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

NCT03549650 | Terminated Phase 2 DMC

• 1 other identifier: 17-149
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Lower Urinary Tract Symptoms; Bladder Carcinoma; BCG

Keywords

Non-Muscle-Invasive Bladder Cancer; LUTS

Outcome Measures

Primary Outcomes (4)

• Determine the efficacy (Urgency episodes assessed by bladder diary) a of co-administration of Pentosan Polysulphate in preventing BCG-related LUTS in adult subjects with a diagnosis of NMIBC.

  Primary outcome assessment (change from baseline to end of treatment): -Mean change in number of urgency episodes per 24 hours based on a 3-day bladder diary

  Start of treatment to End of treatment (6weeks)

• Determine the efficacy (Urgency episodes assessed by ICIQ-LUTSqol questionnaire) a of co-administration of Pentosan Polysulphate in preventing BCG-related LUTS in adult subjects with a diagnosis of NMIBC.

  Primary outcome assessment (change from baseline to end of treatment): -Mean change in ICIQ-LUTSqol questionnaire score

  Start of treatment to End of treatment (6weeks)

• Determine the efficacy (Urgency episodes assessed by OAB-V8 questionnaire) a of co-administration of Pentosan Polysulphate in preventing BCG-related LUTS in adult subjects with a diagnosis of NMIBC.

  Primary outcome assessment (change from baseline to end of treatment): -Mean change in OAB-V8 questionnaire score

  Start of treatment to End of treatment (6weeks)

• Determine the safety (Adverse events or reactions as assessed by CTCAE v5.0) of co-administration of Pentosan Polysulphate in preventing BCG-related LUTS in adult subjects with a diagnosis of NMIBC.

  Safety: (Number of participants with treatment-related adverse events as assessed by CTCAE v5.0) -Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 at the End of treatment Visit (week 6)

  Start of treatment to End of treatment (6weeks)

Secondary Outcomes (6)

• Efficacy of BCG therapy (cancer recurrence and progression assessed by cystoscopy) following co-administration of Pentosan Polysulphate

  12 weeks and 24 weeks

• Efficacy of BCG therapy (cancer recurrence and progression assessed by urine cytology) following co-administration of Pentosan Polysulphate

  12 weeks and 24 weeks

• Predisposing factors to developing BCG-related LUTS involving secondary analysis of patient's characteristics pre- and post-treatment

  Start of treatment to End of treatment (6weeks)

• Predisposing factors to developing BCG-related LUTS evaluated by ELISA quantitative measures of urinary inflammatory markers before and after BCG therapy

  Start of treatment to End of treatment (6weeks)

• Health-related quality of life (HRQoL) assessed by ICIQ-LUTSqol questionnaire

  Baseline, 6weeks , 12 weeks and 24 weeks

Study Arms (2)

Pentosan Polysulfate Na 100Mg Cap

EXPERIMENTAL

Drug intervention of Pentosan Polysulfate Na 100Mg Cap (ELMIRON) thrice daily PO for 6 weeks, after meeting the eligibility criteria during the the two-week Screening period.

Drug: Pentosan Polysulfate Na 100Mg Cap

Placebo oral capsule

PLACEBO COMPARATOR

Participants will receive Placebo oral capsule, similar to (ELMIRON 100mg) thrice daily PO for 6 weeks, , after meeting the eligibility criteria during the the two-week Screening period.

Drug: Placebo oral capsule

Interventions

Pentosan Polysulfate Na 100Mg Cap DRUG

Participants will be randomly assigned to receive Pentosan Polysulfate Na 100Mg Cap TID for 6 weeks. For blinded distribution, each bottle of medications will be labeled with a random number for identification. The study participants will be monitored every 2 weeks with phone calls from the study team to evaluate their condition and decide if the medication is tolerated and whether it should be continued or stopped.

Also known as: ELMIRON

Pentosan Polysulfate Na 100Mg Cap

Placebo oral capsule DRUG

Participants will be randomly assigned to receive Placebo oral capsule TID for 6 weeks. For blinded distribution, each bottle of medications will be labeled with a random number for identification. The study participants will be monitored every 2 weeks with phone calls from the study team to evaluate their condition and decide if the medication is tolerated and whether it should be continued or stopped.

