REDUCE - A Clinical Research Study To Reduce The Incidence Of Prostate Cancer In Men Who Are At Increased Risk

Study Overview
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Brief Summary
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This 4-year study will compare how safe and effective an oral investigational medicine is (compared to placebo) in preventing the development of prostate cancer in men that are defined by the study entrance criteria as being at an increased risk for prostate cancer. Study visits to the clinic will occur every 6 months for up to 4 years (10 clinic visits), and a prostate biopsy will be performed at 2 and 4 years of treatment.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5 mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer

Conditions
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Neoplasms, Prostate

Intervention / Treatment
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* Drug: Dutasteride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Informed consent to participate in study. Have had a single negative prostate biopsy within 6 months prior to enrollment in study. Have a PSA (prostate specific antigen) between 2.5 and 10 if 50-60 years of age; or a PSA between 3.0 and 10 if over age 60. Ability and will to participate in study for 4 years. Exclusion criteria: More than one previous negative prostate biopsy. History of prostate cancer. Previous prostate surgery. Inability to urinate requiring the need of a catheter during the previous 2 years. Any condition (other than benign prostatic hypertrophy) which may result in urinary symptoms or changes in urine flow rate. Cancer within previous 5 years (other than basal or squamous cell cancers of the skin). Any unstable serious medical condition. Use within the past 12 months of finasteride (Proscar or Propecia), dutasteride (Avodart), testosterone, or drugs that can block the action of male hormones.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Arm<br>Eligible subjects will complete a 4-week placebo run-in followed by randomization to matched placebo in a 1:1 ratio. | Drug: Placebo<br>* After successful completion of the placebo run-in phase, subjects who continue to meet eligibility requirements will be randomized into the double-blind phase of the study and issued a 6-month supply of study drug. Subjects will self-administer study drug once daily orally for up to 4 years.<br>|
| Experimental: dustasteride arm<br>Eligible subjects will complete a 4-week placebo run-in followed by randomization to 0.5mg dutasteride in a 1:1 ratio. Randomization will be stratified by center. | Drug: Dutasteride<br>* After successful completion of the placebo run-in phase, subjects who continue to meet eligibility requirements will be randomized into the double-blind phase of the study and issued a 6-month supply of study drug. Subjects will self-administer study drug once daily dosing of 0.5mg of dutasteride orally for up to 4 years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Biopsy-detectable Prostate Cancer at Years 2 and 4 (Crude Rate Approach) | Study biopsies consisted of 10 biopsy samples (cores) in a pre-defined pattern. Biopsies were read at the central pathology laboratory (CPL, which processed the majority, 94%, of biopsies). Biopsy cases that were positive for prostate cancer or precancerous lesions (high-grade prostatic intraepithelial neoplasia[HGPIN] or typical small acinar proliferation [ASAP]) and prostate surgeries were reviewed by the lead pathologist. | Years 1-2, Years 3-4, and Overall (Years 1-4) | 
| Number of Participants With Biopsy-detectable Prostate Cancer at Years 2 and 4 (Modified Crude Rate Approach) | Study biopsies (biop.) consisted of 10 biop. samples (cores) in a pre-defined pattern and were read at the central pathology laboratory. Biop. cases that were positive for prostate cancer or precancerous lesions (HGPIN or ASAP) and prostate surgeries were reviewed by the lead pathologist. Participants included in the risk sets at Years 1-2 and Years 3-4 included those with a positive biop. at Years 1-2 or a biop. after Months 18-24, and those with a positive biop. at Years 3-4 or a biop. after Month 42, respectively. Overall included participants with a positive biop. or biop. after Month 42. | Years 1-2, Years 3-4, and Overall (Years 1-4) | 
