ARTS - AVODART After Radical Therapy For Prostate Cancer Study

GlaxoSmithKline294 enrolled

Overview

ARI109924 will be a 2-year, multicentre, randomised, double-blind, placebo-controlled trial assessing the efficacy and safety of dutasteride in extending time to prostate specific antigen (PSA) doubling in men who have been treated for clinically localised prostate cancer (PCa) with a radical therapy (radical prostatectomy, primary radiotherapy or salvage radiotherapy) with curative intent but who experience a biochemical failure (PSA rise) afterwards without signs or symptoms of metastases.

A Randomised, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Dutasteride (AVODART™) 0.5 mg in Extending the Time to PSA Doubling in Men with Prostate Cancer and Biochemical Failure (PSA increase) after Radical Therapy with Curative Intent (ARTS - AVODART after Radical Therapy for prostate cancer Study)

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

294

Conditions

Neoplasms, Prostate Prostate Cancer After a Radical Treatment

Interventions

AvodartDRUG

0.5 mg administered orally once daily

placeboOTHER

Patients will be randomized at Visit 2 in 1:1 ratio to receive either 0.5 mg dutasteride or placebo

Eligibility

Sex: ALLMin age: 18 YearsMax age: 85 Years

Medical Language ↔ Plain English

Inclusion Criteria: Patients eligible for enrolment in the study must meet all of the following criteria: * Males \<85 years of age * No clinically relevant abnormal findings on the screening ECG * Patients with asymptomatic PSA failure following radical therapy with curative intent for clinically localised prostate cancer. PSA failure is defined as: * After primary radiotherapy: * 3 rises in PSA levels from nadir PSA, with each determination at least 4 weeks apart and a final PSA level ≥2 ng/mL above nadir PSA * Time from radiotherapy should be at least 1 year from termination of radiotherapy treatment * After radical prostatectomy with or without salvage radiotherapy: * 3 rises in PSA level from nadir PSA, with each determination at least 4 weeks apart and each PSA level ≥0.2 ng/mL and a final PSA level ≥0.4 ng/mL (nadir PSA is defined as the lowest PSA value achieved after therapy) * Serum PSA levels: * ≥2 ng/mL and ≤20ng/mL for primary radiotherapy patients * ≥0.4 ng/ml and ≤10ng/ml for radical prostatectomy with or without salvage radiotherapy patients * PSADT \>3 months and ≤24 months * Clinical stage T1-T3a N0 M0 * Non-metastatic prostate cancer, as confirmed on a negative bone scan performed within 6 months prior to randomisation (Visit 2)3. * No evidence of local recurrence in radical prostatectomy or salvage radiotherapy patients * Expected survival ≥2 years * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 (see Appendix 1) Miscellaneous: * Able to swallow and retain oral medication * Able and willing to participate in the full 2 years of the study * Able to read and write (the MAX-PC questionnaire is self-administered), understand instructions related to study procedures and give written informed consent * In France, a patient will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. Exclusion Criteria: * Any unstable serious co-existing medical condition(s) including but not limited to myocardial infarction, coronary bypass surgery, unstable angina, cardiac arrhythmias, clinically evident congestive heart failure or cerebrovascular accident within 6 months prior to Visit 1, or uncontrolled diabetes or peptic ulcer disease which is uncontrolled by medical management * Abnormal liver function tests (greater than 2 times the upper limit of normal \[ULN\] for alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\] or alkaline phosphatase \[ALP\] or \>1.5 x ULN for bilirubin). * Serum creatinine \>1.5 x ULN * History of another malignancy within 5 years that could affect the diagnosis of prostate cancer * History or current evidence of drug or alcohol abuse within 12 months prior to Visit 1 * History of any illness (including psychiatric) that, in the opinion of the investigator, might confound the results of the study or pose additional risk to the patient * Known hypersensitivity to any 5-AR inhibitor or to any drug chemically related to dutasteride Disease characteristics: * Serum PSA levels * \>20 ng/mL in primary radiotherapy patients * \>10 ng/mL in radical prostatectomy with or without salvage radiotherapy patients * PSADT ≤3 months or \>24 months * Biochemical failures in post brachytherapy patients * Clinical stage N+ or M+ * Patient has previously been treated for prostate cancer with any of the following: * Chemotherapy * Oestrogens (e.g. megestrol, medroxyprogesterone, cyproterone, Diethylstilbestrol \[DES\]) * Drugs with anti-androgenic properties (e.g. spironolactone if \>50mg/day, flutamide, bicalutamide, ketoconazole, progestational agents), (except when used for adjuvancy or neoadjuvancy in the context of a primary radical treatment in which case their use should have been for no more than 6 months and should have completed at least 1 year before Visit 1 \[Note: the use of topical ketoconazole is permitted prior to and during the study and the use of cimetidine is permitted prior to study entry\] * GnRH analogues (e.g., leuprolide, goserelin) except when used for adjuvancy or neoadjuvancy in the context of a primary radical treatment (in this case use should have been for no more than 6 months and should have finalised at least 1 year before Visit 1) * Orchiectomy Concomitant medications: * Glucocorticoids, except inhaled or topical, are not permitted within 3 months prior to Visit 1 or during the study * Current and/or previous use of finasteride (Proscar, Propecia) or dutasteride (GI198745, AVODART™) exposure within 6 months prior to Visit 1 * Anabolic steroids within 6 months prior to Visit 1 * Participation in any other investigational or marketed drug trial within the 30 days prior to Visit 1 or any time during the study period

