Assessment Of Dutasteride (AVODART) In Extending The Time To Progression Of Low-Risk, Localized Prostate Cancer In Men

Study Overview
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Brief Summary
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The purpose of this study is to examine the effect of dutasteride on the inhibition of low-risk, localized prostate cancer progression in men who would otherwise receive no active therapy (expectant management).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Dutasteride in Extending the Time to Progression of Low-Risk, Localized Prostate Cancer in Men Who Are Candidates for or Undergoing Expectant Management

Conditions
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Neoplasms, Prostate

Intervention / Treatment
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* Drug: Dutasteride
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Must be male ≥48 and ≤82 years of age Have biopsy proven, low-risk, localized prostate cancer and active in expectant management not more than 14 months. [For the purposes of assessing subject eligibility a diagnostic biopsy must have included at least 10 cores, (< 4 cores positive and <50% of any one core positive) and must have been obtained within 8 months of screening]. If a saturation biopsy was performed (20 or more cores obtained) 2-3 cores are to be positive for prostate cancer and with <50% of any one core positive. Initial diagnosis of T1a/T1b obtained during a Transrectal ultrasound (TURP) is not allowed. Gleason score ≤6 [Gleason pattern 4 or above must not be present on any biopsy (initial or entry)] Clinical stage T1c-T2a Serum Prostate Specific Antigen (PSA) ≤11ng/mL. If the screening PSA value from the central laboratory is greater than 11ng/ml, one PSA retest is allowed through the central laboratory A life expectancy greater than five years. Able to swallow and retain oral medication Able and willing to participate in the full 3 years of the study Able to read and write (health outcomes questionnaires are self-administered), understand instructions related to study procedures and give written informed consent. Exclusion criteria: Subject has ever been treated for prostate cancer with any of the following: Radiotherapy (external beam or brachytherapy) Chemotherapy Hormonal therapy (e.g., megestrol, medroxyprogesterone, cyproterone, diethylstilbestrol (DES) Oral glucocorticoids Gonadotropin-releasing hormone (GnRH) analogues (e.g., leuprolide, goserelin) Glucocorticoids, except inhaled or topical, are not permitted within 3 months prior to visit one Current and/or previous use of the following medications: Finasteride (Proscar, Propecia), or Dutasteride (GI198745, AVODART) exposure within 6 months prior to study entry are excluded. Any other investigational 5α-reductase inhibitors within the past 12 months. Anabolic steroids (subject must discontinued for 6 months prior to study entry to be eligible) Drugs with antiandrogenic properties within the past 6 months (e.g,. spironolactone, flutamide, bicalutamide, *cimetidine, *ketoconazole, metronidazole, progestational agents) NOTE: Use of dietary and herbal supplements (e.g., selenium, Vitamin E, saw palmetto) during the study is discouraged but not prohibited. All dietary and herbal supplement usage will be recorded in the case report form (CRF). *The use of cimetidine is permitted prior to study entry. The use of topical ketoconazole is permitted prior to and during the study. Prostate volume >80 cc Subject has had prior prostatic surgery including Transurethral needle ablation of the prostate (TUNA), TURP, Transurethral incision of the prostate (TUIP), laser treatment, thermotherapy, balloon dilatation, prosthesis, and ultrasound ablation within 3 months of enrolment Severe Benign Prostatic Hyperplasia (BPH) symptoms as manifested by International Prostate Symptom Score (IPSS) symptom score (calculated using the first 7 questions only) of ≥25 or >20 if already on alpha blocker therapy. Participation in any investigational or marketed drug trial within the 30 days prior to the first dose of study drug or anytime during the study period. 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 Screening visit; uncontrolled diabetes or peptic ulcer disease which is uncontrolled by medical management. Abnormal liver function test (greater than 2 times the upper limit of normal for alanine aminotransferase [ALT], aspartate aminotransferase [AST], or alkaline phosphatase [ALP]); or bilirubin >1.5 times the upper limit of normal. Serum creatinine >1.5 times the upper limit of normal. History of another malignancy within five years that could affect the diagnosis of prostate cancer. History or current evidence of drug or alcohol abuse within the last 12 months. 