Di Stasi 2003.

Methods	Study design: multicentre, prospective, randomised clinical trial Number of study centres: unclear Study dates: June 1994 to March 2001, follow‐up 42–45 months Participants randomly assigned: 108 (36 in each group)
Participants	Inclusion criteria: histologically confirmed multifocal Cis concurrent pT1 papillary transitional cell carcinoma adequate bone marrow reserve, normal renal function, normal liver function Karnofsky performance score 50–100 Exclusion criteria: prior carcinoma of the bladder or upper urinary tract, or both other malignancies within 5 years of registration pregnancy
Interventions	Group A: MMC 40 mg with 960 mg excipient saline dissolved in 100 mL water instilled and retained in the bladder for 60 minutes Group B: 81 mg wet weight (mean 10.2, SEM 9.0 × 108 cfu) intravesical Pasteur BCG. Lyophilised BCG was suspended in 50 mL bacteriostatic‐free saline 0.9% solution. Instillations retained for 120 minutes. Group C: MMC 40 mg with 960 mg excipient saline dissolved in 100 mL water instilled and retained in the bladder for 30 minutes with 20 mA pulsed electric current (600 mA minute) Procedure: all groups were scheduled to receive an initial 6 intravesical treatments at weekly intervals commencing approximately 3 weeks after multiple biopsy/TUR procedures; participants who had a complete response to the initial 6 weekly treatments underwent a further 10 monthly instillations; if cancer persisted at 3 months, a second 6‐week course was given. If disease persisted at 6 months, there was a cross‐over to a 6‐week second‐line course of BCG for participants in the 2 MMC groups and electromotive MMC for participants in the BCG group.
Outcomes	Time to first recurrence, time to progression, time to death from any cause, adverse effects
Funding sources	Supported by grants Progetti di Ricerca di Ateneo ex 60% 1999–2000 and 2000–2001 from Tor Vergata University of Rome. Electromotive equipment provided by Physion Srl, Medolla, Italy.
Declarations of interest	No interest, except 1 coauthor, who reported financial interest with the company.
Notes	53 participants underwent cross‐over: 25 with electromotive MMC and 15 with MMC switched to a 6‐week BCG course; 13 with BCG failure switched to electromotive MMC. Here we only considered the MMC data with passive administration, not the electromotive MMC data. 1 of the study authors declared financial interest with the company providing the electromotive equipment.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Randomization and data collection were performed using a central computer." Comment: we assumed a low risk for the domain.
Allocation concealment (selection bias)	Low risk	Quote "Randomization and data collection were performed using a central computer. Patients were allocated to 1 of 3 treatment arms by blocked randomisation across 8 (2x2x2) strata resulting from 3 factors, namely Tis [Cis] only vs Tis with concurrent T1 papillary tumours, grades III vs II concurrent T1 papillary tumours and multifocal vs unifocal concurrent T1 papillary tumours." Comment: we assumed a low risk for the domain.
Blinding of participants and personnel (performance bias) all outcomes	High risk	Comment: no information on blinding. We assumed that there was no blinding and that the outcomes might have been influenced by differences in performance due to a lack of blinding.
Blinding of outcome assessment (detection bias) overall survival	Low risk	Comment: no information on blinding. We assumed that there was no blinding but that the absence of blinding had not affected this objective outcome.
Blinding of outcome assessment (detection bias) recurrence and progression free survival	High risk	Comment: no information on blinding. We assumed that there was no blinding. We assumed that the absence of blinding might have had an effect on the detection and measurement of subjective outcomes.
Blinding of outcome assessment (detection bias) serious and non‐serious adverse effects	High risk	Comment: no information on blinding. We assumed that there was no blinding. We assumed that the absence of blinding might have had an effect on the detection and measurement of subjective outcomes.
Blinding of outcome assessment (detection bias) quality of life	Unclear risk	Outcome not reported.
Incomplete outcome data (attrition bias) Survival outcomes	Low risk	Comment: all randomised participants (72/72) were considered in the analyses. Participant flow was clearly reported.
Incomplete outcome data (attrition bias) Adverse effect outcomes	Low risk	Comment: all randomised participants (72/72) were considered in the analyses. Participant flow is clearly reported.
Incomplete outcome data (attrition bias) Quality of life outcomes	Unclear risk	Outcome not reported.
Selective reporting (reporting bias)	Unclear risk	Comment: no study protocol available.
Other bias	Low risk	Comment: we assumed that there was no risk for other bias.