Finasteride (Page 5 of 7)

14.2 Combination with Alpha-Blocker Therapy

The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a doubleblind, randomized, placebo-controlled, multicenter, 4 to 6 year study (average 5 years) in 3047 men with symptomatic BPH, who were randomized to receive finasteride 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The participant’s final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The final doxazosin dose was administered once per day, at bedtime.

The mean patient age at randomization was 62.6 years (±7.3 years). Patients were Caucasian (82%), African American (9%), Hispanic (7%), Asian (1%) or Native American (< 1%). The mean duration of BPH symptoms was 4.7 years (±4.6 years). Patients had moderate to severe BPH symptoms at baseline with a mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was 10.5 mL/sec (±2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was 36.3 mL (±20.1 mL). Prostate volume was ≤ 20 mL in 16% of patients, ≥ 50 mL in 18% of patients and between 21 and 49 mL in 66% of patients.

The primary endpoint was a composite measure of the first occurrence of any of the following five outcomes: a ≥ 4 point confirmed increase from baseline in symptom score, BPH-related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence. Compared to placebo, treatment with finasteride, doxazosin, or combination therapy resulted in a reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p< 0.001), and 67% (p< 0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the primary endpoint compared to treatment with finasteride alone (49%;p≤ 0.001) or doxazosin alone (46 %; p≤ 0.001). (See Table 6.)

Table 6Count and Percent Incidence of Primary Outcome Events by Treatment Group in MTOPS
Event Treatment Group
Placebo N = 737 N (%) Doxazosin N = 756 N (%) Finasteride N = 768 N (%) Combination N = 786 N (%) Total N = 3047 N (%)
AUA 4-point rise 100 (13.6) 59 (7.8) 74 (9.6) 41 (5.2) 274 (9)
Incontinence 8 (1.1) 11 (1.5) 9 (1.2) 3 (0.4) 31 (1)
Recurrent UTI/urosepsis 2 (0.3)2 (0.3)0 (0) 1 (0.1) 5 (0.2)
Creatinine rise 0 (0)0 (0)0 (0) 0 (0) 0 (0)
Total Events128 (17.4) 85 (11.2) 89 (11.6) 49 (6.2) 351 (11.5)

The majority of the events (274 out of 351; 78 %) was a confirmed ≥ 4 point increase in symptom score, referred to as symptom score progression. The risk of symptom score progression was reduced by 30 % (p=0.016), 46 % (p< 0.001), and 64 % (p< 0.001) in patients treated with finasteride, doxazosin, or the combination, respectively, compared to patients treated with placebo (see Figure 5). Combination therapy significantly reduced the risk of symptom score progression compared to the effect of finasteride alone (p< 0.001) and compared to doxazosin alone (p=0.037).

Figure 5

Cumulative Incidence of a 4-Point Rise in AUA Symptom Score by Treatment Group

image 05
(click image for full-size original)

Years from Randomization

Treatment with finasteride, doxazosin or the combination of finasteride with doxazosin, reduced the mean symptom score from baseline at year 4. Table 7 provides the mean change from baseline for AUA symptom score by treatment group for patients who remained on therapy for four years.

Table 7Change From Baseline in AUA Symptom Score by Treatment Group at Year 4 in MTOPS
Placebo N = 534 Doxazosin N = 582 Finasteride N = 565 Combination N = 598
Baseline Mean (SD) 16.8 (6)17 (5.9)17.1 (6)16.8 (5.8)
Mean Change AUA Symptom Score (SD) -4.9 (5.8)-6.6 (6.1)-5.6 (5.9)-7.4 (6.3)
Comparison to Placebo (95% CI) -1.8 (-2.5, -1.1)-0.7 (-1.4, 0)-2.5 (-3.2, -1.8)
Comparison to Doxazosin alone (95% CI) -0.7 (-1.4, 0)
Comparison to Finasteride alone (95% CI) -1.8 (-2.5, -1.1)

The results of MTOPS are consistent with the findings of the 4 year, placebo-controlled study finasteride long-term efficacy and safety study [see Clinical Studies (14.1)] in that treatment with finasteride reduces the risk of the need for BPH-related surgery. In MTOPS, the risk of requiring BPH-related invasive therapy was reduced by 64% in patients treated with finasteride compared to patients treated with placebo (2% for finasteride and 5.4% for placebo).

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