Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US

Abstract

The efficacy and safety of tadalafil, dosed once a day for the treatment of erectile dysfunction, was assessed in a randomized, double-blind, placebo-controlled, parallel-design study at 15 US centers. Following a 4-week treatment-free run-in period, patients (18 years of age) were randomly assigned to 24 weeks treatment with tadalafil 2.5 mg, tadalafil 5 mg or placebo. Primary efficacy endpoints were change at 24 weeks in International Index of Erectile Function Erectile Function (EF) Domain score and mean per-patient percentage ‘yes’ responses to Sexual Encounter Profile diary questions 2 and 3. Tadalafil significantly improved erectile function compared with placebo for all three co-primary efficacy endpoints. Few patients discontinued because of adverse events (2.1%, placebo; 6.3%, tadalafil 2.5 mg; 4.1%, tadalafil 5 mg). Common treatment-emergent adverse events (5%) were nasopharyngitis, influenza, viral gastroenteritis and back pain. Tadalafil 2.5 mg and 5 mg, dosed once a day for 24 weeks, was well tolerated and significantly improved erectile function.

Introduction

Erectile dysfunction (ED) is a prevalent condition characterized by the consistent inability to attain and maintain an erection sufficient for sexual performance.1 The approval of three phosphodiesterase 5 (PDE5) inhibitors, sildenafil citrate (sildenafil), vardenafil HCl (vardenafil) and tadalafil, has provided effective and well-tolerated oral treatments for ED.2, 3, 4 All three drugs are currently marketed for as-needed dosing and are administered before sexual activity with a maximum dosing frequency of once a day. The pharmacokinetic characteristics of tadalafil differ from the other two PDE5 inhibitors.5 The mean half-life for both sildenafil and vardenafil is about 4 h, whereas the mean half-life of tadalafil is 17.5 h and it has been shown to improve erectile function up to 36 h post-dose.6, 7 The pharmacokinetic characteristics of tadalafil are amenable to once-a-day dosing, which may be an alternative attractive treatment for patients with ED.8 Tadalafil dosed once a day was efficacious when compared with tadalafil dosed as needed in two open-label studies.9, 10 Additionally, in an initial 12-week, placebo-controlled study of once-a-day dosing, conducted in Argentina, Brazil, France, Germany and the UK, tadalafil (5 and 10 mg) significantly improved erectile function and was well tolerated.11 The current study evaluated the efficacy and safety of lower doses of tadalafil dosed once a day (2.5 and 5 mg) compared with placebo, evaluated the responses to once-a-day dosing for the longer duration of 24 weeks and extended the analysis of once-a-day dosing to include the US population.

Design and methods

Study design

This randomized, double-blind, placebo-controlled, parallel-design study was conducted at 15 centers in the US from October 2003 to June 2004. Patients with at least a 3-month history of ED, defined as a consistent change in erection quality that adversely affects satisfaction with sexual intercourse, were screened for eligibility and entered a 4-week treatment-free run-in period before assessment of baseline characteristics. Eligible patients were then randomized to 24 weeks of treatment with fixed doses of tadalafil 2.5 mg, tadalafil 5 mg or placebo in a 1:1:1 ratio. Randomization was stratified by geographical region and baseline ED severity (mild, moderate or severe, see Table 1) as defined by International Index of Erectile Function (IIEF) erectile function (EF) Domain scores (sum of questions 1–5 and 15).12 Patients were instructed to take study medication at approximately the same time every day without regard to food or timing of sexual activity. During the study, patients completed the Sexual Encounter Profile (SEP) diary after each sexual encounter. Patient visits occurred at approximately 4-week intervals. At each visit, the IIEF and Psychological and Interpersonal Relationship Scales (PAIRS) were administered.12, 13 Two Global Assessment Questions (GAQs) were asked at the 12- and 24-week visits. Compliance with the dosing requirements was assessed at each visit by reconciling the number of tablets dispensed with the number of tablets returned. Patients were considered compliant if at least 20 of the daily doses were administered in each 28-day period (>70%).

