A phase II, single-blind, randomized, crossover evaluation of the safety and efficacy of avanafil using visual sexual stimulation in patients with mild to moderate erectile dysfunction

Authors


Correspondence: Wayne J.G. Hellstrom, Department of Urology, Tulane University Medical Centre, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112, USA.

e-mail: whellst@tulane.edu

Abstract

What's known on the subject? and What does the study add?

  • Phosphoesterase type 5 inhibitors (PDE5is) are considered standard-of-care for the treatment of men with erectile dysfunction. Recommended administration of currently used PDE5is are between 60- to 120-minutes before sexual activity. RigiScan® monitoring has been validated in previous clinical studies of PDE5 inhibitors.
  • Using a highly objective measure of sexual function (RigiScan monitoring), data show that the onset of action of avanafil was rapid. Response to treatment with avanafil was associated most frequently with the earliest time interval tested (20–40 minutes after dosing), compared with sildenafil 50 mg (100 to 120 minutes after dosing). However, avanafil treatments showed some degree of efficacy across all time intervals tested (including 60–80 minutes and 100–120 minutes post-dosing). These results were consistent with data from phase 3 trials which showed a rapid onset of action with avanafil (as early as 15 minutes) and a long duration of effect (up to 6 hours in some patients). Safety results were consistent with those reported in phase 3 trials, and showed that avanafil was well tolerated and adverse events were generally low and mild in severity.

Objective

  • To evaluate the safety, efficacy and time course of three doses of avanafil (50 mg, 100 mg and 200 mg) compared with sildenafil 50 mg or placebo, given in conjunction with visual sexual stimulation (VSS) videos in men with mild to moderate erectile dysfunction (ED).

Patients and Methods

  • Male patients, 35–70 years of age, with mild to moderate ED of ≥6 months duration, were included in the study.
  • During the course of the study, each patient received placebo, active control (sildenafil 50 mg), and one dose of avanafil (50 mg, 100 mg or 200 mg), all administered in random order at least 72 h apart.
  • RigiScan® (Dacomed Corp., Minneapolis, MN, USA) monitoring was used in conjunction with 20-min VSS videos (20, 60, and 100 min after dosing) to determine the duration of and time to ≥60% penile rigidity, maximum rigidity, tumescent activity units (TAUs), rigidity activity units (RAUs), and responses to the five-point Erection Assessment Scale.
  • Safety assessments included adverse events (AEs), vital sign changes in response to dosing, laboratory results (complete blood counts, chemistry panel, prostate-specific antigen, serum testosterone, prothrombin time and urine analysis) and physical examination findings.

Results

  • Eighty-three patients were randomized and received at least one dose of study medication; 82 patients completed the study.
  • Peak response to avanafil occurred in the early interval (20–40 min after dosing), while peak response to sildenafil occurred either in the middle (60–80 min) or late (100–120 min) intervals after dosing.
  • Results were qualitatively similar for all other efficacy endpoints.
  • During the 20–40-min interval, the majority of values for TAUs and RAUs with the avanafil 50-mg, 100-mg and 200-mg treatments were significantly superior to placebo (P < 0.05).
  • Avanafil treatment was generally well tolerated; facial flushing (7–15%) was the most commonly observed AE, and no visual disturbances were reported.

Conclusion

  • A favourable safety profile and improvement in sexual function, coupled with rapid onset of action and durability of effect, make avanafil an attractive option for males with ED, especially in the setting of on-demand treatment.
Abbreviations
ED

erectile dysfunction

PDE5

phosphodiesterase type 5

AE

adverse event

Tmax

maximum plasma concentration

VSS

visual sexual stimulation

EAS

Erection Assessment Scale

TAU

tumescence activity unit

RAU

rigidity activity unit

IIEF-EF

International Index of Erectile Function–Erectile Function

Introduction

Erectile dysfunction (ED) affects ∼18 million males in the USA [1] and >152 million males globally [2]. The condition itself is not life-threatening, but there is a higher prevalence of ED in males with diabetes, heart disease, previous radical prostatectomy and neurological conditions (e.g. spinal cord injuries and stroke) [1, 3, 4]. The vast majority of ED cases are considered secondary to organic disease, with most being attributable to vasculogenic abnormalities, including diabetes [1, 5].

In clinical studies, ED has been associated with cardiovascular risk factors, including hypertension, diabetes, chronic kidney disease, dyslipidemia and obesity [6-20]. In a cross-sectional analysis of data from 2126 adult male participants (aged ≥20 years) in the US National Health and Nutrition Examination Survey (2001–2002), the prevalence of ED was highly correlated with age and was particularly high among males with a history of cardiovascular disease, one or more cardiovascular risk factors, and hypertension [1].

Currently, first-line treatment for males with ED consists of oral phosphodiesterase type 5 (PDE5)-inhibitor therapy, which helps restore penile blood flow and erections in response to sexual stimulation [21]. PDE5 inhibitors that are currently indicated to treat male ED include sildenafil, tadalafil, vardenafil, and avanafil [22-25]; however, because of varied selectivity, PDE5 inhibitors may also inhibit other PDE isozymes, affecting their target tissues and possibly causing unwanted adverse events (AEs) and the discontinuation of therapy.

