DESIGN AND APPROVAL OF A RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED TRIAL OF THE ACE INHIBITOR CAPTOPRIL IN COMBINATION WITH IBUPROFEN IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA. Erik Kouba1 and Raj S. Pruthi2, MD University of North Carolina School of Medicine; Chapel Hill, North Carolina 1 Division of Urologic Surgery, University of North Carolina School of Medicine; Chapel Hill, North Carolina 2 BACKGROUND OBJECTIVES HYPOTHESIS DESIGN MILESTONES Benign prostatic hyperplasia (BPH) Age related, non-malignant growth of prostate Reduction of diameter of urethra (Figure 1) Dribbling, incomplete emptying, hesitancy Prevalence- 50% men over 50 y/o require treatment for symptoms Currently only 2 drug classes for Treatment: (1) Alpha blockers - decrease muscle tone (2) 5-alpha-reductase inhibitors - reduce prostate size However, 25% patients discontinue drugs after 4 years due to side effects and proceed to surgery Alternative medicines should be investigated Primary: Evaluate the effect of captopril in combination with ibuprofen on subjective symptoms of BPH Prostate related symptoms (validated International Prostate Symptom Scale) (Figure 2) Clinical efficacy defined as 3.0 reduction in IPSS scores from baseline Quality of Life (validated SF-12 Version 2 scale) Secondary: (a) Evaluate the objective response Peak flow rate during urination (Figure 3) Residual urine in bladder after voiding (Figure 4) (b) Safety of medications Frequent monitoring of renal function, blood pressure, CBC, GI effects By modulating the inflammatory component of BPH with captopril and ibuprofen, the symptoms associated with this disorder will improve in men older than 50 years. August 2005: Initial protocol completed August 2005: IND submitted to FDA September 2005: Reviewed by GCRC and IRB Concerns of medication October 2005: Initial feedback by FDA Study modified per recommendations December 2005: Approval of IND by FDA December 2005 : Re-reviewed by GCRC January 2006: Reviewed by IRB Concerns of placebo March 2006: Re-reviewed by IRB Approved pending clarification April 2006: Re- reviewed by IRB May 2006: Approved by IRB May 2006: Recruitment efforts started STUDY DESIGN 3-month randomized, placebo controlled, double-blinded study Captopril 50 mg tid in combination with ibuprofen 400 mg tid (Figure 5) Sample = 50 men ( 25 placebo: 25 medication) presenting to UNC Urology with symptomatic BPH 80% power to detect mean treatment difference at 0.05 level Major Inclusion: Men age 50-80, moderate to severe symptoms (IPSS Score > 8) Major Exclusion: Prior prostate disease or treatment for BPH Hypertension Contraindication to captopril or ibuprofen Renal dysfunction (proteinuria, GFRcalc< 60 mL/min/1.73 m2 Figure 1: BPH and effect on prostate REFERENCES (additional references available by request) 1. Dinh D. et. al. Endocrinology 2001 ; 142 : 1349-1356 2. Wang W. et. al. Prostate. 2004 ; 61 :60-72 3. Lieberman J. et. al. Lab Invest 1983; 48: 711-717. 4. Andrews J. et. al. Cancer Chemther Pharmacol 2002 ; 50 : 277-284. 5. Palayoor S et. al. Oncogene 1999; 18: 7389-7394. 6. Yashumara M. et.al. Cancer Res. 2003 ; 63 : 6726-34. Potential target is inflammatory component Studies show prostatic inflammation in BPH Increased incidence of acute urinary retention Faster progression to surgical treatment BPH tissue has markers of inflammation (1, 2) Local COX-2 upregulation Local ACE upregulation & Angiotensin-II production Products of pathways are mitogenic to prostate cells Ibuprofen and captopril each inhibit growth prostate cells in vitro and in vivo models (3, 4, 5) Combination treatment has synergistic effect in vitro and in vivo (6) Figure 2: Sample IPSS Questionnaire Figure 3: Toilet mounted urine flowmeter Figure 4: Non-invasive ultrasound measurement of postvoid urine Figure 5: Flowchart of study