Study No.: ARIB3003 (Year 1) Title: A Randomized, Double-Blind, Placebo-Controlled, Two-Year Parallel-Group Study of the Efficacy and Safety of GI198745 in the Treatment and Modification of Progression of Benign Prostatic Hyperplasia, Followed by a Two Year Open-Label GI198745 Treatment Phase (Report on Year 1 Data). Rationale: ARIB3003 is one of three large (approximately 1500 subjects) Phase III studies (ARIA3001 and ARIA3002) of a similar type and duration assessing the efficacy and safety of dutasteride () in subjects with benign prostatic hyperplasia (BPH) over a 4-year treatment period. ARIB3003 was designed to examine the effect of on the treatment of BPH using both subjective (American Urological Association Symptom Index [AUA-SI]), and objective (prostate volume, urine flow) assessments. The longer-term effect of on disease management (as measured by the incidence of acute urinary retention [AUR] and surgical intervention), and the effects of treatment on health status, will be examined over a 2-year treatment period. Phase: III Study Period: 06 October 1997 14 February 2000 Study Design: Randomized, double-blind, placebo-controlled, 2-year parallel group study Centers: 205 in Australia, Belgium, Canada, Denmark, Finland, France, Germany, Greece, The Netherlands, Norway, New Zealand, Poland, Portugal, South Africa, Spain, Sweden, Switzerland, UK and the US Indication: BPH Treatment: Four weeks of, in a run-in phase, followed by two years of 0.5mg or once daily. Objectives: This report presents results from Year 1 of the double-blind treatment phase. The primary objective for Year 1 of this study was to assess efficacy (AUA-SI) of repeat oral once daily dosing of 0.5mg compared with. Primary Outcome/Efficacy Variable: The primary efficacy outcome for the Year 1 report was the improvement from baseline in symptom scores (AUA-SI). Secondary Outcome/Efficacy Variable: The secondary efficacy measures were the percentage change in prostate volume and change from baseline in maximum urine flow (Qmax). Statistical Methods: Five hundred (500) subjects per treatment group would provide > 90% power at the 0.05 significance level to detect a 1.5 unit difference in AUA-SI between and (assuming 7.0 units as the standard deviation) at Month 12. The reported p-values corresponded to the pairwise comparisons between and. All statistical analyses were performed using two-sided tests of significance. To address multiplicity in terms of statistical testing at multiple time points and separately for multiple prostate volume subgroups, a closed test principle was employed. All treatment comparisons were reported; however, interpretation was restricted. The two treatment groups were compared beginning at Month 12 at the 0.05 significance level. If significant, then statistical comparisons at earlier post baseline assessments continued in a step-down manner at the 0.05 level of significance. The impact of this method of addressing multiple time points and subgroups is that failure to reach statistical significance in the above defined hierarchy implied restriction of interpretation for the next lower hierarchical point. The population of subjects which was statistically analyzed was the Intent-to-Treat population 1
which consisted of all subjects randomized to double-blind study treatment (after the 4-week placebo run-in) who received at least one dose of study treatment. Study Population: Male, 50 years of age, with a diagnosis of BPH (according to medical history and physical exam, including a digital rectal exam [DRE]), AUA-SI 12, a urinary flow rate of 15mL/sec with a minimum voided volume of 125mL, and a prostate volume of 30cc as determined by transrectal ultrasound. Subjects were excluded if they had a post void residual volume >250mL or a serum PSA <1.5ng/mL or >10.0ng/mL. Number of