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 subject. Known hypersensitivity to any 5α-reductase inhibitor or to any drug chemically related to dutasteride.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dutasteride<br>Dutasteride 0.5mg | Drug: Dutasteride<br>* Dutasteride 0.5mg<br>|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Matching placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Prostate Cancer (PCa) Progression [Restricted Crude Rate Analysis: Number of Participants With PCa Divided by Number of Participants in the Intent-to-Treat (ITT) Population Who Had >=1 Post-baseline Biopsy or Had a Progression | PC progression (prog.) was defined as the earliest occurrence of primary therapy, also referred to as therapeutic prog., for PC (prostatectomy/radiation/hormonal therapy); or pathological prog., defined as 1 of the following: >=4 cores involved; >=50% of any 1 core involved; or a Gleason pattern of >=4 as a result of any on-study/for-cause biopsy. Primary Gleason grade is assigned to the most common tumor pattern; a second grade to the next most common tumor pattern. The two grades are added together to get a score. Gleason grade= 1-5; Gleason score=2-10; 5 and 10 indicate worst prognosis. | Year 1.5 and Overall (Years 0-3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Therapeutic Progression | Primary therapy, also referred to as therapeutic progression, for prostate cancer can be one of the following: prostatectomy, radiation, or hormonal therapy. | Year 1.5 and Overall (Years 0-3) | 
| Number of Participants With Pathologic Progression | Pathological progression is defined as one of the following: >=4 cores involved; >=50% of any 1 core involved; or a Gleason pattern of >=4 as a result of any on-study/for-cause biopsy. The 2005 International Society of Urological Pathologists recommendations for Gleason scoring (GS) were used to grade tumors. A primary grade is assigned to the most common tumor pattern, and a second grade to the next most common tumor pattern. The two grades are added together to get a GS. The Gleason grade=1-5, with 5 having the worst prognosis. The Gleason score=2-10, with 10 having the worst prognosis. | Year 1.5 and Overall (Years 0-3) | 
| Participants With at Least One Post-baseline Biopsy With the Indicated Prostate Cancer (PCa) Diagnosis | All participants were required by protocol to undergo a transrectal ultrasound (TRUS)-guided 12-core prostate biopsy at 1.5 and 3 years or at the end of the study, if the participant discontinued the study early. Any for-cause biopsy (outside of protocol-mandated biopsies) 12 cores were obtained. If a for-cause biopsy occurred within 6 months prior to the protocol-mandated biopsy, the biopsy was counted as the protocol-mandated biopsy. All biopsies were reviewed and analyzed by a central pathologist. | Baseline to Month 18 | 
| Participants With at Least One Post-baseline Biopsy With the Indicated Prostate Cancer (PCa) Diagnosis for Their Final Biopsy | All participants were required by protocol to undergo a TRUS-guided 12-core prostate biopsy at 1.5 and 3 years or at the end of the study, if the participant discontinued the study early. Any for-cause biopsy (outside of protocol-mandated biopsies) 12 cores were obtained. If a for-cause biopsy occurred within 6 months prior to the protocol-mandated biopsy, the biopsy was counted as the protocol-mandated biopsy. The final biopsy is defined as the latest post-baseline biopsy for which the results are available from the central pathology laboratory. | Years 0-3 | 
| Number of Cancer-positive Cores in a 12-core Biopsy | All participants were required by protocol to undergo a TRUS-guided 12-core prostate biopsy at 1.5 and 3 years or at the end of the study, if the participant discontinued the study early. Any for-cause biopsy (outside of protocol-mandated biopsies) 12 cores were obtained. All biopsies were reviewed and analyzed by a central pathologist. . The final biopsy is defined as the latest post-baseline biopsy for which the results are available from the central pathology laboratory. | Baseline, Year 1.5, Year 3, Years 0-3 (Final biopsy) | 
| Change From Baseline in the Number of Cancer-positive Cores in a 12-core Biopsy at Years 1.5, 3, and 0-3 | All participants were required by protocol to undergo a TRUS-guided 12-core prostate biopsy at 1.5 and 3 years or at the end of the study, if the participant discontinued the study early. Any for-cause biopsy (outside of protocol-mandated biopsies) 12 cores were obtained. All biopsies were reviewed and analyzed by a central pathologist. Change from baseline was calculated as the number of cancer-positive cores at post-baseline biopsy minus the number of cancer-positive cores at baseline. | Baseline, Year 1.5, Year 3, Years 0-3 (Final biopsy) | 
