Tadalafil Administered Once Daily for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Dose Finding Study

Study Design and Participants 

This study was a randomized, double-blind, placebo controlled, parallel design, dose finding, 12-week study performed at 92 centers in a total of 10 countries. Men at least 45 years old with a history of LUTS secondary to BPH of 6 months or longer were eligible for this study unless 1) PSA was more than 10 ng/ml (in men with PSA 4 to 10 ng/ml prostate biopsy negative for malignancy within 12 months was required) or 2) PVR volume was 300 ml or greater at screening visit 1 (fig. 1). Patients reporting the use of other BPH or ED treatments upon study entry underwent a 4-week treatment-free screening/washout period. Otherwise patients began the placebo run-in period after screening results were reviewed. Other key inclusion criteria were a total I-PSS of 13 or greater, a Qmax of 4 to 15 ml per second from pre-void bladder volume, as assessed by ultrasound, and between 150 and 550 ml with a voided volume of 125 ml or greater at visit 2. Men were not required to have a history of ED and the frequency of sexual intercourse was not discussed at study entry.

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Fig. 1. Study design with schedule of events

Excluded from enrollment were men who received recent finasteride or dutasteride treatment within 3 and 12 months, respectively, before visit 2 (the start of the placebo run-in period) and those with penile or pelvic surgery, radiotherapy, lower urinary tract malignancy, trauma or recent instrumentation, urinary retention or bladder stones, a history of urethral obstruction due to stricture, valves, sclerosis or tumor, a neurological condition affecting bladder function, detrusor-sphincter dyssynergia, intravesical obstruction secondary to the prostate median lobe, urinary tract inflammation or infection, or prostate cancer. Other exclusionary medical conditions were clinically significant renal or hepatic insufficiency, cardiovascular conditions such as significant angina, recent myocardial infarction or poorly controlled blood pressure, a recent history of stroke or spinal cord injury, current treatment with nitrates, cancer chemotherapy, antiandrogens or a potent cytochrome P450 3A4 inhibitor, or uncontrolled diabetes (glycosylated HbA1c greater than 9%).

The clinical study was performed in accordance with the Declaration of Helsinki and all applicable regulations. The institutional review board at each site approved the study and all men provided written informed consent before undergoing any study procedure or receiving any study therapy.

Outcomes 

The primary study end point was the I-PSS change after 12 weeks of treatment with 5 mg tadalafil compared with placebo. Figure 1 shows the study design. I-PSS is a validated 7-item questionnaire about LUTS occurring within the last month. The total I-PSS range is 0 to 35 with higher scores indicating more severe symptoms.

Secondary end points were used to examine the efficacy and dose-response relationship of placebo and once daily dosing with 2.5, 5, 10 or 20 mg tadalafil, as assessed by I-PSS (questions 1 to 7), the irritative subscore (questions 2, 4 and 7), the obstructive subscore (questions 1, 3, 5 and 6) and the I-PSS QOL index, “If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?” Secondary end points also included BPH-II, a validated 4-item questionnaire with a score range of 0 to 13 with higher scores indicating more bother or problems associated with urinary symptoms within the previous month, GAQ, “Has the treatment you have been taking since your last visit improved your urinary symptoms?” and uroflowmetry parameters.

Qmax, the mean urinary flow rate and voided volume parameters were recorded using a standard calibrated flowmeter. Qmax read by an investigator was used to determine study eligibility, while a central over read for each tracing was used for analysis. The mean urinary flow rate and voided volume were assessed for descriptive purposes (data not shown).

The IIEF questionnaire was administered to patients answering yes at visit 2 to the question, “Are you sexually active with a female partner and expect to remain so for the duration of the study?” the change in IIEF-EF was analyzed, while other IIEF domains were assessed for descriptive purposes only (data not shown).

Safety assessments included patient reported TEAEs, SAEs, vital signs, changes in clinical laboratory values, including PSA, and PVR. TEAEs were coded using the Medical Dictionary for Regulatory Activities, version 10.

