Medical Therapy of Prostate Symptoms MTOPS

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Medical Therapy of Prostate Symptoms (MTOPS)

• Jeannette Y. Lee, Ph.D.
• University of Alabama at Birmingham

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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

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Prevalence

• Clinical Significant BPH
• AUA symptom score gt 7 points (moderate to severe
  lower urinary tract symptoms)
• Depressed peak uroflow (lt 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

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MTOPS Trial Design

• 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

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Inclusion Criteria

• Men gt 50 yrs of age
• AUA symptom score of 8-35
• Peak urinary flow rate of 4-15 ml/sec
• Voided volume gt 15 ml

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Exclusion Criteria

• Prior medical or surgical intervention for BPH
• Supine blood pressure lt 90/70 mmHg
• PSA gt 10 ng/ml

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Factorial Design
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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.

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Follow-up Evaluations

• Vital signs
• AUA symptom score
• Urinary flow rate
• Adverse Events
• DRE, serum PSAlt urinalysis
• Prostate volume (TRUS)

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Follow-up Questionnaire

• AUA Symptom Score
• QOL Short Form-36 (SF-36)
• Sexual function questionnaire
• Prostatitis Questionnaire

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Primary Endpoints

• Primary endpoint time to BPH progression
  defined as
• gt 4 point increase in AUA symptom score
• Acute urinary retention
• Renal insufficiency
• Recurrent urinary tract infection
• Urinary incontinence

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Secondary Endpoints

• Changes over time
• AUA symptom score
• Maximal urinary flow rate
• PSA level
• Prostate volume
• Cumulative incidence of invasive treatments for
  BPH

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Results

• 3047 men randomized
• Baseline characteristics
• 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

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Clinical Progression of BPHRate per 100 PYs
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Clinical Progression of BPHEvents
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Cumulative Incidence of Progression(N Engl J Med
2003 349 (25) 2387-97)
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Rate of Progression per 100 PYs

• Placebo 4.5 BPH Progressors
• Doxazosin 2.7 BPH Progressors
• Finasteride 2.9 BPH Progressors
• Combination 1.5 BPH Progressors

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Invasive Therapy due to BPH
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Adverse Events Sexual Function(Rate per 100
PYs)
plt0.05 compared to placebo
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Adverse Events Hypotension(Rate per 100 PYs)
plt0.05 compared to placebo
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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.

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Methods papers

• Study Design
• Bautista et al, Controlled Clinical Trials 2003
• Recruitment
• Kusek et al, Controlled Clinical Trials 2002

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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
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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
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MPSA

• MTOPS Prostatic Sample Analysis Consortium
  evaluate biomarkers associated with BPH (Mullins
  et al, J Urol 2008).

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Analyses in Progress

• Longitudinal analyses of sexual function
• Risk of prostate cancer

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MTOPS Data Available

• 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)

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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)

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MTOPS Data from Diagnostic Center

• PSA (ng/ml)
• LH (mIU/ml)
• Testosterone (ng/dl)
• Free PSA
• Total PSA

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MTOPS Samples in NIDDK Repository