BRAVO Study: Surgery vs. Immunotherapy – Which treatment is best in bladder cancer?
| ISRCTN | ISRCTN12509361 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12509361 |
| Secondary identifying numbers | 31724 |
- Submission date
- 30/08/2016
- Registration date
- 06/09/2016
- Last edited
- 27/09/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English Summary
Contact information
Ms Heather Poad
Public
Public
Clinical Trials Research Unit (CTRU)
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom
| Phone | +44 113 343 4033 |
|---|---|
| ctru-bravo@leeds.ac.uk |
Prof James Catto
Scientific
Scientific
Academic Units of Urology and Molecular Oncology
Sheffield Cancer Research Centre
University of Sheffield
GU22, G Floor
The Medical School
Beech Hill Road
Sheffield
S10 2RX
United Kingdom
 ORCID ID |
0000-0003-2787-8828 |
|---|---|
| Phone | +44 114 271 2295 |
| j.catto@sheffield.ac.uk |
Study information
| Study design | Randomized; Both; Design type: Treatment, Screening, Process of Care, Drug, Vaccine, Immunotherapy, Surgery, Qualitative |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | BRAVO: High risk bladder cancer: A randomised controlled feasibility study of radical cystectomy against intra-vesical immunotherapy |
| Study acronym | BRAVO |
| Study hypothesis | The aim of this study is to investigate the feasibility of conducting a definitive phase III randomised controlled trial evaluating the efficacy of radical cystectomy against intra-vesical immunotherapy in the treatment of aggressive bladder cancer when found at an early stage. |
| Ethics approval(s) | Yorkshire & The Humber - South Yorkshire Research Ethics Committee, 12/08/2016, ref: 16/YH/0268 |
| Condition | Specialty: Cancer, Primary sub-specialty: Bladder; UKCRC code/ Disease: Cancer/ Malignant neoplasms of urinary tract |
| Intervention | Participants will be randomised on a 1:1 basis to receive either RC or mBCG. A computer-generated adaptive minimisation algorithm that incorporates a random element will be used to ensure the treatment groups are well balanced for the following characteristics: 1. Age (<75, >=75) 2. Sex (male, female) 3. Cancer centre (Sheffield, Leeds, Bradford, Wakefield, Hull, Newcastle) 4. Tumour stage (pTa/pTis, pT1) 5. Presence of CIS (Yes, No) 6. Previous low risk bladder cancer (Yes, No) mBCG group: Within this study, a maintenance BCG regimen is to be used. The regimen requires that at least 12 months of BCG treatment is given (starting with and including the initial dose). Treatment beyond one year is as per standard care. Induction BCG: Maintenance treatment should start within 2-4 weeks of randomisation (administration once a week for six weeks). Delays and deferrals due to complications or toxicity are common and allowed within this study. BCG induction should include at least 4 doses of BCG. The induction treatment should be completed within 10 weeks from the date of the first dose. First check cystoscopy: Following induction BCG, a check cystoscopy should be performed after a 6-week break. Within this study, the first cystoscopy should be performed using a rigid cystoscope and should include the obtainment of bladder washings or voided urinary cytology, and at least one biopsy of the bladder urothelium (either the tumour scar and/or red areas within the bladder). Fluorescence or narrow band imaging may be used, as per local hospital protocols. Histological review of the bladder biopsies and urinary cells should be performed to determine the presence or absence of BC. In the absence of carcinoma or in the presence of high risk (high grade or grade 3) non-muscle invasive bladder cancer (HRNIMBC) then the patient may continue with mBCG. The presence of an invasive BC requires the cessation of mBCG and a clinical consultation to discuss radical treatment or other treatment options. First BCG maintenance: Following cystoscopy, and after a wait of two weeks (and the cessation of haematuria), then three weeks of intravesical BCG is administered according to hospital practice. Unlike subsequent BCG cycles these first doses of BCG maintenance should take place in the presence of HRNIMBC. After an eight week break from the last BCG dose either a flexible or rigid