Smith 2004.

Methods	Start date, end date of recruitment: Study participants were recruited between May 2000 and May 2002 Follow‐up period: treatment time: 12 months. Participants were evaluated at baseline and at 3, 6, 9 and 12 months Design: randomised controlled trial
Participants	Population/Inclusion criteria: Participants had locally advanced, lymph node–positive or recurrent prostate cancer. Men with prior neoadjuvant or adjuvant hormone therapy were included if the interval between completion of treatment and study entry was longer than 1 year; 10 men (5 men in each group) had received neoadjuvant or adjuvant treatment with a gonadotropin‐releasing hormone agonist Setting: single‐centre trial Geographical location: United States Exclusion criteria: Men with bone metastases by radionuclide bone scan were excluded. Men with Karnofsky performance status less than 90, history of hypogonadism, history of growth hormone or anabolic steroid use, Paget’s disease, hyperthyroidism, Cushing’s disease, hyperprolactinaemia, chronic liver disease, corrected serum calcium 8.4 mg/dL or 10.6 mg/dL or serum creatinine concentration 2.0 mg/dL (177 mol/L) were also excluded. Men were excluded if they had received bisphosphonate, calcitonin or glucocorticoid therapy, or suppressive doses of thyroxine, within 1 year Total number randomly assigned: 52 Baseline imbalances: unclear: balanced for data reported; data for staging not reported Number of participants with non‐metastatic disease: 51 (52 men were randomly assigned to leuprorelin monotherapy or bicalutamide monotherapy. Fifty‐one men completed the baseline evaluation and initiated study treatment; 51 participants completed the study. All 51 participants are included in the analyses, including 3 men who discontinued treatment early) Number of participants with metastatic disease: 0 Age: intervention: mean 63 ± 8 years; control: mean 65 ± 10 years PSA (mean ± SD): intervention: 158 ± 670 ng/mL; control: 40 ± 119 ng/mL Subgroup measured: no
Interventions	Intervention Description/Timing: bicalutamide 150 mg by mouth daily for 12 months Number randomly assigned to this group: 25 Control Description/Timing: Leuprorelin 3‐month depot (Lupron Depot; TAP Pharmaceuticals Inc, Deerfield, Illinois; 22.5 mg intramuscularly every 3 months). Men assigned to leuprorelin treatment also received bicalutamide (50 mg by mouth daily) for 1 month to prevent the potential disease flare associated with initial leuprorelin administration Number randomly assigned to this group: 26
Outcomes	Overall survival Outcome not measured/reported Cancer‐specific mortality Outcome not measured/reported Treatment discontinuation due to adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: at 12 months Time points reported: at 12 months Number of participants randomly assigned: intervention: 25; control: 26 Number of participants in evaluation for ITT: intervention: 25; control: 26 Clinical progression Outcome not measured/reported Biochemical progression Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: at 12 months Time points reported: at 12 months Outcome definition in report: Disease progression was defined as new metastatic disease or a greater than 25% increase in serum PSA concentration from nadir value on 2 determinations and 5 ng/mL absolute increase in PSA Number of participants randomly assigned: intervention: 25; control: 26 Number of participants in evaluation for ITT: intervention: 25; control: 26 Note: This outcome was named as clinical progression by the study authors. However, because of the outcome definition reported, we classified it as biochemical progression Treatment failure Outcome not measured/reported Adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: at 12 months Time points reported: at 12 months Number of participants randomly assigned: intervention: 25; control: 26 Number of participants in evaluation for ITT: intervention: 25; control: 26 Other outcomes reported Primary study end points were percentage change in bone mineral density in posterior‐anterior lumbar spine and percentage change in thigh muscle area from baseline to 12 months
Notes	Email response: "Subjects and study investigators were blinded to treatment assignment. The main outcomes for this 1‐year study were bone mineral density and body composition and the study was NOT designed to evaluate clinical cancer outcomes including time to progression" Study funding source: supported by research award from AstraZeneca PLC Possible conflict of interest: Study authors indicated no potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer random number generator
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) overall survival, cancer‐specific mortality, biochemical progression	Unclear risk	Email response: "Subjects and study investigators were blinded to treatment assignment." However, the method of blinding bicalutamide 150 mg by mouth daily for 12 months and leuprorelin 3‐month depot (22.5 mg intramuscularly every 3 months) for biochemical progression remains unclear
Blinding of participants and personnel (performance bias) treatment discontinuation due to adverse events, clinical progression, treatment failure, adverse events	Unclear risk	Email response: "Subjects and study investigators were blinded to treatment assignment." However, the method of blinding bicalutamide 150 mg by mouth daily for 12 months compared with leuprorelin 3‐month depot (22.5 mg intramuscularly every 3 months) for treatment discontinuation due to adverse events and adverse events remains unclear
Blinding of outcome assessment (detection bias) overall survival, cancer‐specific mortality, biochemical progression	Low risk	Not reported. However, we judge that it is not likely that outcome assessment for biochemical progression is influenced by lack of blinding
Blinding of outcome assessment (detection bias) treatment discontinuation due to adverse events, clinical progression, treatment failure, adverse events	Unclear risk	Not reported. However, original investigators responded that blinding was performed ("Subjects and study investigators were blinded to treatment assignment"). However, blinding of outcome assessment for treatment discontinuation due to adverse events and adverse events remains unclear
Incomplete outcome data (attrition bias) overall survival, cancer‐specific mortality	Unclear risk	Not measured/reported
Incomplete outcome data (attrition bias) treatment discontinuation due to adverse events, adverse events	Low risk	Proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate (52 men were randomly assigned to leuprorelin monotherapy or bicalutamide monotherapy. Fifty‐one men completed baseline evaluation and initiated study treatment; 51 participants completed the study. All 51 participants are included in the analyses, including 3 men who discontinued treatment early)
Incomplete outcome data (attrition bias) clinical progression, biochemical progression	Low risk	Proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate (52 men were randomly assigned to leuprorelin monotherapy or bicalutamide monotherapy. Fifty‐one men completed the baseline evaluation and initiated study treatment; 51 participants completed the study. All 51 participants are included in the analyses, including 3 men who discontinued treatment early)
Incomplete outcome data (attrition bias) treatment failure	Unclear risk	Not measured/reported
Selective reporting (reporting bias)	Low risk	Study protocol is not available, but it is clear that published reports include all expected outcomes
Other bias	Unclear risk	Unclear risk for conflict of interest