Statistical Analyses 

Treatment group differences compared to placebo for continuous variables were evaluated using ANCOVA adjusted for multiplicity by Dunnett's method and by permutation tests20 based on a 10,000 Monte Carlo sample stratified by the randomization factors. The data presented represent ANCOVA results. Permutation test results were presented when the inference from the 2 methods was not similar.

A total of 198 patients per treatment group provided 91% power to detect a difference of 2.0 points from placebo in the I-PSS change from baseline. These calculations were based on the 2-sided t test at a significance level of 0.05.

All efficacy analyses were performed on an intent to treat basis and they included all randomized patients who had a baseline and at least 1 post-baseline measurement available.

ANCOVA using change from baseline as a response variable and including effects for treatment, baseline value of the response variable and randomization factors, that is 4 levels of geographic region, 2 levels of BPH LUTS severity and 2 levels of ED, was used to analyze continuous variables. A last observation carried forward imputation convention was used for these analyses.

Repeated measures analysis was performed for some continuous variables using mixed models with unstructured covariance matrices. These models used the change from baseline as a response variable and they included effects for treatment, baseline value of the response variable, geographic region, BPH LUTS severity, ED history, time and treatment group by time interaction.

Secondary analysis was done to evaluate the LUTS GAQ at end point using the Cochran-Mantel-Haenszel test for general association, stratified by the randomization factors. LUTS GAQ was analyzed according to the proportion of patients with nonmissing responses at the final visit.

Baseline Characteristics 

Of 1,813 men who were screened for eligibility 1,058 were randomly allocated to receive 1 of 4 active treatments or placebo (Fig. 1, Fig. 2). There were no significant treatment group differences in baseline characteristics or in features related to BPH (table 1). In 67 randomized men with moderate to severe LUTS, as assessed at visit 2, LUTS severity improved during the placebo run-in period from moderate or severe to mild (I-PSS 13 or greater to 8 or less, respectively).

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Fig. 2. Patient Consolidated Standards of Reporting Trials diagram. Asterisk indicates that 1 patient randomized at 2 sites was excluded from study and another two who were randomized did not receive study drug.

Table 1. Baseline characteristics of all randomized patients

			Tadalafil (mg)
		Placebo	2.5	5	10	20
	Visit 1
	No. pts	211⁎	208	212	216	209
	Mean age (range)	61.75(45.59–80.62)	62.03(44.99–92.64)	61.95(46.10–85.60)	62.22(45.53–80.04)	62.55(45.81–79.47)
	% Younger than 65	64.93	61.06	64.62	63.89	58.85
	% Race or ethnic group:
	White	84.83	88.46	84.43	86.11	84.21
	Hispanic	13.74	9.62	11.79	11.11	11.96
	Black	1.42	1.44	3.30	2.31	2.39
	Other	0	0.48	0.47	0.46	1.44
	Mean kg/m2 body mass index (range)	28.57(20.23–44.25)	27.98(17.46–40.76)	28.58(20.09–48.09)	28.40(18.35–45.42)	28.46(19.68–53.98)
	% Previous α-blocker use†	29.86	29.33	27.83	26.85	30.14
	% Previous 5α-reductase inhibitor use†	1.90	1.44	1.42	0.93	0.00
	Mean ± SD % ED history	67.30	64.90	67.92	69.44	69.38
	% Sexually active†	80.10	80.77	84.43	80.56	77.03
	Mean ng/ml PSA (range)	1.65(0.03–9.21)	1.71(0.19–8.78)	1.79(0.11–6.69)	1.82(0.21–6.83)	1.73(0.18–5.92)
	Visit 3 (baseline)
	Mean ± SD I-PSS	17.08±6.36	17.48±5.84	17.30±5.97	17.77±5.60	17.11±6.53
	Mean ± SD BPH-II	4.94±2.95	4.73±2.95	4.66±2.98	4.86±2.98	4.75±2.79
	Mean ± SD Qmax (ml/sec)	10.31±4.85	9.97±4.09	10.37±3.86	9.93±3.77	9.82±3.97
	Mean ng/ml PSA (range)	1.73(0.12–10.33)	1.67(0.16–8.41)	1.79(0.14–6.79)	1.86(0.19–8.54)	1.73(0.10–7.23)

⁎ One patient randomized at 2 sites was excluded. † Identified at visit 1 based on patient medical history.

