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

Sponsor:	GlaxoSmithKline
Information provided by (Responsible Party):	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00056407

Purpose

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.

Condition	Intervention	Phase
Neoplasms, Prostate Prostate Cancer	Drug: Dutasteride Drug: Placebo	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Prostate Cancer

Drug Information available for: Dutasteride

U.S. FDA Resources

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:

Number of Participants With Biopsy-detectable Prostate Cancer at Years 2 and 4 (Crude Rate Approach) [ Time Frame: Years 1-2, Years 3-4, and Overall (Years 1-4) ] [ Designated as safety issue: No ]
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.
Number of Participants With Biopsy-detectable Prostate Cancer at Years 2 and 4 (Modified Crude Rate Approach) [ Time Frame: Years 1-2, Years 3-4, and Overall (Years 1-4) ] [ Designated as safety issue: No ]
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.
Number of Participants With Biopsy-detectable Prostate Cancer at Years 2 and 4 (Restricted Crude Rate Approach) [ Time Frame: Years 1-2, Years 3-4, and Overall (Years 1-4) ] [ Designated as safety issue: No ]
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.

Secondary Outcome Measures:

Number of Participants With the Indicated Gleason Score at Diagnosis [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
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.
Number of Participants With HGPIN, ASAP, and Prostate Cancer at Biopsy [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
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").
Volume of HGPIN at Biopsy [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
The amount of prostate biopsy tissue with HGPIN was measured.
Percentage of Core Involved at Diagnosis [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
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.
Number of Cancer-positive Cores [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
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.
Treatment Alteration Score [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
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.
Number of Participants Undergoing Intervention (Surgical and Non-surgical) for Prostate Cancer Treatment [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
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).
Adjusted Mean Change From Baseline in the International Prostate Symptom Score (IPSS) at Month 48 [ Time Frame: Baseline to Year 4 (Month 48) ] [ Designated as safety issue: No ]
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.
Adjusted Mean Percentage Change From Baseline in Prostate Volume at Months 24 and 48 [ Time Frame: Baseline, Month 24, and Month 48 ] [ Designated as safety issue: No ]
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).
Adjusted Mean Change From Baseline in Maximum Urinary Flow (Qmax) at Months 12, 24, 36, and 48 [ Time Frame: Baseline and Months 12, 24, 36, and 48 ] [ Designated as safety issue: No ]
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.
Number of Participants Starting Alpha Blockers to Control Benign Prostatic Hyperplasia (BPH) Symptoms [ Time Frame: Years 1-2, Overall (Years 1-4) ] [ Designated as safety issue: No ]
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.
Number of Participants With at Least One Event of Acute Urinary Retention (AUR) [ Time Frame: Years 1-2 and Overall (Years 1-4) ] [ Designated as safety issue: No ]
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.
Number of Participants With at Least One Urinary Tract Infection (UTI) [ Time Frame: Years 1-2, Years 3-4, and Overall (Years 1-4) ] [ Designated as safety issue: No ]
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.
Number of Participants With Post-biopsy Macroscopic Hematuria [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
Participants reported events of macroscopic hematuria (visible blood in the urine) throughout the study.
Number of Participants With Post-biopsy Macroscopic Hematospermia [ Time Frame: Baseline through Year 4 ] [ Designated as safety issue: No ]
Participants reported events of macroscopic hematospermia (visible blood in semen) throughout the study.
Overall Survival [ Time Frame: From time informed consent is signed to 4-month Safety Follow-Up period ] [ Designated as safety issue: No ]
Overall survival is assessed as the number of deaths reported throughout the study.
Adjusted Mean Change From Baseline in the Benign Prostatic Hypertrophy (BPH) Impact Index (BII) at Month 48 [ Time Frame: Baseline and Month 48 ] [ Designated as safety issue: No ]
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.
Adjusted Mean Change From Baseline in The Medical Outcomes Study Sleep Problems Index 6-item Standard Version (MOS Sleep-6S) at Month 48 [ Time Frame: Baseline and Month 48 ] [ Designated as safety issue: No ]
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.
Adjusted Mean Change From Baseline in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH CPSI) at Month 48 [ Time Frame: Baseline and Month 48 ] [ Designated as safety issue: No ]
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.
Adjusted Mean Change From Baseline in Quality of Life Question 8 (QOL Q8) at Month 48 [ Time Frame: Baseline and Month 48 ] [ Designated as safety issue: No ]
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.
Adjusted Mean Change From Baseline in the Problem Assessment Scale of the Sexual Function Index (PASSFI) at Month 48 [ Time Frame: Baseline and Month 48 ] [ Designated as safety issue: No ]
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.
Number of Participants With the Indicated Serum Dihydrotestosterone (DHT) Concentration at Month 48 [ Time Frame: Month 48 ] [ Designated as safety issue: No ]
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.
Mean Change From Baseline in Testosterone at Month 48 [ Time Frame: Baseline and Month 48 ] [ Designated as safety issue: No ]
Testosterone, a male sex hormone, was measured by taking blood samples at screening and yearly thereafter.

