Medical Therapy of Prostate Medical Therapy of Prostate Symptoms (MTOPS)Symptoms (MTOPS)

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

BirminghamBirmingham

Benign Prostatic Hyperplasia (BPH)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

PrevalencePrevalence

• 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 DesignMTOPS 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

Inclusion CriteriaInclusion Criteria

• 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 CriteriaExclusion Criteria

• Prior medical or surgical intervention for BPH

• Supine blood pressure < 90/70 mmHg

• PSA > 10 ng/ml

Factorial DesignFactorial Design

Finasteride

+

Doxazosin

Finasteride

Doxazosin Placebo

TreatmentsTreatments

• 5- 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 EvaluationsFollow-up Evaluations

• Vital signs

• AUA symptom score

• Urinary flow rate

• Adverse Events

• DRE, serum PSA< urinalysis

• Prostate volume (TRUS)

Follow-up QuestionnaireFollow-up Questionnaire

• AUA Symptom Score

• QOL Short Form-36 (SF-36)

• Sexual function questionnaire

• Prostatitis Questionnaire

Primary EndpointsPrimary 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 EndpointsSecondary Endpoints

• Changes over time – AUA symptom score – Maximal urinary flow rate– PSA level– Prostate volume

• Cumulative incidence of invasive treatments for BPH

ResultsResults

• 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

Clinical Progression of BPHClinical Progression of BPHRate per 100 PYsRate per 100 PYs

Placebo

(N=737)

Doxazosin

(N=756)

Finasteride

(N=768)

Combination

(N=786)

Clinical

Prog.

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 Progression of BPHClinical Progression of BPHEventsEvents

Placebo

(N=737)

Doxazosin

(N=756)

Finasteride

(N=768)

Combination

(N=786)

Clinical

Prog.

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

Cumulative Incidence of ProgressionCumulative Incidence of Progression(N Engl J Med 2003: 349 (25): 2387-97)(N Engl J Med 2003: 349 (25): 2387-97)

Rate of Progression per 100 PYsRate 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

Invasive Therapy due to BPHInvasive 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 FunctionAdverse Events – Sexual Function(Rate per 100 PYs)(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 – HypotensionAdverse Events – Hypotension(Rate per 100 PYs)(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 SummaryMTOPS 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 papersMethods papers

• Study Design – Bautista et al, Controlled Clinical Trials 2003

• Recruitment– Kusek et al, Controlled Clinical Trials 2002

Secondary AnalysesSecondary 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 AnalysesSecondary 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

MPSAMPSA

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

Analyses in ProgressAnalyses in Progress

• Longitudinal analyses of sexual function

• Risk of prostate cancer

MTOPS Data AvailableMTOPS 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)

MTOPS QuestionnairesMTOPS 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 MTOPS Data from Diagnostic CenterCenter

• PSA (ng/ml)

• LH (mIU/ml)

• Testosterone (ng/dl)

• % Free PSA

• Total PSA

MTOPS Samples in NIDDK MTOPS Samples in NIDDK RepositoryRepository

Type of Specimen

Number Number of participants

Serum 102,916

(0.5 ml aliquots)

4127

Frozen tissue 7001

Bx samples

1449

Fixed tissue 14,416

Bx blocks

1449