Subjects: Planned N 500 500 Randomized N 769 753 Completed n (%) 628 (81.7) 621 (82.5) Withdrawn n (%) 141 (18.3) 132 (17.5) Withdrawn due to Adverse 49 (6%) 41 (5%) Events n (%) Withdrawn due to Lack of 25 (3%) 39 (5%) Efficacy n (%) Withdrawn for other reasons 67 (9%) 52 (7%) n (%) Demographics N (ITT) 769 753 Females: Males 0:769 0:753 Mean Age in Years (SD) 66.4 (7.08) 65.7 (7.23) Mean Weight in Kg (SD) 82.2 (12.71) 81.8 (12.34) White n (%) 727 (94.5) 709 (94.2) Primary Efficacy Results: Intention-to-treat and last observation carried forward (LOCF) AUA-SI Change from Baseline Mean (SD) baseline AUA-SI 16.9 (5.95) 17.1 (5.96) Month 1 n=737 n=723 Adjusted mean -1.5-1.4-0.1 95% Confidence Interval -0.6, 0.4 p-value 0.78 Month 3 n=750 n=738 Adjusted mean -2.7-2.8 0.0 95% Confidence Interval -0.5, 0.6 p-value 0.90 Month 6 n=750 n=741 Adjusted mean -3.4-2.8-0.6 95% Confidence Interval -1.2, -0.0 p-value 0.038 Month 12 n=750 n=742 2
Adjusted mean -4.1-2.9-1.2 95% Confidence Interval -1.8, -0.6 p-value <0.001 Secondary Efficacy Results: ITT and LOCF Prostate Volume Percent Change from Baseline Mean (SD) baseline prostate 54.8 (23.88) 53.5 (21.15) volume Month 6 n=674 n=672 Adjusted mean -24.7-7.8-16.9 95% Confidence Interval -19.1, -14.6 Month 12 n=682 n=682 Adjusted mean -27.6-6.0-21.5 95% Confidence Interval -23.9, -19.2 Maximum Urine Flow (Qmax) Change from Baseline (ml/sec) Mean (SD) baseline Qmax 10.1 (3.34) 9.9 (3.56) Month 1 n=710 n=693 Adjusted mean 1.0 0.5 0.5 95% Confidence Interval 0.2, 0.9 Month 3 n=742 n=724 Adjusted mean 1.6 0.6 1.0 95% Confidence Interval 0.6, 1.3 Month 6 n=743 n=730 Adjusted mean 1.5 0.7 0.9 95% Confidence Interval 0.5, 1.2 Month 12 n=744 n=732 Adjusted mean 1.7 0.6 1.1 95% Confidence Interval 0.7, 1.5 3
Safety Results: Adverse events were coded and grouped by body system. Most Frequent Adverse Events - On Therapy N (ITT) 769 753 Subjects with AEs (%) 502 (65) 428 (57) Impotence 53 (7) 26 (3) Viral ear nose and throat 34 (4) 34 (5) infections Viral respiratory infections 34 (4) 42 (6) Musculoskeletal pain 34 (4) 53 (7) Altered (decreased) libido 32 (4) 20 (3) Ear nose and throat 30 (4) 25 (3) infections Hypertension 24 (3) 23 (3) Headaches 22 (3) 28 (4) Bronchitis 21 (3) 21 (3) Dysuria 21 (3) 9 (1) Malaise and fatigue 18 (2) 28 (4) Diarrhea 16 (2) 22 (3) Abdominal discomfort and 11 (1) 22 (3) pain Serious Adverse Events - On Therapy Subjects with SAEs, n (%) 71 (9) [1] 47 (6) [1] [considered by the investigator to be related, possibly related or probably related to study medication] Myocardial infarction 11 (1) [0] 8 (1) [0] Angina pectoris 5 (<1) [0] 6 (<1) [1] Cerebrovascular accidents 5 (<1) [0] 2 (<1) [0] Tachyarrhythmias 5 (<1) [0] 1 (<1) [0] Coronary artery disorders 2 (<1) [0] 3 (<1) [0] Biventricular heart failure 2 (<1) [0] 2 (<1) [0] Arrhythmias 2 (<1) [0] 1 (<1) [0] Cardiac disorders 1 (<1) [0] 1 (<1) [0] Peripheral ischemia Cerebrovascular disorders Disturbances of intracranial blood flow Atherosclerosis and arteriosclerosis Aneurysms Varicosities Cardiac failure Pneumonia 4 (<1) [0] 3 (<1) [0] Asthma 1 (<1) [0] 1 (<1) [0] 4
Primary malignant lower 1 (<1) [0] 1 (<1) [0] respiratory neoplasia Bacterial respiratory infections Bronchitis Lower respiratory hemorrhage Secondary malignant lower respiratory neoplasia Urinary infections 2 (<1) [0] 2 (<1) [0] Primary malignant urinary 2 (<1) [0] 1 (<1) [0] neoplasia Dysuria 2 (<1) [0] 0 Urinary tract obstruction Urinary tract signs and symptoms Urinary neoplasia of uncertain behavior Urinary polyps Primary malignant male 5 (<1) [0] 3 (<1) [0] reproductive neoplasia Inflammation of prostate Primary malignant breast neoplasia Diverticulosis 1 (<1) [0] 1 (<1) [0] Gastroduodenitis Gastrointestinal hemorrhage Gastric ulcers Duodenal ulcers Gastrointestinal fistulae Gastrointestinal varices Gastrointestinal neoplasia of uncertain behavior Primary malignant skin 2 (<1) [0] 2 (<1) [0] neoplasia Skin infections 1 (<1) [0] 1 (<1) [0] Bacterial skin infections Skin rashes 1 (<1) [1] 0 Fractures 4 (<1) [0] 0 Postoperative complications Craniocerebral injuries Dislocations Ligament tendon or cartilage injuries Chest symptoms 2 (<1) [0] 1 (<1) [0] 5