Also known as: Sugar pill

Placebo oral capsule

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing to provide written informed consent
• Confirmed diagnosis (biopsy-proven) of intermediate- and high-risk NMIBC
• Two to four weeks following complete tumor resection
• Candidate for BCG induction therapy based on CUA clinical guidelines
• 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:
• 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
• Use of double-barrier methods of contraception; condoms with the use of caps (with spermicide) and intra-uterine devices are acceptable
• Use of hormonal contraceptives (oral, depots, patches, etc.) with double-barrier methods of contraception as outline above
• 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)

You may not qualify if:

• Contraindications to BCG therapy
• Solitary tumors except pT1 high grade
• Tumor stage ≥ T2
• Previous BCG or chemotherapy instillation
• Carcinoma in situ and variant histology of urothelial carcinoma
• Subjects with concurrent (at Screening), urinary tract infections (positive dipstick for urinary tract infection and abnormal microscopic evaluation, signs and symptoms)
• Unevaluated urinary retention, Post void residual (PVR) urine volume \> 150 ml
• Diagnosis of dementia
• 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.
• Hypersensitivity to PPS or any of its ingredients
• History of clinically significant drug hypersensitivity.
• Clinically significant or unstable, endocrine, hepatic, renal, immunologic, or heart disease
• Patients at increased hemorrhagic risk due to unstable disease course (ulcerative GI lesions, aneurysms, internal or external hemorrhoids, thrombocytopenia, hemophilia, polyps or diverticulae).
• Use of any pharmacologic agent used to treat symptoms of LUTS
• 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

Sponsors & Collaborators

• Sir Mortimer B. Davis - Jewish General Hospital: lead
• Cancer Research Network: collaborator

Study Sites (1)

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Related Publications (22)

• Brausi M, Witjes JA, Lamm D, Persad R, Palou J, Colombel M, Buckley R, Soloway M, Akaza H, Bohle A. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J Urol. 2011 Dec;186(6):2158-67. doi: 10.1016/j.juro.2011.07.076. Epub 2011 Oct 19.

  PMID: 22014799 BACKGROUND

• Gontero P, Bohle A, Malmstrom PU, O'Donnell MA, Oderda M, Sylvester R, Witjes F. The role of bacillus Calmette-Guerin in the treatment of non-muscle-invasive bladder cancer. Eur Urol. 2010 Mar;57(3):410-29. doi: 10.1016/j.eururo.2009.11.023. Epub 2009 Nov 13.

  PMID: 19969411 BACKGROUND

• Lamm DL, van der Meijden PM, Morales A, Brosman SA, Catalona WJ, Herr HW, Soloway MS, Steg A, Debruyne FM. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. J Urol. 1992 Mar;147(3):596-600. doi: 10.1016/s0022-5347(17)37316-0.

  PMID: 1538436 BACKGROUND

• Brausi M, Oddens J, Sylvester R, Bono A, van de Beek C, van Andel G, Gontero P, Turkeri L, Marreaud S, Collette S, Oosterlinck W. Side effects of Bacillus Calmette-Guerin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. Eur Urol. 2014 Jan;65(1):69-76. doi: 10.1016/j.eururo.2013.07.021. Epub 2013 Jul 24.

  PMID: 23910233 BACKGROUND

• de Reijke TM, de Boer EC, Kurth KH, Schamhart DH. Urinary cytokines during intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: processing, stability and prognostic value. J Urol. 1996 Feb;155(2):477-82.

  PMID: 8558640 BACKGROUND

• Ludwig AT, Moore JM, Luo Y, Chen X, Saltsgaver NA, O'Donnell MA, Griffith TS. Tumor necrosis factor-related apoptosis-inducing ligand: a novel mechanism for Bacillus Calmette-Guerin-induced antitumor activity. Cancer Res. 2004 May 15;64(10):3386-90. doi: 10.1158/0008-5472.CAN-04-0374.

  PMID: 15150089 BACKGROUND

• Sylvester RJ, Brausi MA, Kirkels WJ, Hoeltl W, Calais Da Silva F, Powell PH, Prescott S, Kirkali Z, van de Beek C, Gorlia T, de Reijke TM; EORTC Genito-Urinary Tract Cancer Group. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010 May;57(5):766-73. doi: 10.1016/j.eururo.2009.12.024. Epub 2009 Dec 18.

  PMID: 20034729 BACKGROUND

• Vegt PD, van der Meijden AP, Sylvester R, Brausi M, Holtl W, de Balincourt C. Does isoniazid reduce side effects of intravesical bacillus Calmette-Guerin therapy in superficial bladder cancer? Interim results of European Organization for Research and Treatment of Cancer Protocol 30911. J Urol. 1997 Apr;157(4):1246-9.

  PMID: 9120912 BACKGROUND

• Colombel M, Saint F, Chopin D, Malavaud B, Nicolas L, Rischmann P. The effect of ofloxacin on bacillus calmette-guerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind, placebo controlled, multicenter study. J Urol. 2006 Sep;176(3):935-9. doi: 10.1016/j.juro.2006.04.104.

  PMID: 16890660 BACKGROUND

• Oddens J, Brausi M, Sylvester R, Bono A, van de Beek C, van Andel G, Gontero P, Hoeltl W, Turkeri L, Marreaud S, Collette S, Oosterlinck W. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013 Mar;63(3):462-72. doi: 10.1016/j.eururo.2012.10.039. Epub 2012 Nov 2.