| Mean Percentage of Cancer-positive Cores in a 12-core Biopsy | All participants were required by protocol to undergo a TRUS-guided 12-core prostate biopsy at 1.5 and 3 years or at the end of the study, if the participant discontinued the study early. Any for-cause biopsies (outside of protocol-mandated biopsies) 12 cores were obtained. All biopsies were reviewed and analyzed by a central pathologist. The sum of cancer positive cores and the sum of evaluated cores were used to compute the percentage (100* number of positive cores/number of evaluated cores). | Baseline, Year 1.5, Year 3, Years 0-3 (Final biopsy) | 
| Change From Baseline in the Percentage of Cancer-positive Cores in a 12-core Biopsy at Years 1.5, 3, and 0-3 | All participants were required by protocol to undergo a TRUS-guided 12-core prostate biopsy at 1.5 and 3 years or at the end of the study, if the participant discontinued the study early. Any for-cause biopsy (outside of protocol-mandated biopsies) 12 cores were obtained. All biopsies were reviewed and analyzed by a central pathologist. (100 * number of positive cores/number of evaluated cores). | Baseline, Year 1.5, Year 3, Years 0-3 (Final biopsy) | 
| Cumulative Length of Cancer Tumor Core | All participants were required by protocol to undergo a TRUS-guided 12-core prostate biopsy at 1.5 and 3 years or at the end of the study, if the participant discontinued the study early. Any for-cause biopsy (outside of protocol-mandated biopsies) 12 cores were obtained. All biopsies were reviewed and analyzed by a central pathologist. Tumor length is calculated as the number of cores (12) * total tumor length/number of evaluated cores. | Baseline, Year 1.5, Year 3, Years 0-3 (Final biopsy) | 
| Change From Baseline in the Cumulative Length of Cancer Tumor Core at Years 1.5, 3, and 0-3 | All participants were required by protocol to undergo a TRUS-guided 12-core prostate biopsy at 1.5 and 3 years or at the end of the study, if the participant discontinued the study early. Any for-cause biopsy (outside of protocol-mandated biopsies) 12 cores were obtained. All biopsies were reviewed and analyzed by a central pathologist. | Baseline, Year 1.5, Year 3, Years 0-3 (Final biopsy) | 
| Number of Participants With the Indicated Change From Baseline in Gleason Score (GS) on Repeat Biopsy at Year 1.5 | The 2005 International Society of Urological Pathologists recommendations for Gleason scoring were used to grade tumors. A primary grade is assigned to the most common tumor pattern (how the cancer cells look under a microscope), and a second grade to the next most common pattern. The two grades are added together to get a GS. Gleason grade range= 1-5; 5=worst prognosis. GS range=2-10; 10=worst prognosis. Improvement is defined as a decrease in GS from a baseline score of 6 (GS<=6; includes no cancer); worsening is defined as an increase in GS from a baseline score of 6 (GS >6). | Year 1.5 | 
| Number of Participants With the Indicated Change From Baseline in Gleason Score on Repeat Biopsy at Years 0-3 | The 2005 International Society of Urological Pathologists recommendations for Gleason scoring were used to grade tumors. A primary grade is assigned to the most common tumor pattern (how the cancer cells look under a microscope), and a second grade to the next most common pattern. The two grades are added together to get a GS. Gleason grade range= 1-5; 5=worst prognosis. GS range=2-10; 10=worst prognosis. Improvement is defined as a decrease in GS from a baseline score of 6 (GS<=6; includes no cancer); worsening is defined as an increase in GS from a baseline score of 6 (GS >6). | Years 0-3 (Final Biopsy) | 
| Number of Participants With the Indicated Total Gleason Score | All on-study or for-cause biopsies were reviewed and analyzed by a central pathologist. The 2005 International Society of Urological Pathologists recommendations for Gleason scoring were used to grade the tumor. A primary grade is assigned to the most common tumor pattern (how the cancer cells look under a microscope), and a secondary grade to the next most common tumor pattern. The two grades are added together to get a GS. The Gleason grade ranges from 1 to 5, with 5 having the worst prognosis. The Gleason score ranges from 2 to 10, with 10 having the worst prognosis. | Years 0-3 (Final Biopsy) | 
| Number of Biopsies With the Indicated Clinical Tumor Stage at Baseline | All on-study or for-cause biopsies were reviewed and analyzed by a central pathologist. The 2005 International Society of Urological Pathologists recommendations for clinical tumor staging were used. T1c = tumor identified by needle biopsy (e.g., because of elevated prostate-specific antigen [PSA]); T2 = tumor confined within the prostate; T2a = tumor involves one-half of one lobe, but not both lobes of the prostate. | Baseline | 
