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NCT Number: NCT07268339

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.

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Key information

Conditions

High-Risk Non-Muscle Invasive Bladder Cancer Carcinoma Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Male Urogenital Diseases Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Non-Muscle Invasive Bladder Neoplasms Urinary Bladder Diseases Urinary Bladder Neoplasms Urogenital Diseases Urogenital Neoplasms Urologic Diseases Urologic Neoplasms

Age range

16 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Radiotherapy

Radiation

Radiotherapy - 55Gy in 20 fractions treating once daily Monday to Friday over 4 weeks.

BCG

Other

BCG protocol of 6 weekly intravesical instillations, followed by 3 weekly instillations at 3, 6, 12, 18, 24, 30, 36 months.

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

Study contacts

Contact information is provided by the study sponsor or research team.

Amber B Cole

CONTACT

[email protected]

023 8120 5154

Daniel Griffiths

CONTACT

[email protected]

023 8120 5154

Sponsors and collaborators

Lead sponsor

The Christie NHS Foundation Trust

Other

Registry information

Official study title

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.

Acronym: TRAIN

Important dates

Study start
2025
Primary completion
2031
Study completion
2031
First posted
Dec 5, 2025
Registry last updated
Dec 5, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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