Böhle 2009.

Study characteristics
Methods	Study design: randomized, double‐blind, placebo‐controlled multicenter study Setting/country: multicenter (24 centers) in Germany and Turkey Dates when study was conducted: January 2004 to June 2005
Participants	Ethnicity: white Inclusion criteria Clinical evidence of papillary, non‐muscle‐invasive TCC of the bladder and indication for TURBT (stage Ta/T1, G1–G3; no concomitant bladder CIS) Men or women ages ≥ 18 years Karnofsky performance status ≥ 70% with adequate bone marrow reserve (white blood cells: ≥ 4 × 109/L; platelets: ≥ 140 × 109/L; hemoglobin: 10 g/dL), and adequate renal and hepatic function (serum creatinine: < 2.0 mg/dL; bilirubin: < 2.0 mg/dL; alanine transaminase and aspartate transaminase < 2.5 × upper limit of normal) Patient compliance and geographic proximity that allowed adequate follow‐up Women with reproductive potential must have used a reliable contraceptive method if appropriate (e.g. intrauterine device, birth control pills, or barrier device) during study Women with reproductive potential must have had a negative serum pregnancy test within 7 days of study enrollment Signed informed consent Exclusion criteria Weight loss > 15% during the last 6 months, prior chemotherapy within the last 6 month, > 3 prior TURBT, history of CIS Clinical evidence of muscle‐invasive or locally advanced bladder cancer Clinical evidence of upper urinary tract tumor Distant metastases Other malignancies within the last 2 years, except non‐melanotic skin tumors, CIS of the cervix or organ‐confined prostate cancer after curative therapy Severe concomitant psychiatric disease Febrile, active infection Other serious concomitant disorders that would compromise the safety of the patient or his/her ability to complete the study according to the protocol, at the discretion of the investigator (e.g. unstable angina pectoris, uncontrolled diabetes mellitus) Total number of participants randomly assigned Screened: NA Eligible: 355 Disease type: primary and recurrent disease Intervention: gemcitabine Number of all participants randomly assigned: 179 Age: mean 63.2 (SD 11.9) years Gender (men/women): 127/39 Tumor T stage Tx: 3; T0: 0; Tis: 5; Ta: 93; T1: 31; T2: 12 Tumor grade (G1/G2/G3) 59/50/25 Tumor size (< 3 cm/≥ 3 cm): NA Number of tumors (1/> 1): 87/75 Primary disease: 123; recurrent disease: 43 Prior intravesical therapy: NA Comparator: saline Number of all participants randomly assigned: 176 Age: mean 66.3 (SD 11) years Gender (men/women): 136/26 Tumor T stage Tx: 0; T0: 0; Tis: 6; Ta: 88; T1: 36; T2: 10 Tumor grade (G1/G2/G3) 66/48/24 Tumor size (< 3 cm/≥ 3 cm): NA Number of tumors (1/> 1): 96/61 Primary disease: 122; recurrent disease: 40 Prior intravesical therapy: NA
Interventions	Intervention: gemcitabine Gemcitabine 2000 mg/100 mL saline Instilled over 30–40 minutes immediately after TURBT followed by continuous irrigation with saline for 20 hours Comparator: saline 100 mL saline Instilled over 30–40 minutes immediately after TURBT followed by continuous irrigation with saline for 20 hours Follow‐up: median 23.6 months (range 0–46)
Outcomes	Primary outcomes Protocol: recurrence‐free survival Report: recurrence‐free survival in people with histologically confirmed NMIBC (pTa/pT1, G1–G3) How measured: histologically confirmed recurrence (biopsy, TUR) Time point measured: 3 and 6 months after the first TURBT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months Time point reported: 24 months Secondary outcomes Protocol: time to recurrence; recurrence‐free survival in subgroups; tumor recurrence type Report: type of recurrence and toxicity (serious and other adverse events) How measured Recurrence in subgroup: histologically confirmed recurrence (biopsy, TUR) Toxicity: NA Time point measured Recurrence in subgroup: 3 and 6 months after the first TURBT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months Toxicity: up to 3 months Time point reported: Recurrence: 24 months Toxicity: likely cumulative Subgroup analysis; recurrence‐free survival only Low‐grade vs high‐grade tumor Primary vs recurrent disease Single vs multiple disease Second TUR vs without second TUR BCG vs without BCG German centers vs Turkish centers
Funding Sources	The study was funded and sponsored by Eli Lilly and Company, Indianapolis, IN, USA. The sponsor assisted in the design and conduct of the study; contributed to the management, analysis, interpretation, preparation, and review of the data; and approved the manuscript.