Locations (66)

Outcomes

Primary Outcomes

Time to Prostate-specific Antigen (PSA) Doubling From Baseline (in Days)

Time to PSA doubling is defined as the number of days between the baseline date and the study day of the first post-baseline PSA evaluation date (within treatment period, typically up to 24-month evaluations) on which the PSA value was at least twice as much as the baseline PSA value, and the immediate subsequent value, if available, was at least 85% of two times the baseline value. Participants who never achieved PSA doubling were censored at the last post-baseline, non-missing PSA evaluation.

Time frame: up to 28 months

Number of Participants With PSA Doubling From Baseline

PSA doubling is defined as the first post-baseline PSA value (within treatment period, typically up to 24-month evaluations) that was at least twice as much as the baseline PSA value and was confirmed as such (at least 85% of two times the baseline PSA value) in the immediate subsequent PSA value if one is available.

Time frame: up to 28 months

Time to PSA Doubling From Baseline (in Days) Within Year 1

Time to PSA doubling is defined as the number of days between the baseline date and the study day of the first post-baseline PSA evaluation date within Year 1 (Y1; within treatment period, typically up to 12-month evaluations) on which the PSA value was at least twice as much as the baseline PSA value, and the immediate subsequent value, if available, was at least 85% of two times the baseline value.

Time frame: up to 16 months

Number of Participants With PSA Doubling From Baseline During Year 1

PSA doubling is defined as the first post-baseline PSA value (within treatment period, typically up to 12-month evaluations) that was at least twice as much as the baseline PSA value and was confirmed as such (at least 85% of two times the baseline PSA value) in the immediate subsequent PSA value if one is available.

Time frame: up to 16 months

Secondary Outcomes

Data from ClinicalTrials.gov

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GSK Investigational Site

Tallinn, Estonia

GSK Investigational Site

Tallinn, Estonia

GSK Investigational Site

Kouvola, Finland

GSK Investigational Site

Oulu, Finland

GSK Investigational Site

Tampere, Finland

GSK Investigational Site

Angers, France

GSK Investigational Site

Chambéry, France

GSK Investigational Site

Créteil, France

GSK Investigational Site

Lyon, France

GSK Investigational Site

Orléans, France

...and 56 more locations

Time to Disease Progression From Baseline (in Days)

Time to disease progression is defined as the number of days between baseline and the first occurrence of any of the following: PSA doubling time (PSADT)\<=91 days, PSA value is at least 50% more than baseline value (\>20 nanogram/milliliter \[ng/ml\] for primary radiotherapy group or \>10 ng/ml for radical prostatectomy group), rescue treatment, cancer-positive biopsy, cancer-positive bone scan. (Confirmation of PSA criteria is required in an immediate subsequent PSA, if available, and PSA values for consideration are restricted to treatment period, typically up to 24-month evaluations.)

Time frame: up to 28 months

Number of Participants With Disease Progression

Disease progression is defined as the first occurrence of any of the following: PSADT\<=91 days, PSA value is at least 50% more than baseline value (\>20 ng/ml for primary radiotherapy group or \>10 ng/ml for radical prostatectomy group), rescue treatment, cancer-positive biopsy, cancer-positive bone scan. If one of the PSA criteria is qualifying (within treatment period, typically up to 24-month evaluations), an immediate subsequent PSA, if available, must confirm either criterion (or at least 85% of the qualifying value).

Time frame: up to 28 months

Number of Participants Classified as Treatment Responders at Months 3, 6, 9, 12, 15, 18, 21, and 24

Treatment responders at Month X were defined as participants (par.) with either a PSA decrease or an increase \<=15% from baseline to Month X confirmed in all PSA measurements between baseline (BL) and Month X.

Time frame: Months 3, 6, 9, 12, 15, 18, 21, and 24

Time to PSA Rise From Baseline (in Days)

A participant was designated as having a PSA rise if there existed a post-baseline PSA value (within treatment period, typically up to 24-month evaluations) that was \>1.15 times the baseline PSA value, and all subsequent PSA values were \>1.15 times the baseline PSA value. The study day for the first PSA evaluation that qualified for analysis of PSA rise was used for time to PSA rise. If none of the post-baseline PSA values qualified for analysis of PSA rise during the study, time to PSA rise was censored at the last post-baseline PSA evaluation.

Time frame: up to 28 months

Number of Participants With a PSA Rise From Baseline

A participant was designated as having a PSA rise if there existed a post-baseline PSA value (within treatment period, typically up to 24-month evluations) that was \>1.15 times the baseline PSA value, and all subsequent PSA values were \>1.15 times the baseline PSA value.

Time frame: up to 28 months

Time to PSA Progression (in Days)

A participant was designated as having PSA progression if there existed a post-baseline PSA value (within treatment period, typically up to 24-month evaluations) that was \>10 ng/ml if radical prostatectomy or \>20 ng/ml if primary radiotherapy and PSA \>=1.5 times the baseline PSA value, or 0\<PSADT\<=91 days, and all subsequent PSA values satisfied these criteria. The study day for the first PSA qualifying for progression was used for time to PSA progression. If none of the PSA values qualified for PSA progression, time to PSA progression was censored at the last post-baseline PSA evaluation.

Time frame: up to 28 months

Number of Participants With PSA Progression

A participant was designated as having a PSA progression if there existed a post-baseline PSA value (within treatment period, typically up to 24-month evaluations) that was (\>10 ng/ml if radical prostatectomy or \>20 ng/ml if primary radiotherapy) and PSA \>=1.5 times the baseline PSA value), or 0\<PSADT\<=91 days, and all subsequent PSA values satisfied either of these criteria.

Time frame: up to 28 months

Change in Total PSA From Baseline at Months 12 and 24

Change in PSA from baseline at Month X = Month X PSA - Baseline PSA. The missing PSA value for scheduled visits could have been replaced by non-missing PSA values within 30 days after the clinic visit date. If such replacement was not possible, the latest non-missing post-baseline PSA before the scheduled visit was used for the scheduled visit PSA (Last Observation Carried Forward).

Time frame: Baseline; Months 12 and 24

Percent Change in Total PSA From Baseline at Months 12 and 24

Percent change in PSA from baseline at Month X = 100\*(Month X PSA - Baseline PSA)/Baseline PSA. The missing PSA value for scheduled visits could have been replaced by non-missing PSA values within 30 days after the clinic visit date. If such replacement was not possible, the latest non-missing post-baseline PSA before the scheduled visit was used for the scheduled visit PSA (Last Observation Carried Forward).

Time frame: Baseline; Months 12 and 24

Change in PSA From Nadir PSA at Months 12 and 24

Change from nadir PSA at Month X = Month X PSA - nadir PSA. Nadir PSA was reported by the site as the lowest historical PSA value after the radical therapy. A nadir value below the detection level was captured as 0.0. The missing PSA value for scheduled visits could have been replaced by non-missing PSA values within 30 days after the clinic visit date. If such replacement was not possible, the latest non-missing post-baseline PSA before the scheduled visit was used for the scheduled visit PSA (Last Observation Carried Forward).

Time frame: Baseline; Months 12 and 24

Percent Change in PSA From Nadir PSA at Months 12 and 24

Percent change from nadir PSA at Month X = 100\*(Month X PSA - nadir PSA)/Nadir PSA. Nadir PSA was reported by the site as the lowest historical PSA value after the radical therapy. A nadir value below the detection level was captured as 0.0. The missing PSA value for scheduled visits could have been replaced by non-missing PSA values within 30 days after the clinic visit date. If such replacement was not possible, the latest non-missing post-baseline PSA before the scheduled visit was used for the scheduled visit PSA (Last Observation Carried Forward).

Time frame: Baseline; Months 12 and 24

Number of Participants With the Indicated Change in PSA Doubling Time (PSADT) From Baseline at Month 12, Month 24, and End-of-treatment (up to 28 Months)

Participants with improvement included those whose PSADT at a specified visit was positive but more than the baseline PSADT, whose PSA at the visit was the same as the baseline PSA, or whose PSA at the visit was less than the baseline PSA. Participants with worsening included those whose PSADT at the visit was positive but less than the baseline PSADT.

Time frame: Baseline; Month 12, Month 24, End-of-Treatment (up to 28 months)

Changes From Baseline in Disease-related Anxiety Measured by the Memorial Anxiety Scale for Prostate Cancer (MAX-PC)

MAX-PC is an 18-item, self-reported measure that evaluates prostate cancer-related anxiety. The score ranges from 0 to 54, and an increase in the score indicates a worsened anxiety level. Change from Baseline at Month X = Month X MAX-PC score - Baseline MAX-PC score. A missing post-baseline value is replaced by the last available post-baseline value (Last Observation Carried Forward(LOCF)). A general linear model controls for previous therapy, site cluster, and baseline MAX-PC score.

Time frame: Baseline; Months 3, 6, 12, 18, and 24

Number of Participants With a Shift From Normal at Baseline to at Least One Abnormal Laboratory Value for Any Parameter Any Time During the Study

A participant has a normal value for a laboratory parameter if the value is within the low and high range of normal provided by the laboratory. Each laboratory parameter is evaluated for shift from normal at baseline to abnormal any time post-baseline. A participant with any laboratory parameter showing this shift is counted. A participant is counted only once even if he had such a shift in more than one laboratory parameter or more than once among all post-baseline evaluations.