cystoscopy should be carried out. Urinary cells (either voided cytology or bladder washings) should be obtained. A biopsy of the bladder lining is not mandated after the first rigid cystoscopy. Subsequent BCG maintenance: As per the first BCG maintenance doses with the exception that if high risk NMIBC is detected mBCG should be discontinued and a clinical consultation should take place to discuss radical treatment or other treatment options. mBCG and surveillance within this feasibility study ceases after one year post randomisation, or three months after the last patient is randomised. The patient should continue with their care according to standard hospital practice and applicable guidelines. Follow up data will be collected for each cycle of treatment at the cystoscopy visits Radical Cystectomy: Surgery can be performed by either an open, laparoscopic or robotic route as per usual practice within that unit and as per accreditation. Minimally invasive or open surgery are acceptable, however surgeons should avoid undertaking surgery within this study whilst on their learning curve for a modality. In this study surgery should take place within 8 weeks of randomisation. Radical cystectomy should include removal of adjacent organs. In males, this includes the prostate and seminal vesicles. In females, this should include a section of adjacent anterior vaginal wall, the uterus, cervix and fallopian tubes and, if no bladder reconstruction is planned, the urethra. Oophorectomy is optional, as per local practice and individualised for each patient. Exceptions to this surgical plan are acceptable with prior approval from CTRU. Within this study, pelvic lymphadenectomy is mandated. The template for lymphadenectomy should include, at least, the regional lymph nodes up to the level of the ureteric crossing of the common iliac vessels. This includes the obturator fossa, the external iliac and internal iliac nodes. A more extended lymphadenectomy is acceptable. Excised lymphatic tissue should be submitted for histological analysis. Reconstruction through all routes is acceptable. It is anticipated this will mostly include ileal conduit and orthotopic neobladder. As for surgeon accreditation, the pattern of reconstruction should mirror the cases within the submitted RC cases. Perioperative care is to be carried out as per ERAS protocols and standard practice. Post-operative care is to be carried out as per standard practice. Follow up frequency will be in line with current NHS practice, with data collected at routine follow up visits at 3, 6 and 12 months post randomisation +/- 2 weeks. An intravenous urogram (IVU) is carried out at approximately 2-4 weeks post RC and should be carried out per standard care. For both study arms, follow up imaging by CT scan will be performed as per local practice and for the study should be arranged at one year post randomisation (+/-2 weeks). Wherever possible the one year post randomisation CT scan should be in the above time window to allow comparison between the two trial arms. Participants will be asked to complete questionnaires at baseline, 3 months, 6 months and at 12 months post-randomisation or until the end of the study follow-up period (one year post randomisation or three months after the last participant has been randomised if earlier). |
| Intervention type | Procedure/Surgery |
| Primary outcome measure | 1. Eligibility rate is reportedas the number of patients screened for entry to the study and considered eligible within the 18 month recruitment period 2. Recruitment rate is reported as the number of eligible patients randomised within the 18 month recruitment period |
| Secondary outcome measures | 1. Uptake of allocated treatment is reported as the number of randomised participants starting their allocated treatment within the 21 month follow-up period 2. Treatment compliance is reported as the number of randomised participants complying with their allocated treatment regimen within the 21 month follow-up period 3. Withdrawal rate is reported as the number of randomised participants withdrawing from trial procedures within the 21 month follow-up period 4. Loss-to-follow-up rate is reported as the number of randomised participants for whom follow-up data cannot be collected within the 21 month follow-up period 5. Quality of life completion rate is reported as the number of randomised participants for whom quality of life data is available at baseline, 3, 6 and 12 months post-randomisation 6. Quality of life is measured by the EQ5D, EORTC QLQ-C30, EORTC QLQ-NMIBC24, QLQ-BLM-30 at baseline, 3, 6 and 12 months post-randomisation 7. Survival is measured at 12 months post-randomisation 8. Reasons participants / clinicians decline study entry is measured by a qualitative sub-study during the 18 month recruitment period |
| Overall study start date | 01/10/2015 |
| Overall study end date | 30/09/2018 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 60; UK Sample Size: 60 |
| Total final enrolment | 50 |
| Participant inclusion criteria | Inclusion criteria as of 23/03/2017: 1. Male or female aged ≥ 18 years old. 2. Patients with a new diagnosis of high-risk (high grade or grade 3) non-muscle invasive urothelial carcinoma (staged as either pTa, pTis or pT1). Patients with previous low grade NMIBC are suitable. 3. The tumour is either solely urothelial cell carcinoma or has urothelial cell carcinoma as the majority histological component. 4. In addition to the HRNMIBC bladder tumour, there needs to be one or more risk factor from: 4.1. Presence of pTis in the bladder 4.2. Presence of pTis in the prostatic urethra 4.3. Lymphovascular invasion 4.4. Vascular invasion 4.5. Residual Grade 3/High grade UCC on re-resection (or initial TURBT if no re-resection) 4.6. Multifocal disease (>3 tumours at initial resection) 4.7. Young age (<65 years old) 4.8. Initial tumour Size > 3cm (or >5g in histology specimen) 4.9. pT1 stage 5. Either re-resection of the bladder (following the initial diagnostic TURBT) within 3 months prior to randomisation confirming the absence of muscle invasion OR 5.1. The initial diagnostic TURBT biopsy contains muscle, AND 5.2. The radiological and pathological stage assessment are in agreement regarding stage and absence of muscle invasion, AND 5.3. A re-resection is not appropriate in the opinion of the treating clinician AND 5.4. The initial TURBT is within 3 months prior to randomisation 6. CT or cross sectional imaging of the abdomen and pelvis within the year prior to starting treatment. 7. Imaging of the lungs and thorax within 3 months prior to randomisation. 8. Suitable and fit for both mBCG and RC as determined by the treating clinician 9. Central MDT pathological review agrees diagnosis 10. If female, must be (as documented in patient notes): 10.1. Postmenopausal (no menses for 12 months without an alternative medical cause), or 10.2. Surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or 10.3. Using acceptable contraception2 (which must be continued for 7 days after the last dose of BCG or until RC is carried out). Women of child bearing potential must undergo a pregnancy test before randomisation. 10.4. Not breast feeding Original inclusion criteria: 1. Male or female aged ≥ 18 years old 2. Patients with a new diagnosis of high-risk (high grade or grade 3) non-muscle invasive urothelial carcinoma (staged as either pTis, pTa or pT1). Patients with previous low grade NMIBC are suitable 3. The tumour is either solely urothelial cell carcinoma or has urothelial cell carcinoma as the majority histological component 4. In addition to the HRNMIBC bladder tumour, there needs to be one or more risk factor from: 4.1. Presence of pTis in the bladder 4.2. Presence of pTis in the prostatic urethra 4.3. Lymphovascular invasion 4.4. Vascular invasion 4.5. Residual Grade 3/High grade UCC on re-resection 4.6. Multifocal disease (>3 tumours at initial resection) 4.7. Young age ( 3cm (or >5g in histology specimen) 4.8. pT1 stage 5. Re-resection of the bladder (following the initial diagnostic TURBT) within 3 months prior to randomisation confirming the absence of muscle invasion 6. Suitable and fit for both mBCG and RC as determined by the treating clinician 7. Central MDT pathological review agrees diagnosis 8. If female, must be (as documented in patient notes): 8.1. Postmenopausal (no menses for 12 months without an alternative medical cause) 8.2. Surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy) 8.3. Using acceptable contraception (which must be continued for 7 days after the last dose of BCG or until RC is carried out) Women of child bearing potential must undergo a pregnancy test before randomisation. d. not breast feeding |