Avanafil is a potent (half maximum inhibitory concentration = 4.3–5.2 nM) [26] PDE5 inhibitor that has recently been approved by the United States Food and Drug Administration for the treatment of males with ED [25]. Avanafil is highly selective for PDE5. In an in vitro study comparing the selectivity of avanafil for 11 PDE isozymes with that of sildenafil, vardenafil, and tadalafil, avanafil potently inhibited PDE5 activity without significant inhibition of other PDE isozymes [27]. Avanafil is rapidly absorbed from the gastrointestinal tract and has a relatively short half-life. Initial clinical studies with avanafil, which evaluated single doses ranging from 12.5 mg to 800 mg in healthy male volunteers, confirm that the drug is rapidly absorbed, reaches maximum plasma concentration (Tmax) in 30–45 min, and has a half-life of ∼3–5 h [26].

The aim of the present study was to evaluate the safety, efficacy and time course of three doses of avanafil (50 mg, 100 mg and 200 mg) given in conjunction with visual sexual stimulation (VSS) to patients with ED and to compare its efficacy with a 50-mg dose of sildenafil (Tmax, 30–120 min) [24].

Patients and Methods

Study Design

The present study, TA-01, was a phase II, single-blind, multicentre, randomized, crossover study designed to evaluate the safety and efficacy of avanafil 50 mg, 100 mg, and 200 mg compared with active drug (sildenafil 50 mg) and placebo, given in conjunction with VSS, in adult heterosexual males with mild to moderate ED (Fig. 1). It was conducted in compliance with the International Standard of Good Clinical Practice procedures as defined by the International Conference on Harmonization [28], and in accordance with the principles of the Declaration of Helsinki (1964) [29].

Figure 1.

Study design.

Inclusion and Exclusion Criteria

Important inclusion criteria for patients were male sex, 35–70 years of age, with a subjective complaint of mild or mild to moderate ED of ≥6 months' duration. Key exclusion criteria included: patients who had previously failed sildenafil therapy for ED or had attempted ED therapies other than oral medications; had a known allergy or hypersensitivity to avanafil, sildenafil, or any of its components; had a spinal cord injury, diabetes, or a previous radical prostatectomy; had clinically significant penile lesions, abrasions, or anatomical deformities; had major haematological, renal or hepatic disease; had active peptic ulcer disease, clinically significant bleeding disorder, major psychiatric illness, or history of alcohol or drug abuse within the past 6 months; had a stroke or myocardial infarction within the past 6 months; or had angina or congestive heart failure that required medical intervention.

Patients meeting the initial study eligibility requirements at visit 1 (screening) were further evaluated at visit 2 (within 1 week of screening) for baseline erectile response to VSS via RigiScan® (Dacomed Corp., Minneapolis, MN, USA) monitoring. The RigiScan monitor is a validated and predictive approach to detecting efficacy with PDE5 inhibitors [30-33]. The monitor uses a cuff around the penile base and a second cuff around the tip to measure penile tumescence and rigidity.

To be eligible for continued study participation, each patient had to have achieved one of the following erectile responses: (1) ≥60% base penile rigidity for ≥1 min but ≤4 min, cumulatively, during the 20-min video viewing, or (2) achievement of either ≥40% base penile rigidity for ≥1 min, cumulatively, or ≥20% base penile rigidity for ≥2 min, cumulatively.

At visits 3, 4, and 5 (scheduled between 72 h and 1 week after dosing), eligible patients received a single oral dose of each of the following agents in random sequence: placebo, sildenafil 50 mg, and either avanafil 50 mg (group 1), avanafil 100 mg (group 2), or avanafil 200 mg (group 3 [Fig. 2]). For blinding, whole tablets were placed in gelatin capsules. The matching placebo capsules consisted of gelatin capsules that were sized to match the sildenafil capsules and filled with mannitol.

Figure 2.

Schedule of dosing and assessments.

Avanafil dosage selection was based on (1) preclinical pharmacology studies conducted to assess the potency with which avanafil inhibits the PDE5 enzyme [27] and (2) clinical trial results that demonstrated the safety and pharmacokinetics of single doses of avanafil ranging from 12.5 mg to 800 mg in healthy male volunteers [26]. Doses of 50–200 mg were expected to produce an improvement over placebo in the erectile response to VSS as assessed by RigiScan measurements and to be well tolerated [26]. Sildenafil was used in this study as a positive control; the 50-mg dose is the manufacturer's recommended dose for initiating therapy in most patients with ED [24]. The efficacy of the sildenafil 50-mg dose had been shown, both in RigiScan studies [34] and clinical evaluations conducted in the home setting [35].

The dosing of avanafil was increased in sequential study groups beginning with the lowest dose in group 1 (50 mg) and advancing to the next higher dose (group 2, 100 mg), followed by the highest dose (group 3, 200 mg) after the safety of the previous dose had been determined. Dosing visits were separated by at least 72 h.