Efficacy End Points 

Primary end point 

Daily dosing of 5 mg tadalafil resulted in a statistically significant improvement in the I-PSS change from baseline compared to placebo (table 2).

Table 2. Change from baseline to end point in efficacy variables in all treatment groups

	Measure	Placebo	Tadalafil (mg)				Tadalafil vs Placebo p Value
			2.5	5	10	20
	No. pts	210⁎	208⁎	212	216	208⁎
	Least squares mean±SE I-PSS change from baseline:	−2.27±0.49	−3.88±0.50†	−4.87±0.49‡	−5.17±0.49	−5.21±0.50	<0.001
	Mild-moderate at baseline (701 pts)	−1.4±6.44	−2.7±5.18§	−4.3±4.94	−4.4±5.60	−3.7±5.18	<0.001(permutationtest)
	Severe at baseline (352 pts)	−3.9±5.30	−6.5±6.41	−6.2±6.71	−7.3±6.71	−8.4±6.36	<0.05(permutationtest)
	Irritative	−0.99±0.23	−1.58±0.23§	−1.89±0.23	−1.96±0.23	−2.07±0.23	<0.01
	Obstructive	−1.26±0.33	−2.23±0.33†	−2.94±0.33	−3.13±0.32	−3.12±0.33	<0.001
	QoL	−0.49±0.11	−0.74±0.11§	−0.86±0.11	−0.92±0.10	−0.88±0.11	<0.01
	Least squares mean±SE BPH-II change from baseline	−0.83±0.21	−0.96±0.21§	−1.40±0.21	−1.38±0.20§	−1.45±0.21	<0.05
	Least squares mean±SE Qmax change from baseline (cm/sec)	1.24±0.40	1.41±0.39	1.64±0.39	1.58±0.38	1.96±0.39	Not significant
	% Yes LUTS GAQ end point (Cochran-Mantel-Haenszel test)	54.8	61.9§	69.2	73.0	74.2	<0.05
	Least squares mean±SE sexually active ED IIEF-EF change from baseline (55% of pts)	2.20±1.03	5.59±1.01	6.97±1.01	7.98±1.0	8.34±1.01	<0.001

⁎ One patient randomized at 2 sites was excluded and another and 2 randomized did not receive study drug. † p <0.05. ‡ Primary end point. § Not significant.

Secondary end points 

Statistically significant improvements in the I-PSS change from baseline compared to placebo were observed for each tadalafil dose (table 2) and at all post-randomization visits (4, 8 and 12 weeks) (fig. 3, A). The 2.5 mg daily tadalafil dose resulted in significant improvements in the I-PSS obstructive subscore and IIEF-EF compared to those of placebo (table 2). Statistically significant improvements were also noted in the I-PSS irritative and obstructive subscores, the I-PSS QOL subscore, BPH-II, GAQ and IIEF-EF at tadalafil doses of 5 mg or greater, except a nonsignificant finding at the 10 mg dose for BPH-II compared to placebo (p = 0.056, table 2). Improvements in BPH-II were statistically significant at tadalafil doses of 5 mg or greater compared to placebo when assessed in patients completing 4, 8 and 12 weeks of treatment (fig. 3, B).

