Clinical trial NCT04789135: Evaluation of Response to Use of Intravesical Ozone Gas in Interstitial Cystitis /Bladder Pain Syndrome
Official title: Evaluation of Response to Use of Intravesical Ozone Gas in Interstitial Cystitis/Bladder Pain Syndrome
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Interstitial Cystitis, Chronic
Bladder Pain Syndrome
Keywords: Interstitial cystitis
Bladder pain Sydrome
Ozone therapy
Lead sponsor: Anhembi Morumbi University
Sponsor class: OTHER
First posted: 2021-03-09
Enrollment: 50
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Experimental. Nature of descriptive analysis of the exploratory type, as it seeks to gather characteristics and information about the studied phenomena
Primary purpose: TREATMENT

Brief summary: Interstitial Cystitis / bladder pain syndrome (CI / BPS) is a debilitating pathology with a negative impact on the quality of life of affected individuals. It is characterized as the sensation of pain or discomfort related to the urinary bladder, accompanied by symptoms of the lower urinary tract, in the absence of infection. Among the phenotypes are Cystitis with Hunner's ulcer, essentially inflammatory pathology and without Hunner's lesion, non-inflammatory frequently associated with somatoform systemic changes. Functional changes in urothelium and epithelial barrier, neurogenic inflammation and autoimmune mechanisms are involved in the development of the disease.

Medical ozone has anti-inflammatory, antioxidant, cytoprotective, antimicrobial and immunomodulatory properties. When administered, it is dissolved in biological fluids, immediately reacting with glycoproteins composed of carbohydrates and polypeptide chains. This reaction results in the formation of hydrogen peroxide (H2O2), lipid oxidation products (LOS), increased activation of erythroid-related nuclear transcription factors (Nrf2) activation of antioxidant response transcription elements (ARE) and increased variety of antioxidant enzymes that act as free radical scavengers. Benefits of O3 have been demonstrated in the treatment of neuropathic pain and hyperalgesia associated with the analgesic and anti-inflammatory effect.

The objective of this work is to evaluate the effect of intravesical ozone gas administration in patients with Interstitial Cystitis / Painful Bladder Syndrome with low response to conventional therapy.

Detailed description: Interstitial Cystitis / bladder pain syndrome (IC / BPS) is a debilitating pathology with a negative impact on the quality of life of patients. According to the European Society for the Study of IC / BPS (ESSIC) it is expressed as a sensation of pain, pressure or discomfort related to the urinary bladder accompanied by symptoms of the lower urinary tract. Symptoms occur in the absence of infection and obvious pelvic pathologies lasting more than six weeks.

The CI / BPS has a variety of clinical phenotypes and potential etiologies. Among the phenotypes are included cystitis (IC) associated with Hunner's ulcers, known as ESSIC BPS type 3 and without Hunner's lesion, ESSIC type 1,2. Differentiation between the sub-types is performed through cystoscopy by the presence or absence of Hunner's lesions.

The dysfunctions resulting from IC / BPS originate around the bladder, adjacent pelvic organs and part of the neural tissue that controls bladder function. Functional changes in urothelium and epithelial barrier, neurogenic inflammation and autoimmune mechanisms are involved in the development of the disease.

The urothelium is covered by a layer of glycosaminoglycans (GACs) forming a protective barrier to the underlying tissues against urinary constituents and promoting selective control of molecules towards the bladder wall.

Molecular and structural changes in the GACs layer associated with the inflammatory process cause changes in urothelial permeability allowing toxic substances and urinary cations to reach the muscle and neural layer. The loss of the urothelial barrier allows chemical, cytotoxic stimuli to come into direct contact with peripheral bladder afferent neurons with persistent sensitization, central nervous amplification and local inflammatory reaction.

Neurotransmitters released by peripheral neurons, including vasoactive peptides, calcitonin and tachykinins induce mast cell degranulation and release of pro - inflammatory mediators such as histamine, serotonin, tryptase, TNF-α and NGF, IL6 resulting in local inflammation. These inflammatory mediators act on afferent neurons in a positive feedback loop resulting in the release of neurotransmitters that exacerbate mast cell degranulation and local inflammatory response, with functional destruction of bladder tissue, fibrosis, low Detrusor compliance and hyperactivity.

Alterations in the Autonomic Nervous System with sympathetic hyperactivity and exacerbation of the sensation of pain induces a condition of hyperalgesia associated with stress, in addition to contributing to the maintenance and worsening of the functional changes of the bladder. Persistent spinal cord activation can mediate pain after resolution of the inflammatory process.

The bladder pain syndrome is a common cause of chronic pelvic pain. It presents low long-term therapeutic response, innovative therapeutic modalities in the field of current studies.

Ozone gas (O3) is a molecule made up of three oxygen atoms with an unstable structure given a mesomeric effect. It has an average life of 40min at 20º C.

The interest in the therapeutic use of O3 in several diseases is growing. This interest is associated with anti-inflammatory, cytoprotective, antioxidant, antimicrobial and immunomodulatory properties. Animal models suggest beneficial and prophylactic effects of O3 therapy on age-related oxidative stress.

When administered, O3 is dissolved in biological fluids, reacting immediately with glycoproteins composed of carbohydrates and polypeptide chains (proteoglycans, collagen types II and IV). This reaction results in the formation of hydrogen peroxide (H2O2), lipid oxidation products (LOS), increased activation of erythroid-related nuclear transcription factors (Nrf2) activation of antioxidant response transcription elements (ARE) and increased variety of antioxidant enzymes that act as free radical scavengers.

