Lower Urinary Tract SymptomsPhase 2NCT03549650
Prevention and Management of Intravesical BCG-related Lower Urinary Tract Symptoms
A Phase 2 study testing Pentosan Polysulfate Na 100Mg Cap in people with Lower Urinary Tract Symptoms and Bladder Carcinoma, run by Sir Mortimer B. Davis - Jewish General Hospital at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 85 years
- Conditions the study is for
- Lower Urinary Tract Symptoms, Bladder Carcinoma, BCG
- What is being tested?
- Pentosan Polysulfate Na 100Mg Cap
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 3 participants
- Where
- 1 siteCanada
- Study dates
- 3 May 2019to 15 Feb 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult patients aged 18 to 85 will be eligible for inclusion in this study if all of the following criteria apply:
- 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:
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- 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)
Who cannot join
- 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)
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- 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
- 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
- Participation in any clinical study of an investigational drug that may affect urinary function within 1 months prior to screening
- Severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73m2)
- Severe hepatic impairment (Child-Pugh B or greater)
- You are pregnant or breastfeeding
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Prevention and Management of Intravesical BCG-related Lower Urinary Tract Symptoms With Prophylactic Pentosan Polysulphate in Patients With Non-Muscle-Invasive Bladder Cancer: A Randomized Controlled Trial
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.
Read the detailed description
Study purpose and rationale:
BCG-related LUTS is a condition which can have a significant negative impact on the psychological well-being, social functioning, and overall quality of life of bladder cancer patients. Clinical studies have demonstrated effects of PPS on damaged urothelium in the bladder, which is a key feature for diminishing BCG local side effects. The "dual action" protective effect on bladder epithelium and replacing the mucus in the glycosaminoglycan layer of damaged urothelium provides a scientific rationale to evaluate whether PPS treatment may be a preventive option for NMIBC patients treated with BCG.
It is therefore important to find a treatment strategy to control the BCG-related LUTS so that candidate patients do not lose the benefit of BCG treatment while maintaining its efficacy and ensuring optimal outcomes. This study will identify the patients that are more vulnerable to develop these side effects and determine the efficacy of PPS to diminish BCG- related lower urinary tract symptoms (LUTS) and associated impact on quality of life.
Sample Size:
For the first aim, power analysis was estimated using a One-way (ANOVA) hypothesis test with a type 1 error of 5%, 80% power, and 20% dropout rate. It was calculated based on the ICIQ-LUTSqol expected values. The baseline mean ICIQ-LUTSqol score used was 33.1 and SD of 7.3, the outcome ICIQ-LUTSqol score mean used 28.48, with a SD of 4.95, which is the minimally important difference of 3.7124. The investigator calculate a number of 30 patients per group, for a total sample size of 60. (Calculated by pass program v 15.0.03)
For the second aim, a total number of 40 candidates will be recruited for this prospective study. The investigator expect a minimum of 30% of patients to experience BCG related LUTS, therefore 18 patients with LUTS The SD of ICIQ-LUTSqol is 7.3 and its maximum score is 76. Therefore, the investigator estimate a required sample size of 14 (1.96 2 SD 2 / 3.82), for a p value < 0.05, and an absolute error of 0.05.
The comparison between groups of the cohort will be conducted using chi-square analysis. A 2-sample t test will be used to compare baseline scores between study groups. The Wilcoxon rank-sum test will be used to calculate whether the mean difference of all the outcome measures between groups. A p value <0.05 considered statistically significant.
Approximately 100 subjects are expected to be enrolled for this prospective trial. It is expected that 20% of subjects will not qualify for randomization after screening. The study is expected to randomize approximately 80 subjects into the double-blind treatment where subjects will be allocated to ELMIRON 100 mg, or matched placebo TID in a 1:1 ratio. A post randomisation dropout rate of 20% has been estimated, resulting in 60 evaluable subjects. This provides an 80% power for the primary endpoint.
Study design and description This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group study in patients 18 to 85 years old with NMIBC. The study will include a two weeks Screening Period; and a 6-week double-blind Treatment Period. Participants will return to the clinic for a safety Follow-up Visit 6 and 18 weeks after treatment is completed for a total study duration of 24 weeks.
All participants will enter the Screening Period during which eligibility will be assessed, where subjects must have at least 3 days of daily diary symptom collection. Participants who continue to meet eligibility criteria, including collection of diary data, Negative Urine analysis and culture, and bladder scan showing PVR less than 150ml at the end of the Screening Period will enter the Treatment Period.