| Number of Participants With Biopsy-detectable Prostate Cancer at Years 2 and 4 (Restricted Crude Rate Approach) | Study biopsies consisted of 10 biopsy samples (cores) in a pre-defined pattern. Biopsies were read at the central pathology laboratory (which processed the majority, 94%, of biopsies). Biopsy cases that were positive for prostate cancer or precancerous lesions (HGPIN or ASAP) and prostate surgeries were reviewed by the lead pathologist. Participants included in the risk set at Years 1-2, Years 3-4, and Overall (Years 1-4) were those who had a biopsy during the specified time period. | Years 1-2, Years 3-4, and Overall (Years 1-4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Gleason Score at Diagnosis | Gleason score was determined by examining prostate biopsies and surgical samples. The Gleason scoring system sums the two most common Gleason grade patterns in order to predict the likelihood of a participant doing well or badly with their cancer. Gleason grades range from 1 (normal) to 5 (advanced cancer). The lowest Gleason score is 2 (1+1), and the highest Gleason score is 10 (5+5). A Gleason score of 2-6 is a low-grade cancer; a Gleason score of 7-10 is high-grade cancer. The most severe high-grade cancers are the subset of Gleason scores 8-10. | Baseline to Year 4 | 
| Number of Participants With HGPIN, ASAP, and Prostate Cancer at Biopsy | The occurrence and quantity of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) at biopsy were measured. HGPIN and ASAP are considered precancerous conditions. A participant diagnosed with prostate cancer only (i.e., no HGPIN or ASAP) was counted in both the first category (HGPIN or prostate cancer diagnosis) and again in the last category (HGPIN, ASAP, or prostate cancer diagnosis). | Baseline to Year 4 | 
| Volume of HGPIN at Biopsy | The amount of prostate biopsy tissue with HGPIN was measured. | Baseline to Year 4 | 
| Percentage of Core Involved at Diagnosis | The average amount of cancer seen by the pathologist in the prostate tissue samples taken during the biopsy was measured. A core is a prostate biopsy sample. | Baseline to Year 4 | 
| Number of Cancer-positive Cores | The average number of prostate biopsy samples (cores) determined to be cancerous by the pathologist was measured. Normally, 10 cores were taken per biopsy for each participant. | Baseline to Year 4 | 
| Treatment Alteration Score | The treatment alteration score is a measure of the cellular changes due to treatment (effect of male hormone withdrawal) on the nucleus and cytoplasm of the prostate cancer cell. The treatment alteration score is the sum of two scores (the nuclear alteration score and the cytoplasmic architectural score), each ranging from 0 to 3, with 0 indicating no change and 3 indicating severe changes. | Baseline to Year 4 | 
| Number of Participants Undergoing Intervention (Surgical and Non-surgical) for Prostate Cancer Treatment | The number of participants who received treatment for prostate cancer was measured. Prostate cancer interventions included surgical interventions (e.g., prostatectomy, adenomectomy, transurethral resection) and non-surgical interventions (e.g., chemotherapy, hormone therapy, radiation therapy). | Baseline to Year 4 | 
| Adjusted Mean Change From Baseline in the International Prostate Symptom Score (IPSS) at Month 48 | The IPSS is a 7-item questionnaire that measures urinary symptoms. It measures the level of urinary symptoms (including incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) reported as the total IPSS score. Each of the 7 questions has a 6-point response scale (0=none/not at all to 5=almost always) with a total score that can range from 0-35: mild (0-7), moderate (8-19), or severe (20-35). Estimates are based on adjusted means from the general linear model: change from baseline = baseline value and cluster and treatment. | Baseline to Year 4 (Month 48) | 
| Adjusted Mean Percentage Change From Baseline in Prostate Volume at Months 24 and 48 | Prostate volume was measured by transrectal ultrasound (TRUS) when biopsies were performed at Year 2 and Year 4. The investigator calculated the prostate volume using three prostate measurements (anteroposterior, cephalocaudal, and transverse diameters). Estimates are based on the adjusted means from the general linear model: log(Post-Baseline/Baseline value) = treatment and cluster and log (baseline value). | Baseline, Month 24, and Month 48 | 
| Adjusted Mean Change From Baseline in Maximum Urinary Flow (Qmax) at Months 12, 24, 36, and 48 | Maximum urinary flow was measured at selected sites using a Dantec Uroflow meter with a Thompson filter. Change from baseline was calculated as Month 12, 24, 36, and 48 values minus the baseline value. Estimates are based on the adjusted means from the general linear model: change from baseline = baseline Qmax and treatment. This measurement was performed at selected centers. | Baseline and Months 12, 24, 36, and 48 | 
| Number of Participants Starting Alpha Blockers to Control Benign Prostatic Hyperplasia (BPH) Symptoms | Medication taken during the study, including alpha blockers, was recorded at each 6-month study visit and during phone calls that occurred 3 months after each visit. | Years 1-2, Overall (Years 1-4) | 
| Number of Participants With at Least One Event of Acute Urinary Retention (AUR) | A participant was considered to have AUR when he reported being unable to urinate and required catherization. Participants were asked to report any events of AUR during the study. | Years 1-2 and Overall (Years 1-4) | 
