A Phase III Randomised Control Clinical Trial of Radiotherapy With Radiosensitisation Versus Intravesical Bacillus Calmette-Guerin Therapy for High-risk Non-muscle Invasive Bladder Cancer. (TRAIN)

November 25, 2025 updated by: The Christie NHS Foundation Trust

TRAIN - A Phase III Randomised Control Clinical Trial of Radiotherapy With Radiosensitisation Versus Intravesical Bacillus Calmette-Guerin Therapy for High-risk Non-muscle Invasive Bladder Cancer.

In the UK 20,000 people develop urothelial bladder cancer each year with 75-80% having Non-Muscle Invasive Bladder Cancer (NMIBC). The current standard of care for patients with High Risk-NMIBC (HR-NMIBC) is either surgery to remove the tumour (transurethral resection of bladder tumour; TURBT) followed by BCG (Bacillus Calmette Guérin, an immunotherapy drug) given directly into the bladder, or surgery to remove the bladder (cystectomy). BCG is given weekly for six weeks followed by maintenance treatment up to 3 years. However, in up to 50% of patients their cancer returns (recurrence) or gets worse (progression) after BCG and 25% stop treatment due to side effects. Globally BCG supply has been restricted in recent years has increased HR-NMIBC recurrence rates and costs. Improved treatments are required, to prevent recurrence, progression and cystectomy, and mitigate the effects of unpredictable supply.

Trimodality treatment (TMT) is maximal TURBT + radiotherapy + a radiosensitiser (gemcitabine, mitomycin C/fluorouracil or carbogen/nicotinamide) and is an equivalent alternative treatment to cystectomy for muscle-invasive bladder cancer (MIBC). TMT is not routinely used for HR-NMIBC. A study found that 54% of HR-NMIBC patients who received TMT did not have recurrence within 5 years. Modern radiotherapy is expected to further improve outcomes and minimise side-effects.

Patients will be randomised 1:1 to BCG or radiotherapy with radiosensitisation. Patients randomised to the experimental arm will receive 55Gy in 20 fractions. Investigators can then choose from three different options for the radiosensitiser. TRAIN will test if radiotherapy with radiosensitisation improves outcomes for people with HR-NMIBC compared to BCG.

TRAIN will recruit 328 patients with HR-NMIBC following maximal TURBT. All patients will be followed up for a minimum of two years to record their response to treatment.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

328

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Diagnosed with histologically confirmed grade 3 T1 N0 M0 transitional cell carcinoma, OR carcinoma in situ of the bladder (and N0 M0), OR both, with detrusor muscle present in the biopsy specimen if T1 disease (or a repeat resection that does contain muscle that is clear)
  • Suitable for BCG treatment
  • Suitable for radiotherapy and radiosensitisation according to the schedule of administration outlined in the Radiotherapy Planning Guidance document.
  • Life expectancy over 12 months
  • ECOG performance status 0 - 2
  • Age >=16 years
  • Provided written informed consent

Exclusion Criteria:

  • MDT selected patients with HR-NMIBC who are deemed best suited for primary cystectomy (patients that have had this treatment recommendation but then decline cystectomy remain eligible for TRAIN)
  • Previous radiotherapy to the pelvis
  • Previous intravesical therapy
  • Poor bladder function (IPSS >16)
  • A recent or current other cancer. Current non-melanoma skin cancer, cervical carcinoma in situ or localized prostate cancer not requiring current treatment are permissible, as is a history of a separate other malignancy having completed all active treatment ≥2 years previously and without evidence of relapse
  • Pre-existing medical conditions that preclude treatment options in either trial arm
  • Patient currently recruited to another interventional trial or participation within an interventional clinical trial within 3 months of the point of registration within TRAIN.
  • Pregnant or breast-feeding
  • Not able to use appropriate adequate effective contraception during and for 3 months after the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Control Arm: BCG
This arm is standard of care for this patient group. A standard protocol of 6 weekly intravesical installations, followed by 3 weekly instillations at approximately 3, 6, 12, 18, 24, 30 months and 36 months (depending on toxicity). Stock is taken and given per local hospital guildlines.
Other: BCG
BCG protocol of 6 weekly intravesical instillations, followed by 3 weekly instillations at 3, 6, 12, 18, 24, 30, 36 months.
Experimental: Experimental Arm: Radiotherapy with Radiosentiser drugs.

Patients randomised to the radiotherapy arm will receive a hypofractionated schedule of external beam radiotherapy with a regimen of 55Gy in 20 fractions given once daily Monday to Friday over 4 weeks. Radiotherapy will be delivered with a conventional or 3D conformal technique with an empty bladder. It will be administered concurrently with a radiosensitiser (detailed below) selected by the treating physician according to local institutional practice.