Participants will be randomly assigned (1:1) to receive study drug (ELMIRON 100 mg, or placebo) TID for a duration of 6weeks.
Efficacy will be assessed by number of urgency episodes per 24 hours based on a 3-day bladder diary, the Overactive Bladder-Validated 8- Question (OAB-V8), the visual analogue scale for suprapubic and perineal pain (VAS), the ICIQ-Lower Urinary Tract Symptoms Quality of Life Questionnaire (ICIQ-LUTSqol), and quantitative measures of urinary inflammatory markers levels (TRAIL, IFN, IL-2, IL-10).
Safety assessments will be conducted throughout the trial and will include physical examinations, vital signs, clinical laboratory evaluations, cystoscopy, urine cytology, and adverse events (AEs).
Study conduct:
AIM 1: Determine the effectiveness of co-administration of Pentosan Polysulphate in preventing BCG-related LUTS.
Rationale: The investigator aim to compare the effect of PPS (ELMIRON) to placebo on the incidence and severity of local adverse effects of BCG intravesical therapy and its impact on health-related quality of life (HRQoL) in patients with superficial bladder cancer. As the currently used symptomatic treatment drugs failed to prove optimal efficacy, new treatment options are warranted. PPS could be a promising drug especially when considering its effectiveness in controlling LUTS related to similar pathologies.
The first aim will be a prospective, randomized, double-blinded, placebo-controlled pilot study, A total of 60 subjects will be assessed and included in the study after obtaining their consent and fulfilling the inclusion criteria. Within 14 days after TURBT, patients will undergo baseline evaluation and will be randomized into two groups as the following:
- Group A will receive PPS 100 mg (ELMIRON) thrice daily PO. (30 subjects)
- Group B will receive placebo thrice daily PO. (30 subjects) Treatment period for all groups will be 6 weeks as co-administration with BCG instillation.
AIM 2: Identify predisposing factors to developing BCG-related LUTS based on clinical, demographic and voiding parameters The second aim will involve an in-depth pre-treatment analysis of clinical parameters of patients planned for BCG instillation and correlation with the development of BCG local side effects. Prior to receiving BCG induction, patients will be evaluated for baseline demographics, voiding diary, non-invasive uroflowmetry with post-void residual, LUTS and quality of life questionnaires (OAB-V8, ICIQ-LUTSqol, and VAS). Objective outcomes assessment using quantitative measures of TRAIL, IFN, IL-2, and IL-10 levels in the urine before and following BCG induction treatment will be quantitated using a sandwich ELISA and correlated with the severity of LUTS. This prospective cohort will be followed 3 months after completing the induction phase by repeating the clinical assessment described and identify their oncological response to the treatment by urine cytology/cystoscopy.
Confidentiality:
All study outcomes and documents will be considered as confidential. The Investigator and members of his/her research team must not disclose such information without prior written authorization. The anonymity of participating patients must be maintained. Subjects will be identified on CRFs and other documents by their subject number/code, not by name. Documents that identify the subject (eg, the signed informed consent) must be retained in confidence by the Investigator. All data will remain confidential and will be available for access by the investigators only. A unique identifier to keep their identity confidential will identify the participant. The information will be kept for duration of 10 years.
Statement on ethical consideration:
The proposed study protocol ensures that the Sponsor and Investigator adhere to the principles of the GCP guidelines of the ICH, and of the recent version of the Declaration of Helsinki. The study also will be following with local ethics requirements.
- Conditions
- Lower Urinary Tract Symptoms, Bladder Carcinoma, BCG
- Being tested
- Pentosan Polysulfate Na 100Mg Cap, Placebo oral capsule
- Keywords
- Non-Muscle-Invasive Bladder Cancer, LUTS
- Medical subject headings
- Lower Urinary Tract Symptoms, Urinary Bladder Neoplasms, Non-Muscle Invasive Bladder Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pentosan Polysulfate Na 100Mg CapDrug
Also called ELMIRON
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.
