Condition category
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status

Plain English Summary

Lay summary under review with external organisation.

Trial website

Contact information



Primary contact

Ms Heather Poad


Contact details

Clinical Trials Research Unit (CTRU)
Leeds Institute of Clinical Trials Research
University of Leeds
United Kingdom
+44 113 343 4033



Additional contact

Prof James Catto


Contact details

Academic Units of Urology and Molecular Oncology
Sheffield Cancer Research Centre
University of Sheffield
G Floor
The Medical School
Beech Hill Road
S10 2RX
United Kingdom
+44 114 271 2295

Additional identifiers

EudraCT number number

Protocol/serial number


Study information

Scientific title

BRAVO: High risk bladder cancer: A randomised controlled feasibility study of radical cystectomy against intra-vesical immunotherapy



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

12/08/2016, ref: 16/YH/0268

Study design

Randomised; Both; Design type: Treatment, Screening, Process of Care, Drug, Vaccine, Immunotherapy, Surgery, Qualitative

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet


Specialty: Cancer, Primary sub-specialty: Bladder; UKCRC code/ Disease: Cancer/ Malignant neoplasms of urinary tract


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



Drug names

Primary outcome measures

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 trial start date


Overall trial end date


Reason abandoned


Participant 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 type


Age group




Target number of participants

Planned Sample Size: 60; UK Sample Size: 60

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


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

Royal Hallamshire Hospital
Glossop Road
S10 2JF
United Kingdom

Trial participating centre

Bradford Royal Infirmary
Duckworth Lane
United Kingdom

Trial participating centre

Castle Hill Hospital
Castle Road Cottingham
HU16 5JQ
United Kingdom

Trial participating centre

Freeman Hospital
Freeman Road High Heaton
Newcastle Upon Tyne
United Kingdom

Trial participating centre

Pinderfields Hospital
Aberford Road
United Kingdom

Trial participating centre

St James’ University Hospital
Beckett Street
United Kingdom

Trial participating centre

Airedale General Hospital
Skipton Road
BD20 6TD
United Kingdom

Trial participating centre

Barnsley Hospital NHS Foundation Trust
Gawber Road
S75 2EP
United Kingdom

Trial participating centre

Calderdale Royal Hospital
United Kingdom

Trial participating centre

Huddersfield Royal Infirmary
Acre Street
United Kingdom

Trial participating centre

Chesterfield Royal Hospital
Chesterfield Road Callow
S44 5BL
United Kingdom

Trial participating centre

Doncaster Royal Infirmary
Armthorpe Road
United Kingdom

Trial participating centre

Harrogate District Hospital
Lancaster Park Road
United Kingdom

Trial participating centre

West Cumberland Hospital
Homewood Road
CA28 8JH
United Kingdom

Trial participating centre

Cumberland Infirmary
Newton Road
United Kingdom

Trial participating centre

Scunthorpe General Hospital
Cliff Gardens
DN15 7BH
United Kingdom

Trial participating centre

Rotherham Hospital
Moorgate Road
S60 2UD
United Kingdom

Sponsor information


Sheffield Teaching Hospitals NHS Foundation Trust

Sponsor details

Northern General Hospital
Herries Road
S5 7AU
United Kingdom

Sponsor type

Hospital/treatment centre



Funder type


Funder name

Yorkshire Cancer Research

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit


United Kingdom

Results and Publications

Publication and dissemination plan

Planned dissemination through peer reviewed scientific journal articles, internal reports, and conference presentations.

Intention to publish date


Participant level data

Not expected to be available

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes