Prevention and Management of Intravesical BCG-related Lower Urinary Tract Symptoms

Common local side effects are generally seen during induction and during the first 6 months of BCG maintenance. BCG-related cystitis is frequent and unavoidable. Furthermore, repeated BCG instillation increases the incidence and severity of irritative bladder symptoms. Several methods attempted to reduce the intensity and frequency of BCG- related lower urinary tract symptoms (LUTS), such as, administration of anti-tuberculosis drug isoniazid or oral antibiotic ofloxacin or by reducing the BCG dose, but without any encouraging results. Local side effects requiring cessation of treatment are seen more frequently in the first year of therapy, preventing patients from receiving their BCG maintenance regimen. Pentosan Polysulphate (PPS), is an oral medication with unique analgesic properties used to relieve bladder pain and discomfort related to other conditions, has been investigated in a small study with encouraging result in this patient population. This suggest that PPS is well tolerated and effective at decreasing BCG-related LUTS. The purpose of this study is first to investigate the efficacy of co-administration of Pentosan Polysulphate to prevent these adverse events and the impact of this intervention on quality of life. The second goal is to determine which patients are more vulnerable to develop BCG- related lower urinary tract symptoms (LUTS), based on clinical assessment, demographics data, voiding parameters, and urinary inflammatory markers, and then to assess the effectiveness of BCG therapy following co-administration of ELMIRON.

Sex

All

Minimum age

18 Years

Maximum age

85 Years

Inclusion Criteria:

Adult patients aged 18 to 85 will be eligible for inclusion in this study if all of the following criteria apply:

1. Willing to provide written informed consent
2. Confirmed diagnosis (biopsy-proven) of intermediate- and high-risk NMIBC
3. Two to four weeks following complete tumor resection
4. Candidate for BCG induction therapy based on CUA clinical guidelines
5. Subjects must not be pregnant, lactating, or actively trying to become pregnant, Subjects who are premenopausal and of childbearing potential must have a negative pregnancy test at Screening (serum) and at Day 0 (urine) and must use a medically acceptable and effective method of birth control for the duration of the study, which can include:

   1. Having a male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject
   2. Use of double-barrier methods of contraception; condoms with the use of caps (with spermicide) and intra-uterine devices are acceptable
   3. Use of hormonal contraceptives (oral, depots, patches, etc.) with double-barrier methods of contraception as outline above
   4. True abstinence: When this is in line with the preferred and usual lifestyle of the subject (period abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception)

Exclusion Criteria:

1. Contraindications to BCG therapy
2. Solitary tumors except pT1 high grade
3. Tumor stage ≥ T2
4. Previous BCG or chemotherapy instillation
5. Carcinoma in situ and variant histology of urothelial carcinoma
6. Subjects with concurrent (at Screening), urinary tract infections (positive dipstick for urinary tract infection and abnormal microscopic evaluation, signs and symptoms)
7. Unevaluated urinary retention, Post void residual (PVR) urine volume \> 150 ml
8. Diagnosis of dementia
9. Any concurrent condition or any clinically significant abnormality on the screening physical examination, laboratory tests, which, in the opinion of the Investigator, may affect the interpretation of efficacy or safety data, or which otherwise contraindicates participation in a clinical study with PPS.

   1. Hypersensitivity to PPS or any of its ingredients
   2. History of clinically significant drug hypersensitivity.
   3. Clinically significant or unstable, endocrine, hepatic, renal, immunologic, or heart disease
   4. Patients at increased hemorrhagic risk due to unstable disease course (ulcerative GI lesions, aneurysms, internal or external hemorrhoids, thrombocytopenia, hemophilia, polyps or diverticulae).
10. Use of any pharmacologic agent used to treat symptoms of LUTS
11. Participation in a clinical study within the month prior to screening, or exposure to an investigational drug which has not washed out since the last administration prior to screening
12. In the opinion of the Investigator, is at risk of non-compliance with study procedures, or cannot read, understand, or complete study-related materials, particularly informed consent
13. Participation in any clinical study of an investigational drug that may affect urinary function within 1 months prior to screening
14. Severe renal impairment (estimated glomerular filtration rate \< 30 mL/min/1.73m2)
15. Severe hepatic impairment (Child-Pugh B or greater)
16. You are pregnant or breastfeeding

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