [interleukin-6 (IL-6), IL-10, IL-12p70, IL-13, IL-17F, and IL-27] in blood samples were detected using a magnetic bead-based multiplex immunoassay MILLIPLEX MAP Human Th17 Magnetic Bead Panel (Merck KGaA, Darmstadt, Germany) according to the manufacturer's protocol. The MAGPIX® System reader was used to acquire the data of cytokines, which was output as concentration (pg/mL) using the Belysa™ Immunoassay Curve Fitting Software (Merck KGaA, Darmstadt, Germany). | Up to 7 months | 
| Statistics Analysis | Urinary voiding symptoms analysis, the score of questionnaires (GRA, IPSS-TOTAL, IPSS-V, IPSS-S, VAS, ICSI, ICPI, BSRS5, and FSFI5), Luminex assay result of growth factors and cytokines assay were compared between and after treatment. Results are presented as mean values plus or minus standard deviations. Statistical comparisons between the groups were tested using a chi-square test for categorical variables, and an independent t test or a Wilcoxon test for nonparametric data was used for multiple comparisons. The correlation analysis and coefficient statistical method were performed for comparing VAS questionnaire and growth factor relation. A P value of <0.05 was considered statistically significant. Statistical analyses were performed using SPSS 18.0 statistical software (SPSS Inc., IL, USA). | Up to 7 months |