Placebo oral capsuleDrug
Also called Sugar pill
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Placebo oral capsule |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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
Measured: 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)
Measured: 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
All patients will be also evaluated at 12 and 24 weeks by cystoscopy to evaluate the impact of this intervention on the efficacy of BCG therapy as well as to check for cancer recurrence and progression as routine standard of care
Measured: 12 weeks and 24 weeks
Efficacy of BCG therapy (cancer recurrence and progression assessed by urine cytology) following co-administration of Pentosan Polysulphate
All patients will be also evaluated at 12 and 24 weeks by urine cytology to evaluate the impact of this intervention on the efficacy of BCG therapy as well as to check for cancer recurrence and progression as routine standard of care
Measured: 12 weeks and 24 weeks
Predisposing factors to developing BCG-related LUTS involving secondary analysis of patient's characteristics pre- and post-treatment
This will involve an in-depth pre-treatment analysis of clinical parameters of patients planned for BCG instillation and correlation with the development of BCG local side effects
Measured: 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
Objective outcomes assessment using quantitative measures of TRAIL, IFN, IL-2, and IL-10 levels in the urine before and following BCG induction treatment will be quantitated using a sandwich ELISA and correlated with the severity of LUTS
Measured: Start of treatment to End of treatment (6weeks)
Health-related quality of life (HRQoL) assessed by ICIQ-LUTSqol questionnaire
Assess the impact of this intervention on Health-related quality of life (HRQoL) in bladder cancer patients using quality of life questionnaire ICIQ-LUTSqol
Measured: Baseline, 6weeks , 12 weeks and 24 weeks
Health-related quality of life (HRQoL) assessed by VAS questionnaire
Assess the impact of this intervention on Health-related quality of life (HRQoL) in bladder cancer patients using quality of life questionnaire VAS
Measured: Baseline, 6weeks , 12 weeks and 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jun 2018
- Study start3 May 2019
- Primary completion15 Feb 2022
- Study completion15 Feb 2022
Why it stopped: Given the updated precautions on Elmiron as well as the risk benefit profile, we have decided to terminate the study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (22)Papers the sponsor has linked to this study.
- Other trials for Lower Urinary Tract SymptomsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sir Mortimer B. Davis - Jewish General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Cancer Research Network
- Responsible party
- Principal investigator, Lysanne Campeau, MDCM, PhD, FRCSC, Sir Mortimer B. Davis - Jewish General Hospital
- Investigators
- Lysanne Campeau, MD, PhD, Principal investigator, SirMortimer JGH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03549650
- Sponsor's protocol ID
- 17-149
- Status last verified
- Feb 2022
- First submitted
- 23 Apr 2018
- Last updated
- 4 Mar 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 22014799Gontero 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.
PubMed 19969411Lamm 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.
PubMed 1538436Brausi 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.
PubMed 23910233de 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.
PubMed 8558640Ludwig 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.
PubMed 15150089Sylvester 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.
PubMed 20034729Vegt 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.
PubMed 9120912Colombel 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.
PubMed 16890660Oddens 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.
PubMed 23141049Anderson 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.
PubMed 16706553Teichman JM. The role of pentosan polysulfate in treatment approaches for interstitial cystitis. Rev Urol. 2002;4 Suppl 1(Suppl 1):S21-7.
PubMed 16986030Yadav 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.
PubMed 27010115Davis 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.
PubMed 18001798Chuang 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.
PubMed 19683290
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prevention and Management of Intravesical BCG-related Lower Urinary Tract Symptoms With Prophylactic Pentosan Polysulphate in Patients With Non-Muscle-Invasive Bladder Cancer: A Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT03549650
- Acronym / sponsor ID
- 17-149
- Conditions
- Lower Urinary Tract Symptoms, Bladder Carcinoma, BCG
- Keywords
- Non-Muscle-Invasive Bladder Cancer, LUTS
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Given the updated precautions on Elmiron as well as the risk benefit profile, we have decided to terminate the study.
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Sir Mortimer B. Davis - Jewish General HospitalUniversity, hospital or other
- Collaborators
- Cancer Research Network
- Study start
- 3 May 2019 (actual)
- Primary completion
- 15 Feb 2022 (actual)
- Study completion
- 15 Feb 2022 (actual)
- First posted
- 8 Jun 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Study purpose and rationale:
BCG-related LUTS is a condition which can have a significant negative impact on the psychological well-being, social functioning, and overall quality of life of bladder cancer patients. Clinical studies have demonstrated effects of PPS on damaged urothelium in the bladder, which is a key feature for diminishing BCG local side effects. The "dual action" protective effect on bladder epithelium and replacing the mucus in the glycosaminoglycan layer of damaged urothelium provides a scientific rationale to evaluate whether PPS treatment may be a preventive option for NMIBC patients treated with BCG.
It is therefore important to find a treatment strategy to control the BCG-related LUTS so that candidate patients do not lose the benefit of BCG treatment while maintaining its efficacy and ensuring optimal outcomes. This study will identify the patients that are more vulnerable to develop these side effects and determine the efficacy of PPS to diminish BCG- related lower urinary tract symptoms (LUTS) and associated impact on quality of life.
