|- candidate number||14927|
|- NTR Number||NTR4011|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||3-jun-2013|
|- Secondary IDs||EAU RF 2008-01 Eudract 2010-019181-91|
|- Public Title||Treatment of High Grade Non-Muscle Invasive Urothelial Carcinoma of the Bladder by Standard Number and Dose of Intravesical BCG Instillations Versus Reduced Number of Intravesical Instillations with Standard Dose of BCG. |
A European Association of Urology Research Foundation Randomised Phase III Clinical Trial
|- Scientific Title||Standard BCG vs Reduced Frequency BCG|
|- hypothesis||Intravesical instillation of BCG is a widely accepted strategy to prevent recurrence of non muscle invasive bladder cancer. The most accepted treatment schedule is induction of BCG: weeks 1 through 6 plus maintenance (weeks 1,2,3) at months 3,6 and 12, but it is unknown how many administrations are really necessary. |
Scientific evidence prones to the hypothesis that after an initial sensitization to BCG antigens has occurred the number of instillations can be reduced for a proper anamnestic immune response resulting in similar clinical efficacy and potentially less side-effects and costs.
|- Healt Condition(s) or Problem(s) studied||Non-Muscle Invasive Urothelial Carcinoma of the Bladder.|
|- Inclusion criteria||1. Presence of high grade (Ta-T1) urothelial carcinoma of the bladder with or without CIS|
1.a. Tumors can be primary or recurrent;
1.b. Tumors can be single or multiple.
2. Re-TUR should be performed at weeks 4-6 after initial resection, which must include the deep resection or cold cup biopsy (deep enough to obtain muscle tisssue) of the initial tumor site(s).
3. All visible tumors must be completely resected.
4. Random biopsies either at initial or re-TUR should be performed prior to any induction BCG course from specific areas of the bladder.
5. Early postoperative (within 6 hours of resection) single dose chemotherapy is allowed after the first resection. However, it should not be given after re-TUR if the patient is considered eligible for this study.
6. Prior multi-instillation intravesical chemotherapy is allowed, provided that the last instillation was completed 3 months before randomisation in this study.
7. Signed and dated informed consent form.
|- Exclusion criteria||1. Any previous intravesical BCG therapy;|
2. Presence of primary CIS only;
3. Presence of histopathologically proven muscle invasive urothelial carcinoma of the bladder at first or re-TUR surgical specimens;
4. Patients with incomplete resection of visible tumors;
5. Absence of muscle tissue in the re-TUR specimen(s);
6. Presence of any upper urinary tract tumors at any time;
7. Presence of any other histological type of resected tumor other than urothelial carcinoma on the first or second resection;
8. Presence of another malignancy other than the basal cell carcinoma of the skin;
9. Presence of pregnancy or lactation;
10. Presence of active tuberculosis, any form of immunodeficiency (eg HIV + serology, transplant recipients) and/or any other contraindication of BCG therapy;
11. Patients with a WHO performance score of > 2 or ASA grade 4-5;
12. Patients who have received any systemic cytostatic agents within the last 3 months;
13. Patients older than 80 years of age;
14. Patients with uncontrollable UTI;
15. Patients with White Blood Count (WBC) below 3.0 x 10 (9)/l or platelet count below 100 x 10 (9)/l at baseline;
16. Renal and hepatic function values exceeding two times the upper normal value of the local laboratory.
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||24-mei-2013|
|- planned closingdate||24-mei-2019|
|- Target number of participants||1000|
|- Interventions||This is a multicentre prospective, randomized, parallel group, not blinded, trial to compare the efficacy and safety of two different adjuvant treatment schedules:|
1) Induction cycle BCG-full dose; weeks 1 through 6 plus maintenance cycles at months 3, 6 and 12 (wks 1,2,3); total 15 full dose BCG instillations;
2) Induction cycle BCG-full dose (reduced frequency); weeks 1,2, and 6 plus maintenance cycles at months 3, 6 and 12 (wks 1,3); total 9 full dose BCG instillations.
BCG intravesical instillation therapy is registered as adjuvant treatment for the prevention of recurrence of NMIBC and can be considered as standard treatment for the type of patients requested in this trial. For each individual centre, one of the three locally available BCG strains in Europe will be used: BCG Tice, BCG Medac or BCG Connaught. After the first transurethral resection (TUR), patient undergoes re-TUR at weeks 4-6 after initial resection.
Treatment with the randomised treatment schedule will start 2 weeks after and no later than 6 weeks after the last resection. The first maintenance therapy should be given 3 months after the last instillation of the induction BCG cycle (week 6) and hereafter at months 6 and 12 after the last instillation of the induction BCG cycle. Standard Dose Instillations will take place with 1 vial of BCG.
Follow up cystoscopy and cytology will be done every 3 months the first 2 years; bi-annually until the fifth year and yearly thereafter.
|- Primary outcome||Time to first recurrence|
|- Secondary outcome||- Number and grade of recurrent tumors;|
- Rate of progression to a higher stage (T2 or higher);
- Incidence and severity of side effects.
|- Timepoints||The timing of measurement of the outcomes are variable and will be done each time a patient comes into the clinic for A) control of the disease or B) for the instillation of adjuvant BCG treatment (See INTERVENTIONS).
When the patient comes for the instillation of adjuvant BCG treatment, the incidence and severity of side effects will be measured or registered. Also during subsequent follow up visits, side effects that have not resolved will be measured or registered.
When the patient comes for control of the disease which is cystoscopy and cytology and the investigator suspects a recurrent bladder cancer, the patient will be scheduled for transurethral resection of the suspect lesion. If the suspect lesion is pathologically confirmed bladder cancer, the time of first recurrence, number and grade of recurrent tumors and progression to a higher stage can be determined.
|- Trial web site||www.uroweb.org/research/projects|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES|| Wim P.J. Witjes|
|- CONTACT for SCIENTIFIC QUERIES|| Wim P.J. Witjes|
|- Sponsor/Initiator ||European Association of Urology|
(Source(s) of Monetary or Material Support)
|EAU Research Foundation, National Grants: Deutsche Krebshilfe|
|- Brief summary||A total of 1000 patients with high grade Ta-T1 urothelial carcinoma of the bladder with or without CIS and who did not receive any BCG intravesical instillation therapy are to be recruited from urology departments in European hospitals participating in this study.|
The primary objective of this study is to identify if reduced number of BCG instillations are not inferior to standard number and dose intravesical BCG treatment in patients with high grade NMIBC. The primary endpoint for inferiority analysis is time to first recurrence.
The secondary objectives are to identify if number and grade of recurrent tumors, rate of progression to a higher stage (T2 or higher) of the disease and safety, specifically the presence of treatment related toxicity > grade 2 differ between the two study arms.
|- Main changes (audit trail)|
|- RECORD||3-jun-2013 - 14-jun-2013|