Table 1 Patient demographic and baseline characteristics

The clinical trial was conducted in accordance with the Declaration of Helsinki and conformed to the principles of good clinical practice and applicable laws and regulations. Ethical review boards approved the study protocol for each study site and the patients provided written informed consent before any study procedures.

Study population

Men (18 years old) with a minimum 3-month history of ED of psychogenic, organic or mixed origin and who anticipated having the same adult female partner during the study were eligible for this trial. Patients agreed to make at least four attempts at sexual intercourse during the 4-week treatment-free run-in period.

The exclusion criteria for this study included: ED caused by premature ejaculation or untreated endocrine disease (e.g. hypopituitarism, hypothyroidism or hypogonadism); failure to achieve erections following radical prostatectomy or other pelvic surgery; presence of penile implant or clinically significant penile deformity; clinically significant renal or hepatic insufficiency; unstable angina within prior 6 months; myocardial infarction, coronary artery bypass graft surgery or percutaneous coronary intervention within prior 90 days; supraventricular arrhythmia with uncontrolled ventricular response; history of spontaneous or induced sustained ventricular tachycardia; presence of automatic internal cardioverter-defibrillator; history of sudden cardiac arrest; evidence of NYHA Class II or above congestive heart failure within prior 6 months; new significant conduction defect within prior 90 days; systolic blood pressure >170 or <90 mm Hg or diastolic blood pressure >100 or <50 mm Hg (measured at screening visit); recent history of stroke, spinal cord injury or other significant central nervous system injuries; HIV infection; current treatment with nitrates, cancer chemotherapy or anti-androgens; or recent history of drug, alcohol or substance abuse. Patients who had received prior ineffective treatment with PDE5 inhibitors, in the opinion of the investigator based on patient medical history, were also excluded.

Efficacy measures

Efficacy was measured using the IIEF, SEP diary, GAQ questions and PAIRS. The three co-primary efficacy endpoints for this study were change from baseline to 24 weeks in mean IIEF EF Domain score and mean per-patient percentage of ‘yes’ responses to SEP question 2 (SEP2; ‘Were you able to insert your penis into partner's vagina?’), and SEP3 (‘Did your erection last long enough for you to have successful intercourse?’).

Secondary efficacy endpoints included the 12-week change from baseline in IIEF EF Domain, SEP2 and SEP3 as well as the 12- and 24-week change from baseline for IIEF Intercourse Satisfaction (IS) Domain (questions 6–8), IIEF Overall Satisfaction (OS) Domain (questions 13 and 14), IIEF question 3 (penetration ability), IIEF question 4 (maintenance of erection), the mean per-patient percentage of ‘yes’ responses to SEP4 (‘Were you satisfied with the hardness of your erection?’) and SEP 5 (‘Were you satisfied overall with this sexual experience?’), PAIRS Sexual Self-confidence and Spontaneity Domain scores, the percentage of positive responses to GAQ1 (‘Has the treatment you have been taking during this study improved your erections?’) and GAQ2 (‘If yes, has the treatment improved your ability to engage in sexual activity?’) and the proportion of patients with an IIEF EF Domain score <26 at baseline and 26 at endpoint, indicating a return to normal erectile function.

Safety

Safety was assessed by monitoring patient-reported adverse events as well as changes in clinical laboratory values, electrocardiogram readings and vital signs. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) (version 7) preferred term. Safety analyses included all randomly assigned patients.

Statistical analyses

All analyses were conducted on an intent-to-treat basis. For each of the three co-primary efficacy variables, two-tailed testing of the hypotheses was based on least-squares means with a significance level of 0.05. P-values for tadalafil 2.5 and 5 mg vs placebo were adjusted by the method of Dunnett. For either tadalafil 2.5 or 5 mg, tadalafil was claimed to be superior to placebo only if the null hypotheses for each co-primary endpoint were rejected in favor of tadalafil.