Sample Size:
For the first aim, power analysis was estimated using a One-way (ANOVA) hypothesis test with a type 1 error of 5%, 80% power, and 20% dropout rate. It was calculated based on the ICIQ-LUTSqol expected values. The baseline mean ICIQ-LUTSqol score used was 33.1 and SD of 7.3, the outcome ICIQ-LUTSqol score mean used 28.48, with a SD of 4.95, which is the minimally important difference of 3.7124. The investigator calculate a number of 30 patients per group, for a total sample size of 60. (Calculated by pass program v 15.0.03)
For the second aim, a total number of 40 candidates will be recruited for this prospective study. The investigator expect a minimum of 30% of patients to experience BCG related LUTS, therefore 18 patients with LUTS The SD of ICIQ-LUTSqol is 7.3 and its maximum score is 76. Therefore, the investigator estimate a required sample size of 14 (1.96 2 SD 2 / 3.82), for a p value < 0.05, and an absolute error of 0.05.
The comparison between groups of the cohort will be conducted using chi-square analysis. A 2-sample t test will be used to compare baseline scores between study groups. The Wilcoxon rank-sum test will be used to calculate whether the mean difference of all the outcome measures between groups. A p value <0.05 considered statistically significant.
Approximately 100 subjects are expected to be enrolled for this prospective trial. It is expected that 20% of subjects will not qualify for randomization after screening. The study is expected to randomize approximately 80 subjects into the double-blind treatment where subjects will be allocated to ELMIRON 100 mg, or matched placebo TID in a 1:1 ratio. A post randomisation dropout rate of 20% has been estimated, resulting in 60 evaluable subjects. This provides an 80% power for the primary endpoint.
Study design and description This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group study in patients 18 to 85 years old with NMIBC. The study will include a two weeks Screening Period; and a 6-week double-blind Treatment Period. Participants will return to the clinic for a safety Follow-up Visit 6 and 18 weeks after treatment is completed for a total study duration of 24 weeks.
All participants will enter the Screening Period during which eligibility will be assessed, where subjects must have at least 3 days of daily diary symptom collection. Participants who continue to meet eligibility criteria, including collection of diary data, Negative Urine analysis and culture, and bladder scan showing PVR less than 150ml at the end of the Screening Period will enter the Treatment Period.
Participants will be randomly assigned (1:1) to receive study drug (ELMIRON 100 mg, or placebo) TID for a duration of 6weeks.
Efficacy will be assessed by number of urgency episodes per 24 hours based on a 3-day bladder diary, the Overactive Bladder-Validated 8- Question (OAB-V8), the visual analogue scale for suprapubic and perineal pain (VAS), the ICIQ-Lower Urinary Tract Symptoms Quality of Life Questionnaire (ICIQ-LUTSqol), and quantitative measures of urinary inflammatory markers levels (TRAIL, IFN, IL-2, IL-10).
Safety assessments will be conducted throughout the trial and will include physical examinations, vital signs, clinical laboratory evaluations, cystoscopy, urine cytology, and adverse events (AEs).
Study conduct:
AIM 1: Determine the effectiveness of co-administration of Pentosan Polysulphate in preventing BCG-related LUTS.
Rationale: The investigator aim to compare the effect of PPS (ELMIRON) to placebo on the incidence and severity of local adverse effects of BCG intravesical therapy and its impact on health-related quality of life (HRQoL) in patients with superficial bladder cancer. As the currently used symptomatic treatment drugs failed to prove optimal efficacy, new treatment options are warranted. PPS could be a promising drug especially when considering its effectiveness in controlling LUTS related to similar pathologies.
The first aim will be a prospective, randomized, double-blinded, placebo-controlled pilot study, A total of 60 subjects will be assessed and included in the study after obtaining their consent and fulfilling the inclusion criteria. Within 14 days after TURBT, patients will undergo baseline evaluation and will be randomized into two groups as the following:
- Group A will receive PPS 100 mg (ELMIRON) thrice daily PO. (30 subjects)
- Group B will receive placebo thrice daily PO. (30 subjects) Treatment period for all groups will be 6 weeks as co-administration with BCG instillation.
AIM 2: Identify predisposing factors to developing BCG-related LUTS based on clinical, demographic and voiding parameters The second aim will involve an in-depth pre-treatment analysis of clinical parameters of patients planned for BCG instillation and correlation with the development of BCG local side effects. Prior to receiving BCG induction, patients will be evaluated for baseline demographics, voiding diary, non-invasive uroflowmetry with post-void residual, LUTS and quality of life questionnaires (OAB-V8, ICIQ-LUTSqol, and VAS). Objective outcomes assessment using quantitative measures of TRAIL, IFN, IL-2, and IL-10 levels in the urine before and following BCG induction treatment will be quantitated using a sandwich ELISA and correlated with the severity of LUTS. This prospective cohort will be followed 3 months after completing the induction phase by repeating the clinical assessment described and identify their oncological response to the treatment by urine cytology/cystoscopy.