| Participant exclusion criteria | 1. Solely non-urothelial or variant urothelial pathology 2. Unable or not willing to give informed consent 3. Previous high risk (high grade or grade 3) NMI or invasive bladder cancer 4. Any previous treatment with intravesical BCG 5. Any other malignancy (excluding non-melanomatous skin cancer, low-risk prostate cancer and prior low risk bladder cancer) |
| Recruitment start date | 01/10/2016 |
| Recruitment end date | 31/03/2018 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom
Sheffield
S10 2JF
United Kingdom
Bradford Royal Infirmary
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom
Bradford
BD9 6RJ
United Kingdom
Castle Hill Hospital
Castle Road
Cottingham
Hull
HU16 5JQ
United Kingdom
Cottingham
Hull
HU16 5JQ
United Kingdom
Freeman Hospital
Freeman Road
High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom
High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom
Pinderfields Hospital
Aberford Road
Wakefield
WF1 4DG
United Kingdom
Wakefield
WF1 4DG
United Kingdom
St James’ University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom
Leeds
LS9 7TF
United Kingdom
Airedale General Hospital
Skipton Road
Keighley
BD20 6TD
United Kingdom
Keighley
BD20 6TD
United Kingdom
Barnsley Hospital NHS Foundation Trust
Gawber Road
Barnsley
S75 2EP
United Kingdom
Barnsley
S75 2EP
United Kingdom
Calderdale Royal Hospital
Salterhebble
Halifax
HX3 0PW
United Kingdom
Halifax
HX3 0PW
United Kingdom
Huddersfield Royal Infirmary
Acre Street
Huddersfield
HD3 3EA
United Kingdom
Huddersfield
HD3 3EA
United Kingdom
Chesterfield Royal Hospital
Chesterfield Road
Callow
Chesterfield
S44 5BL
United Kingdom
Callow
Chesterfield
S44 5BL
United Kingdom
Doncaster Royal Infirmary
Armthorpe Road
Doncaster
DN2 5LT
United Kingdom
Doncaster
DN2 5LT
United Kingdom
Harrogate District Hospital
Lancaster Park Road
Harrogate
HG2 7SX
United Kingdom
Harrogate
HG2 7SX
United Kingdom
West Cumberland Hospital
Homewood Road
Whitehaven
CA28 8JH
United Kingdom
Whitehaven
CA28 8JH
United Kingdom
Cumberland Infirmary
Newton Road
Carlisle
CA2 7LT
United Kingdom
Carlisle
CA2 7LT
United Kingdom
Scunthorpe General Hospital
Cliff Gardens
Scunthorpe
DN15 7BH
United Kingdom
Scunthorpe
DN15 7BH
United Kingdom
Rotherham Hospital
Moorgate Road
Rotherham
S60 2UD
United Kingdom
Rotherham
S60 2UD
United Kingdom
Sponsor information
Sheffield Teaching Hospitals NHS Foundation Trust
Hospital/treatment centre
Hospital/treatment centre
Northern General Hospital
Herries Road
Sheffield
S5 7AU
England
United Kingdom
"ROR" |
https://ror.org/018hjpz25 |
|---|
Funders
Funder type
Charity
Yorkshire Cancer Research
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/09/2020 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Planned dissemination through peer reviewed scientific journal articles, internal reports, and conference presentations. |
| IPD sharing plan | Not provided at time of registration |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 11/08/2017 | 27/11/2020 | Yes | No |
| Results article | results | 20/01/2021 | 17/08/2021 | Yes | No |
| Plain English results | 22/09/2022 | No | Yes | ||
| HRA research summary | 28/06/2023 | No | No | ||
| Other publications | 26/09/2024 | 27/09/2024 | Yes | No |
Editorial Notes
27/09/2024: Publication reference added.
22/09/2022: Link to plain English results added.
17/08/2021: Publication reference added.
27/11/2020: Publication reference added.
19/09/2019: The following changes have been made:
1. The final enrolment number has been added.
2. The intention to publish date has been changed from 30/09/2019 to 30/09/2020.
07/08/2018: The intention to publish date was changed from 30/09/2018 to 30/09/2019
23/03/2017: The following updates have been made to the trial record:
1. The overall trial start date has been updated from 01/06/2015 to 01/10/2015
2. The inclusion criteria have been updated
08/12/2016: Cancer Help UK lay summary link added to plain English summary field.