  PMID: 23141049 BACKGROUND

• Anderson VR, Perry CM. Pentosan polysulfate: a review of its use in the relief of bladder pain or discomfort in interstitial cystitis. Drugs. 2006;66(6):821-35. doi: 10.2165/00003495-200666060-00006.

  PMID: 16706553 BACKGROUND

• Teichman JM. The role of pentosan polysulfate in treatment approaches for interstitial cystitis. Rev Urol. 2002;4 Suppl 1(Suppl 1):S21-7.

  PMID: 16986030 BACKGROUND

• Yadav S, Tomar V, Yadav SS, Priyadarshi S, Banerjee I. Role of oral pentosan polysulphate in the reduction of local side effects of BCG therapy in patients with non-muscle-invasive bladder cancer: a pilot study. BJU Int. 2016 Nov;118(5):758-762. doi: 10.1111/bju.13489. Epub 2016 Apr 23.

  PMID: 27010115 BACKGROUND

• Davis EL, El Khoudary SR, Talbott EO, Davis J, Regan LJ. Safety and efficacy of the use of intravesical and oral pentosan polysulfate sodium for interstitial cystitis: a randomized double-blind clinical trial. J Urol. 2008 Jan;179(1):177-85. doi: 10.1016/j.juro.2007.08.170. Epub 2007 Nov 14.

  PMID: 18001798 BACKGROUND

• Chuang YC, Lee WC, Lee WC, Chiang PH. Intravesical liposome versus oral pentosan polysulfate for interstitial cystitis/painful bladder syndrome. J Urol. 2009 Oct;182(4):1393-400. doi: 10.1016/j.juro.2009.06.024. Epub 2009 Aug 15.

  PMID: 19683290 BACKGROUND

• Grigsby PW, Pilepich MV, Parsons CL. Preliminary results of a phase I/II study of sodium pentosanpolysulfate in the treatment of chronic radiation-induced proctitis. Am J Clin Oncol. 1990 Feb;13(1):28-31. doi: 10.1097/00000421-199002000-00008.

  PMID: 1689537 BACKGROUND

• De Reijke TM, De Boer LC, Steerenberg PA, Vos PC, Kurth KH, Schamhart DH. The effects of intravesical pretreatment with pentosan polysulfate on the bacillus Calmette-Guerin induced immune reaction of the guinea pig. J Urol. 1994 Mar;151(3):746-9. doi: 10.1016/s0022-5347(17)35079-6.

  PMID: 7508528 BACKGROUND

• Schamhart DH, de Boer EC, Kurth KH. Interaction between bacteria and the lumenal bladder surface: modulation by pentosan polysulfate, an experimental and theoretical approach with clinical implication. World J Urol. 1994;12(1):27-37. doi: 10.1007/BF00182048.

  PMID: 7516779 BACKGROUND

• Abdo KM, Johnson JD, Nyska A. Toxicity and carcinogenicity of Elmiron in F344/N rats and B6C3F1 mice following 2 years of gavage administration. Arch Toxicol. 2003 Dec;77(12):702-11. doi: 10.1007/s00204-003-0472-9. Epub 2003 Sep 24.

  PMID: 14508637 BACKGROUND

• National Toxicology Program. NTP technical report on the toxicology and carcinogenesis studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in female Harlan Sprague-Dawley rats (Gavage Studies). Natl Toxicol Program Tech Rep Ser. 2006 Apr;(521):4-232.

  PMID: 16835633 BACKGROUND

• Kassouf W, Traboulsi SL, Kulkarni GS, Breau RH, Zlotta A, Fairey A, So A, Lacombe L, Rendon R, Aprikian AG, Siemens DR, Izawa JI, Black P. CUA guidelines on the management of non-muscle invasive bladder cancer. Can Urol Assoc J. 2015 Sep-Oct;9(9-10):E690-704. doi: 10.5489/cuaj.3320. Epub 2015 Oct 13. No abstract available.

  PMID: 26664503 BACKGROUND

• Nystrom E, Sjostrom M, Stenlund H, Samuelsson E. ICIQ symptom and quality of life instruments measure clinically relevant improvements in women with stress urinary incontinence. Neurourol Urodyn. 2015 Nov;34(8):747-51. doi: 10.1002/nau.22657. Epub 2014 Aug 22.

  PMID: 25154378 BACKGROUND

MeSH Terms

Conditions

Lower Urinary Tract Symptoms; Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms

Interventions

Capsules; Pentosan Sulfuric Polyester; Sugars

Condition Hierarchy (Ancestors)

Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Sulfuric Acids; Sulfur Acids; Sulfur Compounds; Organic Chemicals; Polysaccharides; Carbohydrates

Study Officials

• Lysanne Campeau, MD, PhD

  SirMortimer JGH

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: April 23, 2018
• First Posted: June 8, 2018
• Study Start: May 3, 2019
• Primary Completion: February 15, 2022
• Study Completion: February 15, 2022
• Last Updated: March 4, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)