Enrollment:	8231
Study Start Date:	March 2003
Study Completion Date:	May 2009
Primary Completion Date:	January 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: Placebo Arm Eligible subjects will complete a 4-week placebo run-in followed by randomization to matched placebo in a 1:1 ratio.	Drug: Placebo 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.
Experimental: dustasteride arm 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 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. Other Name: Dutasteride

More Information

Publications:

Bostwick DG, Qian J, Drewnowska K, Varvel S, Bostwick KC, Marberger M, Rittmaster RS. Prostate needle biopsy quality in reduction by dutasteride of prostate cancer events study: worldwide comparison of improvement with investigator training and centralized laboratory processing. Urology. 2010 Jun;75(6):1406-10. Epub 2009 Nov 25.

Gerald L. Andriole, David G. Bostwick, Otis W. Brawley, Leonard G. Gomella, Michael Marberger, Francesco Montorsi, Curtis A. Pettaway, Teuvo L. Tammela, Claudio Teloken, Donald J. Tindall, Matthew C. Somerville, Timothy H. Wilson, Ivy L. Fowler, Roger S. Rittmaster. Effect of Dutasteride on the Risk of Prostate Cancer. N Engl J Med. 2010;362:1192-202

Gerald L. Andriole on behalf of the REDUCE study group. The Effect of Dutasteride on the Usefulness of Prostate Specific Antigen for the Diagnosis of High Grade and Clinically Relevant Prostate Cancer in Men With a Previous Negative Biopsy: Results From the REDUCE Study. [Journal of Urology]. 2011;185(1):126-131.

E. David Crawford, Gerald Andriole, Michael Marberger, Roger Rittmaster. Reduction in the risk of prostate cancer: future directions after PCPT. Urology. 2009;Dec 24:

G Andriole, D Bostwick, O Brawley, L Gomella, M Marberger, F Montorsi, C Pettaway, T Tammela, C Teloken, D Tindall, M Somerville, I Fowler and R Rittmaster on behalf of the REDUCE Study Group. Risk reduction in men at increased risk: outcomes of the REduction by Dutasteride of prostate Cancer Events (REDUCE) trial. [N Engl J Med]. 2010;362(13):1192-202.

Aubin SMJ, Reid J, Sarno MJ, Blase A, Aussie J, Rittenhouse H, Rittmaster R, Andriole GL, Groskopf J. PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: Validation in the placebo arm of the dutasteride REDUCE trial. [J Urol]. 2010;184(4):1947-52.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nickel JC, Roehrborn C, Montorsi F, Wilson TH, Rittmaster RS. Dutasteride reduces prostatitis symptoms compared with placebo in men enrolled in the REDUCE study. J Urol. 2011 Oct;186(4):1313-8. Epub 2011 Aug 17.

Andriole GL, Bostwick D, Brawley OW, Gomella L, Marberger M, Montorsi F, Pettaway C, Tammela TL, Teloken C, Tindall D, Freedland SJ, Somerville MC, Wilson TH, Fowler I, Castro R, Rittmaster RS; REDUCE Study Group. The effect of dutasteride on the usefulness of prostate specific antigen for the diagnosis of high grade and clinically relevant prostate cancer in men with a previous negative biopsy: results from the REDUCE study. J Urol. 2011 Jan;185(1):126-31. Epub 2010 Nov 12.

Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH, Fowler IL, Rittmaster RS; REDUCE Study Group. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010 Apr 1;362(13):1192-202.

Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00056407 History of Changes
Other Study ID Numbers:	ARI40006
Study First Received:	March 11, 2003
Results First Received:	February 1, 2010
Last Updated:	April 19, 2012
Health Authority:	Canada: Health Canada Sweden: Medical Products Agency United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:

Prostate cancer prevention
prostate
BPH

enlarged prostate
PSA
prostate cancer

Additional relevant MeSH terms:

Neoplasms
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male

Prostatic Diseases
Dutasteride
5-alpha Reductase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 24, 2012

Ages Eligible for Study:	50 Years to 75 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	No