Collagen vascular disease Non-site specific death Primary malignant neoplasia Cholelithiasis 1 (<1) [0] 2(<1) [0] Cholecystitis 2 (<1) [0] 0 Hepatic cirrhosis Degenerative arthritis Bone and cartilage disorders Diabetic coma and ketoacidosis Electrolyte disturbances Vertigo Visual disturbances Subjects with Fatal SAEs n 3 (0.4) [0] 5 (0.7) [0] (%) [considered by the investigator to be related, possibly related or probably related to study medication] Cancer of rectum 0 1 (0.1) [0] (diagnosed in run-in phase) Lung cancer 1 (0.1) [0] 1 (0.1) [0] Lung metastases 0 1 (0.1) [0] Cerebrovascular events 0 1 (0.1) [0] Acute myocardial infarction 0 1 (0.1) [0] Death due to natural 1 (0.1) [0] 0 causes Myocardial infarction 1 (0.1) [0] 0 Date Updated: 22-Dec-2004 Publications: Andriole G, Roehrborn CG, Nickel CJ, et al. Effect of the dual 5alpha-reductase inhibitor dutasteride on serum total PSA, free PSA and the ratio of F/T PSA. AUA 2002 Andriole G, Roehrborn CG, Schulman C, et al. Effect of dutasteride on the incidence of prostate cancer (PCa) in men with benign prostatic hyperplasia. AUA 2004 Boyle P. Early use of dutasteride arrests prostate growth, improves clinical parameters and prevents complications in men with benign prostatic hyperplasia. AUA 2003 Boyle P. Predictive model for acute urinary retention in man with benign prostatic hyperplasia. AUA 2003 Boyle P, Andriole G, Nickel CJ, et al. Effect of the dual 5alpha-reductase inhibitor dutasteride on total and transitional zone prostate volume. SIU 2002 Boyle P, Robertson C, Wilson T, et al. Risk factors for acute urinary retention in men with benign prostatic hyperplasia. EAU 2003 6
Boyle P, Roehrborn C, Andriole G, et al. The impact of dutasteride, a novel 5alpha-reductase inhibitor, on the hallmarks of BPH progression and outcomes. EAU 2002 Boyle P, Roehrborn C, Debruyne F, Barkin J, Roehrborn CG. Long-term dutasteride therapy results in continued improvements in symptoms and peak urinary flow in men with symptomatic benign prostatic hyperplasia. EAU 2004 Emberton M. Earlier initiation of treatment with the dual 5alpha reductase inhibitor dutasteride reduces the risk of acute urinary retention and surgical intervention in men with benign prostatic hyperplasia. EAU 2004 Fenter T, Tully A, Debruyne F. Long-term therapy with the dual 5alpha reductase inhibitor dutasteride is well tolerated in men with symptomatic benign prostatic hyperplasia. AUA 2004 Freedman S, Brosman S, Emberton M, et al. Earlier initiation of treatment with the dual 5alpha reductase inhibitor dutasteride reduces the risk of acute urinary retention and surgical intervention in men with benign prostatic hyperplasia. AUA 2004 Gittelman M, Barkin J, Zinner N. Sustained prostate volume reduction with dutasteride over 4 years is independent of baseline prostate volume. AUA 2004 Roehrborn C. asteride provides sustained and continued improvement in BPH-related symptoms over 4 years. AUA 2003 Roehrborn CG, Marks L, Fenter T, et al. Long-term dutasteride therapy results in continued improvements in symptoms and peak urinary flow in men with symptomatic benign prostatic hyperplasia. AUA 2004 Roehrborn CG, Dineen M, Bock D, et al. Change in symptom severity status in 4-year dutasteride studies in men with symptomatic BPH. AUA 2004 Tammela T, Barkin J, Roehrborn CG. Long-term dutasteride therapy results in sustained reductions in total prostate volume in men with symptomatic benign prostatic hyperplasia. EAU 2004 Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5 alphareductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002; 60: 434-441. O'Leary MP, Roehrborn CG, Andriole G, et al. Improvements in benign prostatic hyperplasiaspecific quality of life with dutasteride, the novel dual 5alpha-reductase inhibitor. BJU International 2003; 92: 262-6. Debruyne F, Barkin J, Van Erps P, et al. Efficacy and safety of long-term treatment with the dual 5a-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol; 46(4): 488 495 Andriole G, Roehrborn CG, Nickel CJ, et al. Effect of the dual 5alpha-reductase inhibitor dutasteride on serum total PSA, free PSA and the ratio of F/T PSA. AUA 2002 Andriole G, Roehrborn CG, Schulman C, et al. Effect of dutasteride on the incidence of prostate cancer (PCa) in men with benign prostatic hyperplasia. AUA 2004 Boyle P. Early use of dutasteride arrests prostate growth, improves clinical parameters and prevents complications in men with benign prostatic hyperplasia. AUA 2003 Boyle P. Predictive model for acute urinary retention in man with benign prostatic hyperplasia. AUA 2003 7
Boyle P, Andriole G, Nickel CJ, et al. Effect of the dual 5alpha-reductase inhibitor dutasteride on total and transitional zone prostate volume. SIU 2002 Boyle P, Robertson C, Wilson T, et al. Risk factors for acute urinary retention in men with benign prostatic hyperplasia. EAU 2003 Boyle P, Roehrborn C, Andriole G, et al. The impact of dutasteride, a novel 5alpha-reductase inhibitor, on the hallmarks of BPH progression and outcomes. EAU 2002 Boyle P, Roehrborn C, Debruyne F, Barkin J, Roehrborn CG. Long-term dutasteride therapy results in continued improvements in symptoms and peak urinary flow in men with symptomatic benign prostatic hyperplasia. EAU 2004 Emberton M. Earlier initiation of treatment with the dual 5alpha reductase inhibitor dutasteride reduces the risk of acute urinary retention and surgical intervention in men with benign prostatic hyperplasia. EAU 2004 Fenter T, Tully A, Debruyne F. Long-term therapy with the dual 5alpha reductase inhibitor dutasteride is well tolerated in men with symptomatic benign prostatic hyperplasia. AUA 2004 Freedman S, Brosman S, Emberton M, et al. Earlier initiation of treatment with the dual 5alpha reductase inhibitor dutasteride reduces the risk of acute urinary retention and surgical intervention in men with benign prostatic hyperplasia. AUA 2004 Gittelman M, Barkin J, Zinner N. Sustained prostate volume reduction with dutasteride over 4 years is independent of baseline prostate volume. AUA 2004 Roehrborn C. asteride provides sustained and continued improvement in BPH-related symptoms over 4 years. AUA 2003 Roehrborn CG, Marks L, Fenter T, et al. Long-term dutasteride therapy results in continued improvements in symptoms and peak urinary flow in men with symptomatic benign prostatic hyperplasia. AUA 2004 Roehrborn CG, Dineen M, Bock D, et al. Change in symptom severity status in 4-year dutasteride studies in men with symptomatic BPH. AUA 2004 Tammela T, Barkin J, Roehrborn CG. Long-term dutasteride therapy results in sustained reductions in total prostate volume in men with symptomatic benign prostatic hyperplasia. EAU 2004 Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5alpha-reductase inhibitor dutasteride: results of 4-year studies. Roehrborn, C. G., Lukkarinen, O., Mark, S., Siami, P., Ramsdell, J., and Zinner, N. BJU Int 2005; 96 (4):572-7. Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Roehrborn, C. G., Marks, L. S., Fenter, T., Freedman, S., Tuttle, J., Gittleman, M., Morrill, B., and Wolford, E. T. Urology 2004; 63 (4):709-15. 8
Abstract: The transition zone hypothesis in benign prostatic hyperplasia. Roehrborn, C. 1, Marks, L. 2, Wolford, E. 3, and Wilson, T. 4 20th Congress of the European Association of Urology 3/16/2005 Istanbul; Turkey 9