| Number of Participants With at Least One Urinary Tract Infection (UTI) | A participant was considered to have a UTI if the investigator noted that the participant had UTI symptoms and had been prescribed antibiotics. Participants were asked to report any events of UTI during the study. | Years 1-2, Years 3-4, and Overall (Years 1-4) | 
| Number of Participants With Post-biopsy Macroscopic Hematuria | Participants reported events of macroscopic hematuria (visible blood in the urine) throughout the study. | Baseline to Year 4 | 
| Number of Participants With Post-biopsy Macroscopic Hematospermia | Participants reported events of macroscopic hematospermia (visible blood in semen) throughout the study. | Baseline through Year 4 | 
| Overall Survival | Overall survival is assessed as the number of deaths reported throughout the study. | From time informed consent is signed to 4-month Safety Follow-Up period | 
| Adjusted Mean Change From Baseline in the Benign Prostatic Hypertrophy (BPH) Impact Index (BII) at Month 48 | The BII is a 4-item questionnaire that rates the level of BPH-related physical discomfort, worry, and interference with normal activities the participant has experienced. The total BII score ranges from 1 (no impact on symptoms) to 13 (major impact on symptoms). Participants completed the questionnaire at Baseline and at each 6-month visit. Participants whose language did not have a validated translation of the questionnaire did not participate. Estimates are based on the adjusted means from the general linear model:change from baseline = baseline value and cluster and treatment. | Baseline and Month 48 | 
| Adjusted Mean Change From Baseline in The Medical Outcomes Study Sleep Problems Index 6-item Standard Version (MOS Sleep-6S) at Month 48 | The MOS Sleep-6S is a 6-item questionnaire measuring quality of sleep. Scores range from 1 (all of the time) to 6 (none of the time) and are converted to a 1-100 scale and then averaged; a higher score indicates greater negative impact, which indicates more sleep disturbance. Participants completed the questionnaire at Baseline and at each 6-month visit. Participants whose language did not have a validated translation of the questionnaire did not participate. Estimates are based on the adjusted means from the general linear model: change from baseline=baseline value and cluster and treatment. | Baseline and Month 48 | 
| Adjusted Mean Change From Baseline in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH CPSI) at Month 48 | The NIH CSPI is a 9-item questionnaire that measures chronic prostatitis symptoms. The total score ranges from 0 to 43. A higher score indicates greater negative impact of prostatitis. Participants completed the questionnaire at Baseline and at each 6-month visit. Participants whose language did not have a validated translation of the questionnaire did not participate. Estimates are based on the adjusted means from the general linear model: change from Baseline = Baseline Value and Cluster and Treatment. | Baseline and Month 48 | 
| Adjusted Mean Change From Baseline in Quality of Life Question 8 (QOL Q8) at Month 48 | The QOL Q8 is the last question of the IPSS Questionnaire. It is a question about the participant's quality of life as it relates to prostate symptoms. Responses range from 0 (most positive) to 6 (most negative). A higher score indicates worse quality of life. Participants completed the questionnaire at Screening, Baseline, and at each 6-month visit. Estimates are based on the adjusted means from the general linear model: change from baseline = baseline value and cluster and treatment. | Baseline and Month 48 | 
| Adjusted Mean Change From Baseline in the Problem Assessment Scale of the Sexual Function Index (PASSFI) at Month 48 | The PASSFI is a 3-item questionnaire that measures sexual function. Responses range from 0 (big problem) to 4 (no problem), with a total score of 12. A higher score indicates fewer problems with sexual functioning. Participants completed the questionnaire at Baseline and then yearly . Participants whose language did not have a validated translation of the questionnaire did not participate. Estimates are based on the adjusted means from the general linear model: change from baseline = baseline value and cluster and treatment. | Baseline and Month 48 | 
| Number of Participants With the Indicated Serum Dihydrotestosterone (DHT) Concentration at Month 48 | Number of participants whose DHT, the active form of the male sex hormone testosterone, was less than 0.555 nanomoles/liter and below the level of detection at Month 48 was measured. It was measured by taking blood samples at screening and yearly thereafter. | Month 48 | 
| Mean Change From Baseline in Testosterone at Month 48 | Testosterone, a male sex hormone, was measured by taking blood samples at screening and yearly thereafter. | Baseline and Month 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate cancer prevention, prostate, BPH, enlarged prostate, PSA, prostate cancer