Efficacy analyses included all patients with baseline and at least one post-baseline observation. Analyses of IIEF and PAIRS scores used the last-observation-carried-forward convention. Results from IIEF EF, IIEF OS, and IIEF IS Domains, IIEF questions 3 and 4, SEP2, SEP3, SEP4, SEP5 and PAIRS were analyzed as continuous variables using analysis of covariance (ANCOVA) models. The models included terms for baseline value of the variable, treatment group, geographic region and baseline-by-treatment-group interaction (if the interaction term was significant, P<0.1).

Results from GAQ1, GAQ2 and the proportion of patients returning to normal erectile function (IIEF EF Domain score <26 at baseline and 26 at endpoint) were analyzed as categorical data using a logistic regression model with terms for baseline IIEF EF Domain value, treatment group and geographic region.

IIEF EF Domain, SEP2 and SEP3 change-from-baseline scores were compared at weeks 4, 8, 12, 16, 18 and 24 using a repeated-measures mixed linear model. This model included the fixed categorical effects of treatment group, time and treatment group-by-time interaction, as well as baseline value, and baseline-by-treatment group interaction (if the interaction term was significant, P<0.1). The corresponding covariance structures were selected as the best fit using Akaike's information criterion.

Safety analyses included all patients assigned to randomized treatment. The most commonly reported treatment-emergent adverse events (TEAEs, 3%) and serious adverse events for each treatment group were summarized.

Results

Patient disposition and demographics

Of the 314 patients screened for this study, 287 were randomly assigned to treatment with tadalafil 2.5 mg (96 patients), tadalafil 5 mg (97 patients) or placebo (94 patients; Figure 1). A majority of patients (82.9%) completed the 24-week treatment period. The most common reasons for discontinuation in the tadalafil treatment groups were adverse events and patient decision (Figure 1).

Figure 1
figure1

Patient disposition.

Baseline characteristics were well balanced across the treatment groups (Table 1). The mean patient age ranged from 58.8 to 60 in the three treatment groups with 31–40% of the patients older than 65 years of age. Approximately, 39% of the patients had severe ED and 96% of the patients had experienced ED for 1 year or longer. Organic ED was the most prevalent etiology (68%).

The mean number of doses taken per week was 7 for the tadalafil 2.5 mg, tadalafil 5 mg and placebo treatment groups, with 94.8% of the patients taking >70% of the daily doses.

Efficacy

Tadalafil significantly improved erectile function compared with placebo for all three co-primary study efficacy endpoints (Figures 2 and 3). At 24 weeks, a significantly larger mean change from baseline IIEF EF Domain score was observed in the tadalafil 2.5 mg (6.1) and tadalafil 5 mg (7.0) groups compared with the placebo group (1.2; both P<0.001). The change (mean per-patient percent ‘yes’) from baseline to 24-week endpoint for SEP2 (tadalafil 2.5 mg, 24.3%; tadalafil 5 mg, 26.2% and placebo, 5.2%) and for SEP3 (tadalafil 2.5 mg, 31.2%; tadalafil 5 mg, 35.1% and placebo, 9.5%) were also significantly larger in the tadalafil treatment groups compared with placebo (all P<0.001).

Figure 2
figure2

Mean IIEF EF Domain score at baseline and 24-week endpoint for all patients and for patients stratified by ED severity at baseline. The number (n) of patients in each group is indicated under each bar. A few patients in the mild subgroup had baseline IIEF EF Domain scores 26 (1, placebo; 3, tadalafil 2.5 mg; 5, tadalafil 5 mg). *P<0.05, **P<0.001 for the comparison of IIEF EF Domain change from baseline for tadalafil vs placebo.