| Number of Post-baseline Biopsies With the Indicated Change From Baseline in Clinical Stage | All on-study or for-cause biopsies were reviewed and analyzed by a central pathologist. The National Comprehensive Network (NCCN), 2005 clinical practices guidelines in Oncology-prostate cancer were used for clinical tumor staging. T0: no evidence of primary tumor; T1: clinically inapparent tumor, neither palpable nor visible by imaging; T2: tumor confined within the prostate; T3: tumor extends through the prostate capsule; T4: tumor is fixed or invades adjacent structures other than seminal vesicles. A clinical stage of T0 in post-baseline biopsies has been interpreted as No Worsening. | Months 0-18 | 
| Prostate Volume (PV) LOCF | Prostate volume was determined at baseline, at Year 1.5, and at Year 3. The anteroposterior, cephalocaudal, and transverse diameters of the prostate were obtained by transrectal ultrasound (TRUS) to calculate the prostate volume using the following formula: π/ 6 (anteroposterior width * cephalocaudal width * transverse width). Prostate volume calculated by pre-programmed equipment is unacceptable for the on-study prostate volume measurements. | Baseline and Years 1.5 and 3 | 
| Change From Baseline in Prostate Volume at Years 1.5 and 3 | Prostate volume was determined at baseline, Year 1.5, and Year 3. The anteroposterior, cephalocaudal, and transverse diameters of the prostate were obtained by transrectal ultrasound (TRUS) to calculate the prostate volume using the following formula: π/ 6 (anteroposterior width * cephalocaudal width * transverse width). Prostate volume calculated by pre-programmed equipment was unacceptable for the on-study prostate volume measurements. | Baseline and Years 1.5 and 3 | 
| Percent Change From Baseline in Prostate Volume at Years 1.5 and 3 | Prostate volume was determined at baseline, Year 1.5, and Year 3. The anteroposterior, cephalocaudal, and transverse diameters of the prostate were obtained by transrectal ultrasound (TRUS) to calculate the prostate volume using the following formula: π/ 6 (anteroposterior width * cephalocaudal width * transverse width). Prostate volume calculated by pre-programmed equipment is unacceptable for the on-study prostate volume measurements. | Baseline and Years 1.5 and 3 | 
| Total Memorial Anxiety Scale Scores for Prostate Cancer (MAX-PC) | The MAX-PC is a self-reported measure evaluating three aspects of PC-related anxiety: general anxiety related to PC/treatment, fear of recurrence, and anxiety related to PSA testing. The MAX-PC consists of 18 questions, each score ranging from 0 (least anxiety) to 3 (maximum anxiety). Total score is the sum of each question score, thus ranging from 0 to 54. A higher MAX-PC score indicates greater anxiety. At Months 18 and 36, participants were given an additional copy of the questionnaire and were asked to complete at home once they were notified of their PSA result and to send back to clinic. | Baseline and Month 3, 6, 12, 18, and 36 | 
| Change From Baseline in Total Memorial Anxiety Scale Scores for Prostate Cancer (MAX-PC) LOCF | The MAX-PC is a self-reported measure evaluating three aspects of PC-related anxiety: general anxiety related to PC/treatment, fear of recurrence, and anxiety related to PSA testing. The MAX-PC consists of 18 questions, each score ranging from 0 (least anxiety) to 3 (maximum anxiety). Total score is the sum of each question score, thus ranging from 0 to 54. A higher MAX-PC score indicates greater anxiety. At Months 18 and 36, participants were given an additional copy of the questionnaire and were asked to complete at home once they were notified of their PSA result and to send back to clinic. | Baseline and Months 3, 6, 12, 18, and 36 | 
| Total MAX-PC Anxiety Subscale Score Related to PSA Testing | The MAX-PC anxiety subscale consists of 3 questions related to PSA testing; I have been so anxious about my PSA test that I have thought about delaying it., I have been so worried about my PSA test result that I have thought about asking my doctor to repeat the test., I have been so concerned about my PSA test result that I have thought about having the test repeated at another laboratory to make sure the test results were accurate. A higher MAX-PC score indicates greater anxiety.Scores range from 0 to 3 for each question. The total score is the sum of the 3 question scores; 0 to 9. | Baseline and Months 3, 6, 12, 18, and 36 | 
| Change From Baseline in MAX-PC Anxiety Subscale Score Related to PSA Testing (LOCF) | The MAX-PC anxiety subscale consists of 3 questions related to PSA testing; I have been so anxious about my PSA test that I have thought about delaying it., I have been so worried about my PSA test result that I have thought about asking my doctor to repeat the test., I have been so concerned about my PSA test result that I have thought about having the test repeated at another laboratory to make sure the test results were accurate. A higher MAX-PC score indicates greater anxiety.Scores range from 0 to 3 for each question. The total score is the sum of the 3 question scores; 0 to 9. | Baseline and Months 3, 6, 12, 18, and 36 | 