Benefits of O3 have been demonstrated in the treatment of neuropathic pain and hyperalgesia associated with the analgesic and anti-inflammatory effect. Animal models demonstrate decreased and normalized expression of caspases and IL -1β, TNF. At low doses, O3 reduces the synthesis of prostaglandins (PGS) by inhibiting prostaglandin endoperoxide synthase (PGHS2) and cyclooxygenase (COXs). This fact is critical in preventing neural sensitization following persistent stimulation of intracellular pathways responsible for the excessive release of cytokines, PGs, or glutamate.

ETHICAL CRITERIA. All patients must undergo the signature of the Informed Consent Form for Medical Treatment with Medicinal Ozone METHODOLOGY This is an interventional, controlled study that provides for the application of intravesical ozone gas as an alternative treatment for patients with interstitial cystitis/bladder pain syndrome The study foresees the participation of 50 patients with interstitial cystitis /bladder pain syndrome and will be developed in the Hospital Unit of Nephrology and Urology Distal, located in the city of Jacareí, São Paulo, Brazil.

DIAGNOSTIC CRITERIA 1.1 History A thorough general medical history to identify typical diagnostic symptoms of Interstitial cystitis and bladder pain syndrome and other potential mimicking causative conditions. Figure 1 shows a flowchart of clinical approach.

1.2 Physical examination The physical exam include an abdominal and pelvic exam, with particular focus for masses, bladder distension and suprapubic tenderness. In men, sensitivity will be analyzed through palpation of the perineal area between the scrotum and anus. In women sensitivity will be analyzed through palpation of the anterior vaginal wall along the course of the urethra up to the bladder neck.

1.3 DIAGNOSTIC METHODS A. Urinalysis and Culture A urine dipstick will be performed on all patients The laboratory method of qualitative and quantitative determination of pathogenic microorganisms in the urinary tract will be performed. Urinary tract infection will be characterized by the bacterial growth of at least 105 Colony Forming Units per ml of urine (100.000 CFU / mL). The collection of urinary sample will be performed with aseptic technique avoiding contamination with the microbiota of the perineum, prostate, urethra and vagina.

B. Ultrasound Urinary Tract Abdominal and pelvic ultrasonography will be performed on all patients. C. Urodynamic Assessment Study carried out with the purpose of obtaining functional information on vesical storage and emptying.

D Symptom scores Symptom score IC / BPS will be used to establish a baseline of symptom severity at admission and subsequently, track response to treatment and disease relapse. It Will be used in the O'Leary-Sant Symptom and Problem Index, that is validated and widely used as a self-report measure of urinary and pain symptoms and how problematic these symptoms are for individuals. The measure assesses both symptoms and problems of IC/BPS each with four questions, yielding a symptom score (ICSI), problem score (ICPI), and total severity score. Symptom scores (ICSI) range from 0 to 21 and problem scores (ICPI) range from 0 to 16, with a total ICSI/ICPI combined score ranging from 0 to 37\[21\].

TREATMENT PROTOCOL Patients who meet inclusion criteria will be subjected to conventional treatment of the diagnoses made and submitted to the application of intravesical medicinal ozone gas.

Therapeutic Scheme

1° Bladder wash with 0.9% Saline - 500 ml performed through urethral tube n° 10; 2° Bladder emptying ; 3° Medical Ozone gas infusion 20 µg / ml - 60ml, intravesical forecast of two weekly sessions, with a total of six applications.

Clinical Follow-up Patients will be evaluated at each session using the score IC/BPS and possible side effects. At the end of the sixth session, Uroculture and Urofluxometry will be scheduled.

Monthly assessments will be scheduled for up to six months from the end of treatment to verify the maintenance of therapeutic response over time DATA ANALYSIS Qualitative data will be grouped into categories followed by the corresponding percentage. The analysis will be performed using SPSS software and Microsoft Excel.

Quantitative data will be presented in frequency distribution tables with mean, median and descriptive statistics. Statistical analysis performed using Student's t-test with significance values p\> 0.05.

CLINICAL RISK It is a risk procedure estimated as small since the administration of Ozone with controlled doses is safe and determinant of small side effects. The discomfort caused by the use of the urethral tube is small and performed safely.

The specialized professionals who will conduct the experiments will be available and able to offer any necessary attention BENEFIT Patients who will be included in the present study have chronic pathology with impaired quality of life and inadequate response to conventional therapy. Based on scientific evidence, Ozone Therapy is expected to be a treatment alternative.

Eligibility criteria: Inclusion Criteria:

* Interstitial Cystitis
* Bladder pain Syndrome

Exclusion Criteria:

* Malignant Neoplasm
* Bladder Lithiasis.
* Lower Tract Infections

Primary outcomes:
measure: Evaluation of the response to the use of intravesical medicinal ozone gas in patients with Interstitial Cystitis / Bladder Pain Syndrome (IC / BPS) using the O'Leary Sant Symptom and Problem Index questionnaire
timeFrame: The O'Leary Sant Symptom and Problem Index questionnaire will be applied upon admission, after the third and sixth application of intravesical. Follow-up will be carried out monthly thereafter until the sixth month of the intervention as a response check
Secondary outcomes:
Other outcomes:
Locations:
city: Jacareí
country: Brazil
facility: Distal Nefrologia e Urologia
state: SP
Study officials:
affiliation: Anhembi Morumbi University
name: Maria Pires, Pires
role: PRINCIPAL_INVESTIGATOR
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