Figure 3
figure3

Mean per-patient SEP2 and SEP3 score at 24-week endpoint for all patients and for patients stratified by ED severity at baseline. The number (n) of patients in each group is indicated under each bar. A few patients in the mild subgroup had baseline IIEF EF Domain scores 26 (1, placebo; 3, tadalafil 2.5 mg; 5, tadalafil 5 mg). The baseline SEP2 score for patients in the placebo treatment group with mild ED was 81.0% and the 24-week score was 79.9%. *P<0.05, **P<0.001 for the comparison of change from baseline SEP2 and SEP3 for tadalafil vs placebo.

The IIEF EF Domain, SEP2 and SEP3 scores at 24 weeks were also stratified by baseline ED severity (Figures 2 and 3). For all three efficacy measures, tadalafil 2.5 and 5 mg both significantly improved erectile function compared with placebo for patients with mild, moderate or severe baseline ED (tadalafil 2.5 mg, P<0.05; tadalafil 5 mg, P<0.01).

Tadalafil treatment also significantly improved erectile function compared with placebo for all secondary study efficacy endpoints, except the PAIRS Spontaneity Domain scores (Table 2). Tadalafil 2.5 mg and tadalafil 5 mg were compared with placebo and significant improvements were observed at the 24-week study endpoint in the IIEF IS Domain score (P=0.007 for tadalafil 2.5 mg; P<0.001 for tadalafil 5 mg), IIEF OS Domain score (both P<0.001), IIEF Q3 (both P<0.001), IIEF Q4 (tadalafil 2.5 mg, P=0.004; tadalafil 5 mg, P<0.001), SEP4 and SEP5 for all patients (all P<0.001), GAQ1 and GAQ2 (all P<0.001) and number of patients with a return to normal erectile function (IIEF EF Domain score <26 at baseline, 26 at endpoint; both P<0.001). In a post hoc analysis examining patient satisfaction (SEP4 and SEP5) with successfully completed intercourse attempts (SEP3 ‘yes’ attempts), tadalafil improved the percentage of positive SEP4 (satisfaction with hardness) and SEP5 (overall satisfaction with sexual experience) responses compared with placebo. Treatment with tadalafil 2.5 and 5 mg improved PAIRS Sexual Self-confidence Domain scores when compared with placebo at 24 weeks (both P<0.001), with no significant differences in the PAIRS Spontaneity Domain scores.

Table 2 Summary of secondary efficacy measures

A numerically greater treatment effect was observed with tadalafil 5 mg treatment compared with tadalafil 2.5 mg treatment for every efficacy measure, except the PAIRS scores and the change from baseline IIEF EF Domain scores for the subgroup of patients with moderate baseline ED (Figures 2 and 3, Table 2). The efficacy results at 12 weeks were numerically similar to the 24-week results presented here. A repeated-measures analysis performed for IIEF EF, SEP2 and SEP3 responses at weeks 4, 8, 12, 16, 18 and 24 indicated that the placebo-adjusted treatment effects were not significantly different across the post-randomization visits (P>0.05). The IIEF EF Domain, SEP2 and SEP3 responses at 12 weeks were compared to values reported in the literature for other studies that included 2.5 or 5 mg doses (Table 5).

Table 5 Comparison with efficacy results presented in the literature

Safety

The proportion of patients who discontinued the study because of adverse events was low (tadalafil 2.5 mg, 6.3%, six patients; tadalafil 5 mg, 4.1%, four patients; placebo, 2.1%, two patients; Figure 1). TEAEs occurring in 3% of patients in any treatment group were nasopharyngitis, influenza, viral gastroenteritis, back pain, upper respiratory tract infection, dyspepsia, nasal congestion, gastroesophageal reflux disease, myalgia, headache, hypertension, bronchitis and sinus congestion (Table 3). Among these TEAEs, the adverse events most commonly judged by the investigators as related to study drug were back pain, dyspepsia, myalgia and headache. No clinically significant changes in laboratory parameters, vital signs or electrocardiogram readings were observed for patients during this study. There were no deaths during this study, and serious adverse events were experienced by seven patients (Table 4).