Declarations of interest	H Buttner, K Helsberg, B Lubben, V Soldatenkova, and C Stoffregen are employees of Lilly Deutschland GmbH, the German affiliate of Eli Lilly and Company, Indianapolis, IN, USA. H Buttner, K Helsberg, B Lubben, and C Stoffregen also own Eli Lilly stocks or stock options (or both). A Böhle has received honoraria for lectures from Cytochemia, Apogepha, Bard, and Hexal.
Notes	Protocol: NCT00191477 Language of publication: English Data extraction and risk of bias assessment were performed using the NCT00191477 result section (gemcitabine: n = 166, saline: n = 162 including pT2, CIS, no malignancy, pathologic specimen lost participants included).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from publication: "Random" only. Comment: randomization stated and we received the author response "computer generate random number"; therefore, low risk of selection bias.
Allocation concealment (selection bias)	Low risk	Comment: we received the author response "central randomisation"; therefore, low risk of selection bias.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote from publication: "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)." Comment: participants and personnel were blinded.
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Quote from publication: "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" Comment: outcome assessor was blinded; therefore, low risk of detection bias.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Comment: outcome assessor was blinded; therefore, low risk of detection bias.
Incomplete outcome data (attrition bias) Time to recurrence	Low risk	Comment: 166/179 (92.7%) in gemcitabine arm and 162/176 (92.1%) in saline arm were included in the analysis. Owing to the small number of participants excluded from the analysis and balanced in both groups, we considered this a low risk of attrition bias.
Incomplete outcome data (attrition bias) Time to progression	Low risk	Comment: the study did not investigate this outcome, but reported several progressions from per‐protocol participants in each arm (124/179 [69.2%]). Attrition rates were balanced in each arm. We approximated the effect estimates (HR) using an indirect method (Parmar 1998). Thus, low risk of attrition bias.
Incomplete outcome data (attrition bias) Grade III–V adverse events	Low risk	Comment: 166/179 (92.7%) in gemcitabine arm and 162/176 (92.1%) in saline arm were included in the analysis. Owing to the small number of participants excluded from the analysis and balanced in both groups, we considered this a low risk of attrition bias.
Incomplete outcome data (attrition bias) Time to death from bladder cancer	Low risk	Comment: the study did not investigate this outcome, but reported several progressions from 166/179 (92.7%) in gemcitabine arm and 162/176 (92.1%) in saline arm. We approximated the effect estimates (HR) using an indirect method (Parmar 1998). Thus, low risk of incomplete outcome bias.
Incomplete outcome data (attrition bias) Time to death from any cause	Low risk	Comment: the study did not investigate this outcome, but reported several progressions from 166/179 (92.7%) in gemcitabine arm and 162/176 (92.1%) in saline arm. We approximated the effect estimates (HR) using an indirect method (Parmar 1998). Thus, low risk of incomplete outcome bias.
Incomplete outcome data (attrition bias) Grade I or II adverse events	Low risk	Comment: 166/179 (92.7%) in gemcitabine arm and 162/176 (92.1%) in saline arm were included in the analysis. Owing to the small number of participants excluded from the analysis and balanced in both groups, we considered this a low risk of attrition bias.
Selective reporting (reporting bias)	High risk	Comment: the protocol (NCT00191477) was provided, but was changed during the study period due to lower events rates. All predefined outcomes were provided, but the results of primary and secondary outcomes were different between protocol and report. Owing to lower events rates (recurrence), recurrence‐free survival was calculated in subgroups as a post hoc analysis.
Other bias	High risk	Quote from publication: "Concomitant BCG was used in 34 (13.7%) of efficacy eligible patients (GEM [gemcitabine]: 10.5%; PBO [placebo]: 16.9%); 14 patients (5.6%; GEM: n = 5; PBO: n = 9) received more than six BCG." Comment: possible differences in concomitant treatment instillations. Baseline imbalance: age (recalculated using MedCalc Statistical Software).