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Fig. 3. Mean change from baseline to end point after 4, 8 and 12 weeks. A, I-PSS. At weeks 4, 8 and 12 vs placebo 2.5 mg tadalafil (Tad) ANCOVA p = 0.001, 0.028 and 0.007, respectively, and 5, 10 and 20 mg ANCOVA p <0.001. B, for tadalafil 2.5 mg no significance vs placebo. Vs placebo 5 and 10 mg tadalafil at week 8 ANCOVA p <0.001, and at weeks 4 and 12 ANCOVA p <0.05. Vs placebo at weeks 4 and 8, 20 mg tadalafil ANCOVA p <0.001 and at week 12 ANCOVA p <0.05.

On subgroup analysis of patients with a mild to moderate BPH LUTS severity score 5 mg or greater tadalafil significantly improved I-PSS compared to placebo, while all tadalafil doses improved I-PSS in patients with severe BPH LUTS (table 2).

When analyses of covariance and permutation tests were performed, similar results were observed, except a nonsignificant treatment effect compared to placebo for BPH-II at the 5 mg dose (permutation test p = 0.095) and a significant treatment effect on the I-PSS irritative subscore and the I-PSS QOL subscore at the 2.5 mg dose (permutation test p <0.01). No statistically significant treatment effect compared to placebo was noted for Qmax at any tadalafil dose.

Safety End Points 

Individual TEAEs in the tadalafil treatment groups were infrequent. Back pain, myalgia and to a lesser degree headache were more frequent at higher tadalafil doses but no clear dose relationship was evident (table 3). One patient receiving placebo was catheterized because of urinary retention caused by BPH. Table 3 shows the incidence of patients experiencing SAEs or discontinuing due to TEAEs.

Table 3. TEAEs and SAEs

		No. Placebo (%)	No. mg Tadalafil (%)
			2.5	5	10	20	Totals
	Overall	211	209	212	216	209	846
	TEAEs:⁎
	Headache	6 (2.8)	5 (2.4)	6 (2.8)	11 (5.1)	7 (3.3)	29 (3.4)
	Dyspepsia	0	2 (1.0)	10 (4.7)	6 (2.8)	10 (4.8)	28 (3.3)
	Back pain	1 (0.5)	3 (1.4)	2 (0.9)	10 (4.6)	12 (5.7)	27 (3.2)
	Myalgia	0	3 (1.4)	3 (1.4)	6 (2.8)	6 (2.9)	18 (2.1)
	Nasopharyngitis	2 (0.9)	7 (3.3)	4 (1.9)	2 (0.9)	5 (2.4)	18 (2.1)
	Diarrhea	3 (1.4)	2 (1.0)	6 (2.8)	1 (0.5)	5 (2.4)	14 (1.7)
	Gastroesophageal
	Reflux disease	0	2 (1.0)	2 (0.9)	6 (2.8)	3 (1.4)	13 (1.5)
	Extremity pain	0	3 (1.4)	5 (2.4)	2 (0.9)	3 (1.4)	13 (1.5)
	Influenza	1 (0.5)	4 (1.9)	4 (1.9)	1 (0.5)	2 (1.0)	11 (1.3)
	Bronchitis	1 (0.5)	3 (1.4)	1 (0.5)	5 (2.3)	0	9 (1.1)
	Muscle spasms	0	2 (1.0)	0	2 (0.9)	5 (2.4)	9 (1.1)
	1 or Greater TEAE	45 (21.2)	56 (26.8)	65 (30.7)	75 (34.7)	83 (39.7)	279 (33.0)
	1 or Greater SAE	6 (2.8)	3 (1.4)	1 (0.5)	2 (0.9)	5 (2.4)	11 (1.3)
	1 or Greater AE leading to discontinuation	5 (2.4)	4 (1.9)	12 (5.7)	11 (5.1)	14 (6.7)	41 (4.8)

⁎ Reported by 2% or greater of patients in any treatment group.

No clinically relevant changes in laboratory parameters, vital signs, mean PSA or mean PVR were observed. The least squares mean PVR change from baseline to week 12 was 4.81 ml in the placebo group, and 12.13, 6.63, 10.55 and −3.95 ml in the 2.5, 5, 10 and 20 mg tadalafil groups, respectively.