Crawford 2013 (CS37).

Study characteristics
Methods	Study design: parallel‐group randomized controlled clinical trial Study dates: 2009 to 2012 Setting: multicenter, outpatients, national Country: United States Official title: a randomized, controlled, open‐label study investigating the safety and efficacy of degarelix given intermittently vs continuous androgen deprivation therapy with Lupron or degarelix in patients with prostate cancer with prior treatment failure after localized treatment Follow‐up: 14 months
Participants	Inclusion criteria: 18 years or older Rising PSA after prior treatment failure of localized prostate cancer Has a histological confirmed non‐metastatic cancer of the prostate (Gleason graded) based on the most current biopsy Has a screening testosterone within normal range (≥ 1.5 ng/mL) Has Eastern Cooperative Oncology Group score of ≤ 2 Bone scan or CT scan report documenting no evidence of metastasis to the bone or internal organs Life expectancy of at least 15 months Exclusion criteria: Taken hormone therapy in the last 6 months prior to entering this study Being treated with 5‐alpha reductase inhibitor at time of enrollment and remained on a stable dose throughout the trial Has a history of severe uncontrolled asthma, anaphylactic reactions, or severe urticaria and/or angioedema Has hypersensitivity towards any component of the study drug Has a previous history or presence of another malignancy other than prostate cancer or treated squamous/basal cell carcinoma of the skin within the last 5 years Has abnormal laboratory results which in the judgment of the Investigator would affect the patient's health or the outcome of the trial Has a clinically significant medical condition (other than prostate cancer) including but not limited to: renal, hematological, gastrointestinal, endocrine, cardiac, neurological or psychiatric disease and alcohol or drug abuse, or any other condition which could affect the patient's health or the outcome of the trial as judged by the Investigator Has an intellectual incapacity or language barriers precluding adequate understanding or cooperation Has received an investigational drug within the last 28 days before the Screening visit or longer if considered to possibly influence the outcome of the current trial Has received ketoconazole or diflucan in the last 28 days preceding the Screening Visit Has previously participated in any degarelix trial Is part of an ongoing trial Sample size: 409 (randomized)/403 (treated)   Stage of disease: unclear
Interventions	Group 1 (Degarelix Intermittent) (n = 175): Phase A: degarelix 240/80 mg; Phase B: degarelix paused; men in this arm received degarelix with a starting dose of 240 mg at a concentration of 40 mg/mL on Day 0 administered s.c. into the anterior abdominal wall via 2 equivalent injections of 120 mg (3 mL) each. 6 maintenance doses of degarelix 80 mg per month at a concentration of 20 mg/mL (4 mL) at Days 28 to 168 were administered. During Phase B of the trial, if a participant had PSA ≥ 2 ng/mL at any visit, additional doses of degarelix 240 mg followed by 80 mg maintenance dose(s) were administered. Degarelix treatment provided for first 7 months (1 starting dose and 6 maintenance doses) followed by no treatment for next 7‐month period. Group 2 (Degarelix Continuous) (n = 50): degarelix 240/80 mg; men in this arm received degarelix with a starting dose of 240 mg at a concentration of 40 mg/mL administered on Day 0 (Visit 1) s.c. into the anterior abdominal wall via 2 equivalent injections of 120 mg (3 mL) each. 13 maintenance doses of degarelix 80 mg per month at a concentration of 20 mg/mL (4 mL) at Days 28 to 364 administered s.c. into the anterior abdominal wall. Degarelix treatment provided for complete study period (1 starting dose and 13 maintenance doses). Group 3 (Leuprolide Continuous) (n = 178): leuprolide 7.5/22.5 mg; men in this arm received leuprolide 7.5 mg 1‐month depot injection on Day 0, administered i.m. into a large muscle, as per manufacturer's labeling directions. 1 injection of 22.5 mg leuprolide 3‐month depot was administered i.m. as per manufacturer's labeling directions at Day 28 and every 3 months afterwards for 4 additional doses (i.e. at Days 112, 196, 280, and 364, respectively). On Investigator's discretion, men in the arm could take bicalutamide (Casodex) for a maximum of 28 days to alleviate increased signs and symptoms due to initial upsurge in testosterone levels. Leuprolide treatment for complete study period (1 starting dose and 5 maintenance doses of 3‐month depot each)
Outcomes	Primary outcomes: Percentage of patients with serum PSA levels ≤4.0 ng/mL [time frame: at 14 months] Secondary outcomes: Absolute change from baseline in serum PSA levels Percent change from baseline in serum PSA levels Change from baseline in quality of life as assessed by the Functional Assessment of Cancer Therapy‐Prostate (FACT‐P): physical well‐being, emotional well‐being, social well‐being, functional well‐being, additional concerns, total FACT‐P score [time frame: during 14 months] Change from baseline in sexual function as assessed by the Sexual Function Index (SFI): sexual drive, erection, ejaculation, problem assessment, overall satisfaction with sex life, total SFI score [time frame: during 14 months] Percentage of subjects with a serum PSA level ≤4.0 ng/mL [time frame: at 14 months] Time to return to testosterone >0.5 ng/mL level in the degarelix intermittent (DI) treatment group [the time to testosterone >0.5 ng/mL level in the DI group was counted from the start of Phase B at Day 196 (i.e. 28 days after last injection of degarelix)] Time to return to normal range (≥1.5 ng/mL) or baseline testosterone level [the time to return to normal range (≥1.5 ng/mL) or baseline testosterone level in the DI group was counted from the start of Phase B at Day 196 (i.e. 28 days after last injection of degarelix)] Absolute change from baseline in serum testosterone levels Percent change from baseline in serum testosterone levels
Funding sources	Ferring Pharmaceuticals
Declarations of interest	None reported; clinical development support Ferring Pharmaceuticals.
Notes	No full‐text publication available. We did not include data for the degarelix intermittent arm as this information was not relevant to this review. Trial ID: NCT00928434
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: “men were randomized” Comment: insufficient information to permit judgment.
Allocation concealment (selection bias)	Unclear risk	Quote from publication: “men were randomized” Comment: insufficient information to permit judgment.
Blinding of participants and personnel (performance bias) Subjective outcomes	High risk	Quote from ClinicalTrials.gov: “This was an open‐label, randomized, parallel‐arm, multicenter study” Comment: we judge that subjective outcomes are influenced by lack of blinding.
Blinding of outcome assessment (detection bias) Subjective outcomes	Unclear risk	Quote from publication: “open‐label trial”; there was no blinding of outcome assessment (or it was not reported) Comment: insufficient information to permit judgment.
Incomplete outcome data (attrition bias) Biochemical progression	Unclear risk	Comment: the study did not address this outcome.
Incomplete outcome data (attrition bias) Adverse events	Low risk	Comment: no missing outcome data.
Incomplete outcome data (attrition bias) Quality of life	Low risk	Comment: missing outcome data balanced in numbers across intervention groups (Group 2 18.0% vs Group 3 15.7%).
Selective reporting (reporting bias)	Unclear risk	Comment: the study protocol is available, but we did not identify full‐text publications.
Other bias	Low risk	Comment: we did not identify other sources of bias.