Confidentiality:
All study outcomes and documents will be considered as confidential. The Investigator and members of his/her research team must not disclose such information without prior written authorization. The anonymity of participating patients must be maintained. Subjects will be identified on CRFs and other documents by their subject number/code, not by name. Documents that identify the subject (eg, the signed informed consent) must be retained in confidence by the Investigator. All data will remain confidential and will be available for access by the investigators only. A unique identifier to keep their identity confidential will identify the participant. The information will be kept for duration of 10 years.
Statement on ethical consideration:
The proposed study protocol ensures that the Sponsor and Investigator adhere to the principles of the GCP guidelines of the ICH, and of the recent version of the Declaration of Helsinki. The study also will be following with local ethics requirements.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Pentosan Polysulfate Na 100Mg Cap | Experimental | Drug: Pentosan Polysulfate Na 100Mg CapDrug 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. |
| Placebo oral capsule | Placebo comparator | Drug: Placebo oral capsuleParticipants 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. |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Adult patients aged 18 to 85 will be eligible for inclusion in this study if all of the following criteria apply:
- 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
Key exclusion criteria (20 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pentosan Polysulfate Na 100Mg CapAlso: ELMIRONParticipants 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. | Drug | Pentosan Polysulfate Na 100Mg Cap |
| Placebo oral capsuleAlso: Sugar pillParticipants 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. | Drug | Placebo oral capsule |
Primary outcome
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.
Time frame: Start of treatment to End of treatment (6weeks)
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
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.
Time frame: Start of treatment to End of treatment (6weeks)
Primary outcome assessment (change from baseline to end of treatment): -Mean change in ICIQ-LUTSqol questionnaire score
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.
Time frame: Start of treatment to End of treatment (6weeks)
Primary outcome assessment (change from baseline to end of treatment): -Mean change in OAB-V8 questionnaire score
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.
Time frame: Start of treatment to End of treatment (6weeks)
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)
6 secondary outcomes
Efficacy of BCG therapy (cancer recurrence and progression assessed by cystoscopy) following co-administration of Pentosan Polysulphate
Time frame: 12 weeks and 24 weeks
Efficacy of BCG therapy (cancer recurrence and progression assessed by urine cytology) following co-administration of Pentosan Polysulphate
Time frame: 12 weeks and 24 weeks
Predisposing factors to developing BCG-related LUTS involving secondary analysis of patient's characteristics pre- and post-treatment
Time frame: 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
Time frame: Start of treatment to End of treatment (6weeks)
Health-related quality of life (HRQoL) assessed by ICIQ-LUTSqol questionnaire
Time frame: Baseline, 6weeks , 12 weeks and 24 weeks
Health-related quality of life (HRQoL) assessed by VAS questionnaire
Time frame: Baseline, 6weeks , 12 weeks and 24 weeks
Results and safety
The study was stopped early (reason given: Given the updated precautions on Elmiron as well as the risk benefit profile, we have decided to terminate the study.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2022.
- Background: PubMed 22014799Brausi 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.
- Background: PubMed 19969411Gontero 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.
- Background: PubMed 1538436Lamm 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.
- Background: PubMed 23910233Brausi 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.
- Background: PubMed 8558640de 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.
- Background: PubMed 15150089Ludwig 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.
- Background: PubMed 20034729Sylvester 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.
- Background: PubMed 9120912Vegt 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.
- Background: PubMed 16890660Colombel 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.
- Background: PubMed 23141049Oddens 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.
- Background: PubMed 16706553Anderson 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.
- Background: PubMed 16986030Teichman JM. The role of pentosan polysulfate in treatment approaches for interstitial cystitis. Rev Urol. 2002;4 Suppl 1(Suppl 1):S21-7.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lysanne Campeau, MD, PhD principal investigator
SirMortimer JGH
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pentosan Polysulfate Na 100Mg Cap in people with Lower Urinary Tract Symptoms and Bladder Carcinoma, run by Sir Mortimer B. Davis - Jewish General Hospital at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 4 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Given the updated precautions on Elmiron as well as the risk benefit profile, we have decided to terminate the study.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: Start of treatment to End of treatment (6weeks)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03549650, which also lists 22 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2022.