Radiosensitiser will be selected as one option from the following:

  • Gemcitabine 75-100mg/m2 administered once a week during a four-week radiotherapy course. Cycle 1 will be given on the first radiotherapy day, to a planned total of 4 cycles. 2-4 hours prior to radiotherapy
  • 5-FU and Mitomycin C - Fluorouracil 500mg/m2 Days 1-5 and 16-20 via continuous infusion. Mitomycin C 12mg/m2 Day 1 via intravenous infusion
  • Carbogen and nicotinamide (CON) - 2% CO2 and 98% O2 Carbogen will be delivered through a closed breathing system with
Radiation: radiotherapy
Radiotherapy - 55Gy in 20 fractions treating once daily Monday to Friday over 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To compare event-free survival between BCG and radiotherapy with radiosensitisation.
Time Frame: From baseline to at least 96 weeks after initial of treatment.
Event-free survival is defined as recurrence of CIS or high-risk non-muscle invasive papillary tumour, continued presence of HR NMIBC even after treatment completion, progression to muscle-invasive disease, distant metastatic bladder cancer, cystectomy (for any reason) or death from any cause.
From baseline to at least 96 weeks after initial of treatment.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To determine the difference between BCG and radiotherapy in terms of patient-reported symptoms.
Time Frame: From baseline to at least 96 weeks post treatment.
Patient-reported outcomes will be assessed via questionnaires, including the RTOG (late bladder and intestinal toxicity) questionnaire.
From baseline to at least 96 weeks post treatment.
To evaluate each component of the primary outcome comparing between BCG and radiotherapy with radiosensitisation.
Time Frame: From baseline to at least 96 weeks post treatment.

The following event outcomes will be analyzed using the Cox proportional hazards model to estimate hazard ratios, and Kaplan-Meier analysis will be used to estimate event rates.

  • Recurrence-free survival (RFS) defined as time from randomisation to recurrence of non-muscle invasive papillary tumour. Patients are censored at the last follow-up if event free.
  • Progression-free survival (PFS) defined as time from randomisation to progression to muscle-invasive disease. Patients are censored at the last follow-up if event free.
  • Metastasis-free survival (MFS) defined as time from randomisation to progression to distant metastatic bladder cancer. Patients are censored at the last follow-up if event free.
  • Cystectomy-free survival (CFS) defined as time from randomisation to cystectomy. Patients are censored at the last follow-up if event free
  • Overall survival (OS) defined as time from randomisation to death due to any cause. Patients are censored at the last follow-up if event free
From baseline to at least 96 weeks post treatment.
To establish the tolerability and safety of radiotherapy.
Time Frame: From baseline to at least end of 4 week treatment.
MedDRA coded adverse events graded using CTCAE v5.0.
From baseline to at least end of 4 week treatment.
To determine the difference in cancer specific survival between groups.
Time Frame: From baseline to at least 96 weeks post treatment.
Cancer specific survival defined as time from randomisation to death from cancer. Patients who die of a cause other than the cancer under study or who are lost to follow-up are censored at death or the last date on which they were known to be alive.
From baseline to at least 96 weeks post treatment.
To determine the difference in treatment fidelity between the groups.
Time Frame: From baseline to at least 96 weeks post treatment.
Treatment fidelity defined as how well each group implemented treatment as intended. Summary statistics will be presented for any treatment delays, missed treatment, those not starting treatment, and those who completed treatment, by group.
From baseline to at least 96 weeks post treatment.
To determine the cost-effectiveness of radiotherapy with radiosensitisation compared to BCG.
Time Frame: From Baseline to at least 96 weeks post treatment.
  • Within trial analysis. Total costs and QALYs for radiotherapy with radiosensitisation compared to BCG during the trial period.
  • Economic modelling. Total costs and QALYs for radiotherapy with radiosensitisation compared to BCG extrapolated beyond the trial period.
From Baseline to at least 96 weeks post treatment.
To determine the difference between BCG and radiotherapy in terms of patient-reported symptoms.
Time Frame: From baseline to at least 96 weeks post treatment.
Patient-reported outcomes will be assessed via questionnaires, including the EQ-5D questionnaire.
From baseline to at least 96 weeks post treatment.
To determine the difference between BCG and radiotherapy in terms of patient-reported symptoms.
Time Frame: From baseline to at least 96 weeks post treatment.
Patient-reported outcomes will be assessed via questionnaires, including the IPSS questionnaire.
From baseline to at least 96 weeks post treatment.
To determine the difference between BCG and radiotherapy in terms of patient-reported symptoms.
Time Frame: From baseline to at least 96 weeks post treatment.
Patient-reported outcomes will be assessed via questionnaires, including the QLQ-C30 questionnaire.
From baseline to at least 96 weeks post treatment.
To determine the difference between BCG and radiotherapy in terms of patient-reported symptoms.
Time Frame: From baseline to at least 96 weeks post treatment.
Patient-reported outcomes will be assessed via questionnaires, including the QLQ-NMIBC24 questionnaire.
From baseline to at least 96 weeks post treatment.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Christie NHS Foundation Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 1, 2025

Primary Completion (Estimated)

December 1, 2031

Study Completion (Estimated)

December 1, 2031

Study Registration Dates

First Submitted

September 24, 2025

First Submitted That Met QC Criteria

November 25, 2025

First Posted (Actual)

December 5, 2025

Study Record Updates

Last Update Posted (Actual)

December 5, 2025

Last Update Submitted That Met QC Criteria

November 25, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CFTsp223

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data will be made available, including data dictionaries, for approved data-sharing requests. Individual participant data will be shared that underlie the results reported in this article, after de-identification and normalisation of information (text, tables, figures, and appendices). The study protocol and statistical analysis plan will also be available.

IPD Sharing Time Frame

Anonymous data will be available for request from three months after publication of the article, to researchers who provide a completed Data Sharing request form that describes a methodologically sound proposal, for the purpose of the approved proposal and if appropriate, signed a Data Sharing Agreement.

IPD Sharing Access Criteria

Data will be shared once all parties have signed relevant data-sharing documentation, covering SCTU conditions for sharing and if required, an additional Data Sharing Agreement from Sponsor. Proposals should be directed to ctu@soton.ac.uk.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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