| Total MAX-PC Fear of Recurrence Subscale Score | The MAX-PC fear of recurrence subscale consists of 4 questions related to fear of recurrence; Because cancer is unpredictable, I feel I cannot plan for the future., My fear of having my cancer getting worse gets in the way of my enjoying life., I am afraid of my cancer getting worse., I am more nervous since I was diagnosed with prostate cancer. A higher MAX-PC score indicates greater anxiety. Scores range from 0 to 3 for each question. The total score is the sum of the 4 question scores: 0 to 12. | Baseline and Months 3, 6, 12, 18, and 36 | 
| Change From Baseline in MAX-PC Fear of Recurrence Subscale Score (LOCF) | The MAX-PC fear of recurrence subscale consists of 4 questions related to fear of recurrence; Because cancer is unpredictable, I feel I cannot plan for the future., My fear of having my cancer getting worse gets in the way of my enjoying life., I am afraid of my cancer getting worse., I am more nervous since I was diagnosed with prostate cancer. A higher MAX-PC score indicates greater anxiety. Scores range from 0 to 3 for each question. The total score is the sum of the 4 question scores: 0 to 12. | Baseline and Months 3, 6, 12, 18, and 36 | 
| Total Functional Assessment of Cancer Therapy Scale, Prostate Module (FACT-P) Score | The FACT-P consists of a total of 39 questions. This scale is divided into five subscales: the Physical Well-Being Subscale (7 questions); the Social/Family Well-Being Subscale (7 questions); the Emotional Well-Being Subscale (6 questions); the Functional Well-Being Subscale (7 questions); and the Prostate Cancer Subscale (12 questions). The score for each of the 39 questions ranges from 0 to 4. The total FACT-P score thus ranges from 0 to156; a higher score indicates better quality of life. | Baseline and Months 18 and 36 | 
| Change From Baseline in Total FACT-P Score (LOCF) | The FACT-P consists of a total of 39 questions. This scale is divided into five subscales: the Physical Well-Being Subscale (7 questions); the Social/Family Well-Being Subscale (7 questions); the Emotional Well-Being Subscale (6 questions); the Functional Well-Being Subscale (7 questions); and the Prostate Cancer Subscale (12 questions). The questionnaire was administered at baseline and at Months 18 and 36. The score for each of the 39 questions ranges from 0 to 4. The total FACT-P score thus ranges from 0 to156; a higher score indicates better QOL. | Baseline and Months 18 and 36 | 
| Percent Change From Baseline in Total FACT-P Score (LOCF) | The FACT-P consists of a total of 39 questions. This scale is divided into five subscales: the Physical Well-Being Subscale (7 questions); the Social/Family Well-Being Subscale (7 questions); the Emotional Well-Being Subscale (6 questions); the Functional Well-Being Subscale (7 questions); and the Prostate Cancer Subscale (12 questions). The questionnaire was administered at baseline and at Months 18 and 36. The score for each of the 39 questions ranges from 0 to 4. The total FACT-P score thus ranges from 0 to156; a higher score indicates better QOL. | Baseline and Months 18 and 36 | 
| Change From Baseline in FACT-P Physical Well-Being Subscale Score (LOCF) | The FACT-P Physical Well-Being subscale is divided into 7 questions, and the participants rated the outcome over the past 7 days; I have a lack of energy., I have nausea., Because of my physical condition, I have trouble meeting the needs of my family., I have pain., I am bothered by side effects of treatment., I feel ill., I am forced to spend time in bed. The score for each question ranges from 0 to 4; a lower score indicates better physical well-being. The total FACT-P score thus ranges from 0 to156; a higher score indicates a better quality of life. | Baseline and Months 18 and 36 | 
| Change From Baseline in FACT-P Social Well-Being Subscale Score (LOCF) | The FACT-P Social Well-Being subscale is divided into 7 questions, and the participants rated the outcome over the past 7 days; I feel close to my friends., I get emotional support from my family., I get support from my friends., My family has accepted my illness., I am satisfied with family communication about my illness., I feel close to my partner (or the person who is my main support)., I am satisfied with my sex life. The score for each question ranges from 0 to 4; a higher score indicates better social well-being. The total FACT-P score thus ranges from 0 to 156. | Baseline and Months 18 and 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dutasteride Prostate Cancer Expectant management REDEEM