1. 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 :
2. Wang W. et. al. Prostate ; 61 :60-72
3. Lieberman J. et. al. Lab Invest 1983; 48:
4. Andrews J. et. al. Cancer Chemther Pharmacol 2002 ; :
5. Palayoor S et. al. Oncogene 1999; 18:
6. Yashumara M. et.al. Cancer Res ; 63 :
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