E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-Muscle-Invasive Bladder Cancer |
Nicht-Muskel-invasiver Blasenkrebs |
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E.1.1.1 | Medical condition in easily understood language |
superficial bladder cancer |
oberflächlicher Blasenkrebs |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether Synergo® RITE + MMC treatment is efficacious as second-line therapy for NMIBC patients with BCG refractory CIS. The study will be deemed successful if the recurrence-free survival probability after 12 months is at least 30%.
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E.2.2 | Secondary objectives of the trial |
To determine the response rate for patients with BCG refractory CIS within 6 months after first treatment |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
To determine: • progression-free survival time, • recurrence-free survival time, • bladder preservation rate, • overall survival time, and • disease-specific survival time
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E.3 | Principal inclusion criteria |
1. Patients with CIS, with or without coexisting papillary NMIBC, who either: a. fail to achieve a disease-free status by 6 months after initial BCG therapy, with maintenance or re-induction at 3 months due to either persistent or rapidly recurrent disease, or b. experience a worsening in NMIBC state following initial BCG therapy presenting with a new NMIBC instance, other than TaLG. 2. All clinical, intra-operative and pathological items for the EAU risk stratification must be documented including a bladder map. 3. Patients with papillary disease must have undergone a repeat TUR: a. if the initial TUR was incomplete. b. if there was no muscle in the specimen after the initial TUR (except in TaLG tumors). c. in all T1 tumors. TUR of T1 sites must include muscle. d. in all HG tumors > 3cm. 4. CT-IVU or IVU confirmation of absence of tumor(s) in the upper tract, kidney and ureters performed within 6 months before the treatment initiation in selected cases as recommended in latest EAU guidelines published prior to screening. If IVU protocol not available or contrast allergy/poor renal function preclude such imaging, then non-contrast CT or MRI of the abdomen/pelvis within the same timeframe will suffice. 5. Visual inspection to exclude urothelial carcinoma (UC) in the urethra during cystoscopy. 6. Biopsy of the prostatic urethra in male patients prior to recruitment to exclude UC of the prostatic urethra, in patients with: a. tumor of trigone, b. tumor of bladder neck, or c. abnormal prostatic urethra 7. All patients must have urine cytology collected from either voided urine or bladder wash within the screening period prior to recruitment. 8. All patients must have prostatic urethral biopsies collected within the screening period prior to recruitment. 9. Age ≥ 18 yrs. 10. Normal kidneys and ureters. 11. Pre-treatment hematology and biochemistry values within the limits: a. Hemoglobin ≥ 10 g/dl b. Platelets ≥ 150 x 109/L c. WBC ≥ 3.0 x 109/L d. ANC ≥ 1.5 x 109/L e. Serum creatinine < 1.5 x ULN f. SGOT < 1.5 x ULN g. SGPT < 1.5 x ULN h. Alkaline phosphatase < 1.5 x ULN 12. Negative pregnancy test for women of childbearing potential. 13. A life expectancy at least of the duration of the study (up to 13 months). 14. Patients unfit or unwilling to have a full or partial (if appropriate) cystectomy. 15. Signed informed consent.
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E.4 | Principal exclusion criteria |
1. Non-UC tumor of the urinary tract. 2. Upper tract and intramural tumors (e.g., in ostium). 3. Positive selective cytology from the upper tract. 4. History of stage > T1 UC. 5. Papillary tumor in repeat TUR in patients diagnosed with HG > 3cm and/or T1 in the initial TUR. 6. Papillary tumor ≥ T1 in repeat TUR 7. Known or suspected reduced bladder capacity. Patients will have a US estimation of maximum bladder capacity or void spontaneously the maximum they can retain in their bladder, and this will be used to determine urine volume. A minimum volume of 250 ml is required. 8. Bleeding disorder. 9. Macrohematuria of ≥ 250 RBC/uL or equivalent (e.g., > “+++” erythrocytes in a dipstick analysis) within 4 weeks before treatment start. 10. Lactating women. 11. Women of childbearing potential unwilling or unable to use adequate contraception if sexually active. 12. More than a maintenance dose of oral corticosteroids (maintenance dose is defined as the same dose regimen over the past 6 months for a condition requiring continual corticosteroid treatment) or patients with an immunocompromised state for any reason. 13. More than low-dose methotrexate (>17.5 mg once a week). 14. Other malignancy within the past 5 years, except: non-melanomatous skin cancer cured by excision, surgically treated carcinoma in situ of the cervix or ductal CIS (DCIS)/lobular CIS (LCIS) of the breast or stable prostate cancer (under active surveillance or hormone control) with a life expectancy of more than 5 years. 15. Any known allergy (e.g., to MMC) or adverse event that would prevent a prospective study participant from receiving the study treatment. 16. Known untreated urethral strictural disease or bladder neck contracture or any other condition that may prevent catheterization with 21F catheter. Patients may undergo dilation or urethral incision before entering the study. 17. Bladder diverticula with cumulative diameter > 1cm or tumor in a diverticulum. 18. UTI at any time within 4 weeks before treatment start. 19. Significant urinary incontinence (spontaneous, requiring use of pads). 20. History of pelvic irradiation. 21. Patients with implanted electronic devices (such as cardiac pacemakers) unless they receive permission from their treating physician (e.g., cardiologist) and are monitored by a treating physician during the treatment session. 22. Participation in another study, unless discussed with and approved by the study manager
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the time to event. The following will constitute study events: i. failure to achieve disease-free state by 6 months, or ii. having attained a disease-free state by 6 months, failure to remain disease-free. iii. new occurrence of a T1 and/or high-grade lesion at 3 months control Patients experiencing a new occurrence of low grade Ta will be allowed to continue in the study; such an occurrence will not constitute an event. These patients will undergo tumor resection and continue in the study. The study will be deemed successful if the recurrence-free survival probability after 12 months is at least 30%.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cystoscopy at the end of the treatment and at 3, 6, 9 and 12 months of follow up |
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E.5.2 | Secondary end point(s) |
Complete response rate (CRR) by 6 months after first treatment. A satisfactory outcome will be if the CRR at 6 months is at least 40%. Exploratory: • Progression-free survival time. • Recurrence-free survival time. • Bladder preservation rate. • Overall survival time. • Disease-specific survival time.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Before each new instillation: the patient will report any side effect occurred from the last instillation. After the instillation: - the patient will report any side effect occurred during the present instillation. - healthcare professional will report any other side effect occurred during the present instillation. The quality of life questionnaire will be completed by the patients before receiving adjuvant treatment and repeated in the last study visit. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Bulgaria |
Israel |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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For the purpose of Clinical Trial Authorization (CTA) under the European Union Directive 2001/20/EC, the trial is deemed to have ended when the last patient recruited has been followed-up for at least 2 years. This will allow for sufficient data to be collected for the completion of the final report. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |