ARTS - AVODART After Radical Therapy For Prostate Cancer Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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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

Conditions
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Neoplasms, Prostate, Prostate Cancer After a Radical Treatment

Intervention / Treatment
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* Drug: Avodart
* Other: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avodart<br>Patients will receive a 3-month supply of study drug or placebo. Patients will be instructed to take one capsule by mouth once daily. Study medication will be supplied at 3-month intervals during scheduled clinic visits for a total of 24 months. | Drug: Avodart<br>* 0.5 mg administered orally once daily<br>* Other names: Avodart/placebo;|
| Placebo Comparator: Placebo Arm<br>Patients will receive a 3-month supply of study drug or placebo. Patients will be instructed to take one capsule by mouth once daily. Study medication will be supplied at 3-month intervals during scheduled clinic visits for a total of 24 months. | Other: placebo<br>* Patients will be randomized at Visit 2 in 1:1 ratio to receive either 0.5 mg dutasteride or placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | up to 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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.) | 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). | 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. | 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. | 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. | 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. | 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. | 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). | 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). | 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). | 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). | 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. | 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. | 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. | Baseline; up to 28 months | 
| Number of Participants With a Threshold Laboratory Value for Any Parameter at Baseline (BL) and Any Time Post-baseline | Threshold laboratory values are defined in terms of a multiplicative factor of the testing laboratory's normal range, pre-specified in the analysis plan. A laboratory value that is above the upper limit factor multiplied by the upper limit of the normal range is considered a high threshold value. A laboratory value that is below the lower limit factor multiplied by the lower limit of the normal range is considered a low threshold value. | Baseline; up to 28 months | 
| Number of Participants With Palpable Breast Tissue (PBT) at Baseline (BL) and Any Time Post-baseline | Participants underwent clinical examination of the breasts, to evaluate for palpable breast tissue. Clinical significance of the results was determined by subjective judgment of the clinical personnel performing the examination. | Baseline; up to 28 months | 
| Number of Participants With Nipple Tenderness (NT) at Baseline (BL) and Any Time Post-baseline | Participants underwent clinical examination of the breasts, to evaluate for nipple tenderness. Clinical significance of the results was determined by subjective judgment of the clinical personnel performing the examination. | Baseline; up to 28 months | 
| Number of Participants With a Digital Rectal Examination (DRE) Evaluation Changing From Normal/Diffusely Enlarged at Baseline to Focal Abnormality at Any Time Post-baseline | Participants underwent a digital rectal examination to evaluate for focal abnormality of the prostate. | Baseline; up to 28 months | 
| Number of Participants With Threshold Vital Signs at Baseline and Any Time Post-baseline | Threshold vital signs are defined as follows: < 80 mmHg or > 165 mmHg for systolic blood pressure; < 40 mmHg or > 105 mm Hg for diastolic blood pressure, < 40 beats per minute (bpm) or > 100 bpm for heart rate. | Baseline; up to 28 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, AVODART, PSA, dutasteride, PSADT, Prostate specific antigen, radical therapy, doubling time