Transcript Medical Therapy of Prostate Symptoms (MTOPS)

Medical Therapy of Prostate
Symptoms (MTOPS)
Jeannette Y. Lee, Ph.D.
University of Alabama at
Birmingham
Benign Prostatic Hyperplasia
(BPH)
• Common cause of morbidity among older
men
• Characterized by bothersome lower
urinary tract symptoms (LUTS)
• Men with BPH and larger prostates due to
BPH are at increased risk of complications
such as acute urinary retention
Prevalence
• Clinical Significant BPH
– AUA symptom score > 7 points (moderate to
severe lower urinary tract symptoms)
– Depressed peak uroflow (< 15 mL/sec)
• Prevalence by age group
– 17% in men from 50-59 yrs of age
– 27% in men from 60-69 yrs of age
– 35% in men from 70-79 yrs of age
MTOPS Trial Design
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Randomized, double blind, 2 x 2 factorial
Two-year enrollment period
Minimum four-year follow-up period
Objective: to determine if doxazosin or
finasteride, alone or in combination
delayed or prevented clinical progression
of BPH
Inclusion Criteria
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Men > 50 yrs of age
AUA symptom score of 8-35
Peak urinary flow rate of 4-15 ml/sec
Voided volume > 15 ml
Exclusion Criteria
• Prior medical or surgical intervention for
BPH
• Supine blood pressure < 90/70 mmHg
• PSA > 10 ng/ml
Factorial Design
Finasteride
+
Doxazosin
Finasteride
Doxazosin
Placebo
Treatments
• 5-a reductase inhibitor Finasteride dose:
5 mg
• Alpha blocker Doxazosin dose doubled
weekly starting with 1 mg daily until daily
dose of 8 mg reached.
Follow-up Evaluations
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Vital signs
AUA symptom score
Urinary flow rate
Adverse Events
DRE, serum PSA< urinalysis
Prostate volume (TRUS)
Follow-up Questionnaire
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AUA Symptom Score
QOL Short Form-36 (SF-36)
Sexual function questionnaire
Prostatitis Questionnaire
Primary Endpoints
• Primary endpoint: time to BPH
progression defined as
– > 4 point increase in AUA symptom score
– Acute urinary retention
– Renal insufficiency
– Recurrent urinary tract infection
– Urinary incontinence
Secondary Endpoints
• Changes over time
– AUA symptom score
– Maximal urinary flow rate
– PSA level
– Prostate volume
• Cumulative incidence of invasive
treatments for BPH
Results
• 3047 men randomized
• Baseline characteristics
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Mean age: 62.6 yrs
White: 82%
Mean AUA symptom score: 16.9
Mean prostate volume: 36.3 ml
Mean Max urinary flow rate: 10.5 ml/min
Mean post void residual volume: 68.1 ml
Mean serum PSA: 2.4 ng/ml
Mean serum creatinine: 1.1 mg/dl
Clinical Progression of BPH
Rate per 100 PYs
Placebo
(N=737)
Doxazosin
(N=756)
Finasteride
(N=768)
Combination
(N=786)
4.5
2.7
2.9
1.5
> 4 pt rise
AUASS
3.6
1.9
2.5
1.3
AUR
0.6
0.4
0.2
0.1
Incont.
0.3
0.3
0.3
0.1
Clinical
Prog.
Clinical Progression of BPH
Events
Placebo
(N=737)
Doxazosin
(N=756)
Finasteride
(N=768)
Combination
(N=786)
122
73
78
42
> 4 pt rise
AUASS
97
55
65
36
AUR
18
9
6
4
Incont.
6
7
7
1
UTI
1
2
0
1
Clinical
Prog.
Cumulative Incidence of Progression
(N Engl J Med 2003: 349 (25): 2387-97)
Rate of Progression per 100 PYs
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Placebo: 4.5 BPH Progressors
Doxazosin: 2.7 BPH Progressors
Finasteride: 2.9 BPH Progressors
Combination: 1.5 BPH Progressors
Invasive Therapy due to BPH
Cumulative
Placebo
(N=737)
Doxazosin
(N=756)
Finasteride
(N=768)
Combination
(N=786)
Rate per
100 PY
1.3
1.3
0.5
0.4
Events
37
26
14
12
Adverse Events – Sexual Function
(Rate per 100 PYs)
Placebo
(N=737)
Doxazosin
(N=756)
Finasteride
(N=768)
Combination
(N=786)
Erectile
dysfunction
3.32
3.56
4.53*
5.11*
Decreased
libido
1.4
1.56
2.36*
2.51*
Abnormal
ejaculation
0.83
1.10
1.78*
3.05*
* p<0.05 compared to placebo
Adverse Events – Hypotension
(Rate per 100 PYs)
Placebo
(N=737)
Doxazosin
(N=756)
Finasteride
(N=768)
Combination
(N=786)
Dizziness
2.29
4.41*
2.33
5.35*
Postural
hypotension
2.29
4.03*
2.56
4.33*
Asthenia
2.06
4.08*
1.56
4.20*
* p<0.05 compared to placebo
MTOPS Summary
• Combination therapy with doxazosin and
finasteride was safe and reduced the risk
of overall clinical progression more than
each drug alone.
• Finasteride containing regimens reduced
the long-term risk of AUR and need for
invasive therapy.
McConnell et al, N Engl J Med 2003.
Methods papers
• Study Design
– Bautista et al, Controlled Clinical Trials 2003
• Recruitment
– Kusek et al, Controlled Clinical Trials 2002
Secondary Analyses
• Placebo patients – baseline factors
associated with clinical progression *
– Total prostate volume
– PSA
– Peak flow rate
– Post residual volume
– Age
* Crawford et al, J Urol 2006
Secondary Analyses
• Combination therapy is better than either
agent alone (finasteride, doxazosin) in
decreasing the risk of clinical BPH
progression in those with higher prostate
volumes*
Kaplan et al, J Urol 2006
MPSA
• MTOPS Prostatic Sample Analysis
Consortium – evaluate biomarkers
associated with BPH (Mullins et al, J Urol
2008).
Analyses in Progress
• Longitudinal analyses of sexual function
• Risk of prostate cancer
MTOPS Data Available
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Uroflow Measurements (quarterly)
Compliance/pill counts (quarterly)
PSA measurements (semi-annually)
PE, CBC, serum chemistry, urinalysis
(annually)
• TRUS and Biopsy (Screening, 12 mos,
end of study)
MTOPS Questionnaires
• AUA Symptom Questionnaire (quarterly)
• Sexual Function Questionnaire (screening
and end of study)
• Medical Outcomes Study (MOS) – Short
Form 36 (SF-36) (annually)
• Prostatitis Questionnaire (annually)
MTOPS Data from Diagnostic
Center
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PSA (ng/ml)
LH (mIU/ml)
Testosterone (ng/dl)
% Free PSA
Total PSA
MTOPS Samples in NIDDK
Repository
Type of
Specimen
Serum
Frozen tissue
Fixed tissue
Number
Number of
participants
102,916
(0.5 ml aliquots)
4127
7001
Bx samples
1449
14,416
Bx blocks
1449