Change to SAE reporting: - Deaths due to disease progression are no longer excluded from being reported as an SAE. Governance and funding changes in protocol: - Administrative changes throughout the protocol. - Clarification of funding arrangements. Addition of new sites. - Change of PI.

Pre-treatment evaluation (protocol): This should be completed within 4 weeks of randomisation. Cholesterol (no longer fasting) levels taken any time within 3-6 months of randomisation. C-reactive protein levels being measured. Change to exclusion criteria point 16 (protocol): Patients treated with insulin will be excluded. point 3 (protocol): >=T2 TCC or previous history of >=T2. Change to inclusion criteria Point 4 (protocol): No evidence of upper tract TCC on imaging studies within the past 36 months or before randomisation. Addition of new sites. Change of Principal Investigator. Extension of Quality of Life sub study follow-up period. This will now be for 2 years (24 months

Amendment of the exclusion criteria (protocol) point 12 (protocol): Chronic use of NSAIDs is defined as a frequency of 1 or more a day for more than 50 consecutive days in a year. Addition of new sites. Change of Principal Investigator. Extension of Quality of Life sub study follow-up period. This will now be for 3 years (36 months). Amendment to sample collection sub-study PIS The organisers of this study would also consider requests to use these samples for other high quality research studies. The text following this (which was already present in the previous approved version (version 3 25/10/06) confirms that the patient's confidentiality will be protected and that these other research studies would need to have ethics approval to use these samples. Amendment to biological sample collection consent form Am aware that my samples may be used for other research studies. The text following this sentence confirms again this states that the patient's confidentiality will be protected and that these other research studies would need to have ethics approval to use these samples.

Inclusion criteria, point 1 more pragmatic definition of tumour size: Large tumours are defined as equal to or greater than 3cm however when tumour size is not documented tumours described as "large" are considered to be equal to or greater that 3cm and is at the discretion of the urologist. Small tumours are those which are less than 3cm in size. Extension of timeframe between TUR and entry into BOXIT: Randomisation should occur ideally within 6 weeks however up to 10 weeks is allowed where a delay has been unavoidable. Addition of appendix 2 - BOXIT-T with further explanation of BOXIT-T aims and information regarding the collection and storage of BOXIT-T samples. Comprehensive description of the role of the cardio-vascular sub committee ADDITIONAL DOCUMENTATION - Quality of Life extension letters (version 1 19/12/2008) to patients currently participating in the Quality of Life sub-study informing them that the follow-up has been extended for up to 3 years post randomisation (extension approved in Amendment 3) and that we would like them to continue to participate in this substudy if they wish. - Quality of Life baseline patient letters (BCG and no BCG Version 2 19/12/2008) explaining that the - Quality of Life sub-study will be follow-up for 3 years. - Quality of Life follow-up patient letter (version 2 19/12/2008), this has not changed in content but will now be sent to patients not receiving BCG as well as those receiving BCG due to the extension of the Quality of Life sub-study. - Amendment to patient information sheet (version 3 19/12/2008) explaining that the Quality of Life follow-up has been extended up to 3 Addition of new sites. Change of Principal Investigator.

Amendment submitted in error: The Chief Investigator Mr. John. D. Kelly has taken up a new post at University College London. Prof. David. E. Neal would therefore be the Chief Investigator for the study.

Correction following substantial amendment number 5 which was submitted in error, stating a change of Chief Investigator. Professor John Kelly remains the Chief Investigator for BOXIT. Professor David Neal is not the Chief Investigator for BOXIT he is the Principal Investigator at Addenbrooke's Hospital.

INCLUSION CRITERIA (page 10, protocol V1.6) Pt.1. The description of the eligible risk groups (intermediate and high risk patient groups) have been simplified and the full definitions have been placed in appendix 4. The terminology used in these definitions has been amended for the number of bladder tumours/occurrences in the past year for clarification following centre feedback. The number of high and intermediate risk patients to be randomised has also been inserted. Pt. 2. Patients who are equal to or greater (inserted)than 18 years of age would be eligible to enter BOXIT. EXCLUSION CRITERIA (page 11, protocol V1.6) Pt. 4. The definition of a significant bleeding disorder has been further described for clarification. Pt. 14.The use of corticosteroids has been amended to specifiy that only patient use of oral corticosteroids would be excluded. Pt. 15. The stages of the degree of heart failure has been clarified and full defintions of these stages have been inserted into the appendices (appendix 10). Clarification of patient entry criteria for those patients who are hypertensive. Inserted additional exclusion, patients with documented abdominal aortic aneurysm. Pt. 18. The time frame since other malignancy and patient entry has been reduced from 5 years to 2 years. Patients with prostate cancer who have a life expectancy of over 5 years upon trial entry would also now be eligible to enter BOXIT. Reference to superficial TCC of the bladder has been changed to non-muscle invasive TCC of the bladder, to bring in line with current terminology. In addition minor changes have been made throughout the protocol for clarification purposes, please see comments in track changes version of protocol. Addition of new sites and change of principal investigators at existing sites.

Addition of new sites and change of principal investigators at existing sites.

Temporary suspension of recruitment pending replacement o expiring study drug stocks.

Randomisation of new patients has been re-opened after the resupply of expiring drug stock at participating centres has been completed.

Reduction in sample size.

Transfer of all samples collected for the BOXIT-T sub study from Cambridge University Hospitals NHS Trust to University College Hospital NHS Foundation Trust.

The previous version 3.0 of the protocol, version 5.0 of the BOXIT-T PIS and consent form and version 1 of the patient letter specified a specific biobank for storage of the BOXIT-T samples. The location of sample storage has since changed but is still within UCL NHS Foundation Trust. Therefore the storage location has been relaxed to read ‘central UCL Biorepository’. In addition, there is a need for the Patient Information Sheet to be provided in a larger font size for the patient population in the BOXIT Study. The font size of the Sample Collection Sub-Study patient information sheet has been increased. There has been no change to the content of the PIS, but in increasing the font size, the number of pages have increased from 3 to 4. This is not a version change. This large font PIS will run in parallel to version 5.1 of the Sample Collection Sub- Study PIS and the version 5.1 consent form will still apply.

Change in trial sponsor of the BOXIT Trial

Approval of the patient card issued to patients

Increase to the sample size

Change to the ECG reporting requirements during follow-up

Change to the specified BCG strain for standard treatment.

The BOXIT trial management group reviewed the requirements for long-term follow-up for the trial at their recent meeting in November 2012. It was agreed that the protocol should be clarified to confirm that annual long term follow-up should be collected from year 5 onwards for all patients. The first time-point for long term follow-up to be conducted is year 6 (72 months) after the date of randomisation, and annually thereafter.

Introduction of a new Patient Information Sheet (PIS) providing information relating to the request for patients to stop taking study their study medication.

Amendment to long-term follow-up of patients.