Table 3 Treatment emergent adverse events (TEAEs) occurring in 3% of patients in any treatment group
Table 4 Serious adverse events (SAEs)

Discussion

Tadalafil 2.5 and 5 mg, dosed once a day for 24 weeks to treat mild to severe ED, significantly improved patient erectile function as measured by all primary efficacy endpoints and all secondary efficacy endpoints, except the PAIRS Spontaneity Domain score. The treatment effects of tadalafil 5 mg were numerically greater than the effects of tadalafil 2.5 mg for all primary and secondary efficacy outcomes, except the PAIRS Domain scores. This apparent dose response was also observed for IIEF EF Domain scores and responses to SEP2 and SEP3 for patients with mild, moderate and severe ED. Once-a-day treatment with tadalafil 2.5 and 5 mg was well tolerated with low rates of discontinuation due to adverse events and a low incidence of treatment emergent adverse events.

Previous studies of tadalafil have examined the efficacy of a 5-mg dose with either as-needed or once-a-day dosing. The data presented in this paper were compared to this historical data, recognizing that comparisons among studies conducted at different times using different study designs should be viewed with caution. For tadalafil 5 mg dosed once a day, the endpoint values for IIEF EF Domain, SEP2 and SEP3 observed in this study at 12 weeks (Table 5) and at 24 weeks (Figures 2 and 3) were slightly smaller than those reported in a previous 12-week, once-a-day dosing study of tadalafil 5 mg (Table 5).11 However, the endpoint values for IIEF EF Domain, SEP2 and SEP3 observed in this study following once-a-day dosing (Figures 2 and 3, Table 5) were numerically larger than those reported in a pooled analysis of 12-week as-needed dosing studies of tadalafil 5 and 2.5 mg (Table 5).14 Some increase in efficacy might be expected with once-a-day compared with as-needed dosing due to increased plasma concentrations of tadalafil with once-a-day dosing (at steady state, the plasma concentration is approximately 1.6-fold greater than after a single dose).8 Consistent with this expectation, the efficacy responses to once-a-day dosing of tadalafil 5 mg observed in the current study appear comparable to those reported in the pooled analysis of as-needed dosing of tadalafil 10 mg (Table 5).14

Two independent, open-label studies compared once-a-day dosing of tadalafil with as-needed dosing in men with ED. Tadalafil 10 mg dosed once a day and tadalafil 20 mg dosed as needed were compared in 145 Australian men with ED in an open-label, parallel-arm, crossover study.10 The changes in IIEF EF Domain, SEP2 and SEP3 primary efficacy endpoints were significantly higher (P<0.05) in the once-a-day treatment group compared with the as-needed dosing group. In that study, 72% of the patients expressed a preference for once-a-day dosing. A second study examined once-a-day dosing of tadalafil as salvage therapy in Australian men who had been previously non-responsive to tadalafil dosed as needed.9 In an open-label, flexible-dose study, once-a-day dosing of tadalafil 10 or 20 mg significantly improved erectile function compared with as-needed dosing of tadalafil 20 mg (P<0.001). In these open-label studies, the efficacy of tadalafil dosed once a day appeared significantly greater than the efficacy observed with as-needed dosing.

PAIRS is a self-report measure used to assess psychological and social factors associated with ED.13 Tadalafil 2.5 mg and tadalafil 5 mg both significantly improved PAIRS Sexual Self-confidence Domain scores compared with placebo. The Sexual Self-confidence Domain assesses a patient's confidence in his ability to achieve erections and enjoy fulfilling sexual experiences. Tadalafil treatment did not improve PAIRS Spontaneity Domain scores compared with placebo. The Spontaneity Domain assesses the ability to have a flexible and intimate time before intercourse. Tadalafil treatment has previously been shown to significantly increase the PAIRS Spontaneity Domain score in studies comparing different ED therapies and comparing ED treatment responders with ED treatment non-responders.15, 16, 17

The efficacy results observed in this study were similar at 12 and 24 weeks; there was no evidence of tolerance or treatment resistance to tadalafil. This is consistent with recent preclinical studies that found no change in PDE5 expression after prolonged cellular exposure to tadalafil, no upregulation of PDE5 expression in rat penis following treatment with high doses of sildenafil and no change in PDE5 inhibition in rat cavernosum following chronic sildenafil treatment.18, 19, 20 However, it is inconsistent with earlier suggestions of tolerance or tachyphylaxis due to the upregulation of PDE5 expression following cellular exposure to sildenafil.21 Tolerance was also not observed during 6 months of treatment with tadalafil dosed as needed.22

Some TEAEs in the current study (influenza, upper respiratory tract infections, bronchitis and sinus congestion) were more prevalent than observed in as-needed dosing studies and may reflect the longer duration of the clinical study described here and the study timing, which spanned the winter season (October–June).14, 23 The most common TEAEs reported in as-needed dosing studies (headache, dyspepsia, back pain) are also observed in this once-a-day dosing study, but with lower incidence. For example, the incidence of headache reported in this study (3.1% in tadalafil 2.5 mg; 1% in tadalafil 5 mg and 3.2% in placebo) is less than what was observed in a pooled analysis of 11 as-needed dosing studies (12% in tadalafil 10 mg, 15% in tadalafil 20 mg and 5% in placebo).23 This difference may be attributable to lower systemic exposure with tadalafil 2.5 and 5 mg once-a-day dosing compared to a single dose of 10 or 20 mg and suggests that chronic dosing with tadalafil is well tolerated.

In conclusion, tadalafil 2.5 and 5 mg, dosed once a day, improved erectile function at both 12 and 24 weeks compared with placebo. Tadalafil was well tolerated with a low incidence of adverse events. The efficacy results were similar across the 24-week study period, suggesting that treatment resistance did not occur.

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Acknowledgements

We acknowledge the additional study investigators: Stephen Auerbach, MD; Bradley Davis, MD; Eugene Dula, MD; Robert Feldman, MD; Darrell N. Fiske, MD; Michael Gambla, MD; Joel Kaufman, MD; Ira Klimberg, MD; Gary Ruoff, MD; David R Talley, MD; and Jay Young, MD. We thank Kate Loughney, PhD, ICOS Corporation for help in preparation of the manuscript and Steven D Watts, MS, Eli Lilly and Company for statistical analyses.

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Correspondence to J Rajfer.

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Study (study code H6D-MC-LVFP) funded by Lilly ICOS LLC.

Conflict of Interest Statements

Dr J Rajfer

Grants, Advisory Board, and Consultant for Lilly ICOS LLC, Pfizer, Bayer, Glaxo SmithKline.

Dr PJ Aliotta

Principal Investigator, Speaker, and Consultant for Lilly ICOS LLC, Pfizer, Glaxo SmithKline, Watson Pharmaceuticals, Novartis, Schering Plough; Principal Investigator and Consultant for Alza Pharmaceuticals, Speaker and Consultant for Boehringer Ingelheim and Ortho McNeil Pharmaceuticals.

Dr CP Steidle

Speaker and consultant for Lilly ICOS LLC, Speaker and Investigator for Pfizer, Bayer GSK.

Dr WP Fitch III

Speaker, Grant Support, Consultant for Lilly ICOS LLC, Speaker and Grant Support for Glaxo SmithKline, Grant Support from Johnson and Johnson.

Dr Y Zhao

Employee, Eli Lilly and Company.

Dr A Yu

Employee, ICOS Corporation.

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Rajfer, J., Aliotta, P., Steidle, C. et al. Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. Int J Impot Res 19, 95–103 (2007). https://doi.org/10.1038/sj.ijir.3901496

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Keywords

  • erectile dysfunction
  • tadalafil
  • PDE5 inhibitor

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