Patients were seated in a comfortable reclining chair, connected to the RigiScan apparatus, and monitored continuously from 30 min before dosing until 150 min after dosing. A patient-selected VSS video was presented during three discrete 20-min periods beginning 20 min before dosing and concluding at 120 min after dosing (Fig. 1). Patients were instructed to prevent ejaculation and to forgo stimulating themselves manually during the entire session.

During the study, patients were prohibited from using any drugs known to interfere with metabolism by the cytochrome P450 3A4 enzyme (e.g. nitrates, trazadone and ketoconazole). Antidepressants other than trazadone were permitted, provided the patient had been stable on treatment for at least 3 months. Sildenafil or other oral medications used for the treatment of ED were prohibited ≤72 h before any study visit. Androgen replacement therapy and other hormone replacement therapies, including nutritional supplements and herbal products with purported phytoestrogenic activity, were permitted, provided the patient had been on a stable dose for at least 3 months. Treatment with any investigational drug (except avanafil) was prohibited from 30 days before baseline screening until study participation ended. The use of concomitant medications, other than those specifically prohibited or otherwise restricted by the protocol, was allowed. All concomitant medications at study entry, as well as changes in concomitant medication during the course of the study, were monitored and recorded.

Efficacy and Safety Variables

The primary efficacy variables included RigiScan data and responses to the five-point Erection Assessment Scale (EAS) [36]. RigiScan measurements at both the tip and the base of the penis included: (1) time to ≥60% rigidity; (2) duration of ≥60% rigidity; (3) maximum rigidity; (4) tumescence activity units (TAUs); and (5) rigidity activity units (RAUs). EAS patient self-assessment choices were ‘no response,’ ‘some enlargement,’ ‘full enlargement,’ ‘erection sufficient for intercourse’ and ‘rigid erection.’

Safety assessments included AEs, vital sign changes in response to dosing, laboratory results (i.e. complete blood counts, chemistry panel, PSA, serum testosterone, prothrombin time, and urine analysis), and physical examination findings.

Statistical Analysis

The crossover design of this study facilitated within-patient comparisons between placebo, the active control sildenafil, and each dose level of avanafil. RigiScan monitoring allowed both the intensity and the duration of the response to treatment to be characterized objectively. RigiScan data were evaluated by a central reader who was blinded to treatment assignments. Data were also evaluated independently by a secondary reader and inter-reader correlations were evaluated for various study endpoints to confirm the reliability of these study measurements.

Statistical analyses of efficacy parameters were performed on the efficacy-analysis population, which included all patients who had received all three doses of study drug. Descriptive statistics were provided for both the efficacy-analysis population and the all-treated-patients population. The all-treated-patients population included all patients who had received at least one dose of the study drug.

All statistical testing was performed against a two-sided alternative hypothesis with a significance level of 5% (α = 0.05). Tests were considered statistically significant if the calculated P value was <0.05.

All descriptive summaries and statistical analyses of safety data were performed on the all-treated-patients population. Safety data included AEs, vital sign changes in response to dosing, laboratory results and physical examination findings.

Results

Study Population

Eighty-three patients across eight research centres in the USA were randomized, received at least one dose of study medication, and were included in the all-treated-patients population and safety analysis. Eighty-two patients (98.8%) completed the study, and one patient (1.2%) discontinued prematurely (upon request) after receiving only sildenafil treatment. The efficacy-analysis population included 80 patients who received all three doses of study drug (placebo, sildenafil 50 mg and avanafil [50 mg, 100 mg, or 200 mg]); three patients who received fewer than three doses of the study drug were excluded.

The demographic and baseline characteristics of the all-treated-patients population are shown in Table 1. There were no significant differences between treatment groups for baseline characteristics (P > 0.05). The mean (range) duration of ED in this population was 58.1 months (6 months–32 years). The aetiology of ED, which was determined at screening, was primarily organic (60.2%; e.g. hypertension, dyslipidemia and precoronary artery disease for patients presenting with, in particular, mild ED), with 8.4% because of a psychological aetiology and 31.3% because of an ED of mixed aetiology. A diagnosis of psychological aetiology, in which no underlying medical condition was identified to be the cause of ED, was self-reported. The majority of patients experienced ED of moderate severity (81.9%) with a gradual onset (95.2%).

Table 1. Demographics and baseline characteristics for the all-treated-patient population.
CharacteristicOverall*, N = 83Group 1*: avanafil 50 mg, n = 27Group 2*: avanafil 100 mg, n = 28Group 3*: avanafil 200 mg, n = 28
  1. *No differences between groups for all baseline characteristics existed (P > 0.05); Estimated as ‘6 months’ if the exact number of months beyond 6 months was not known; ED severity (for study inclusion) was confirmed by RigiScan monitoring and the five-point EAS.
Age, years    
Mean (sd)51.5 (9.8)52.1 (9.4)53.2 (10.3)49.3 (9.7)
Median49.049.050.048.5
Range26–7035–7031–6926–68
Race, n (%)    
Caucasian56 (67.5)17 (63.0)17 (60.7)22 (78.6)
Black20 (24.1)8 (29.6)9 (32.1)3 (10.7)
Hispanic3 (3.6)2 (7.4)0 (0.0)1 (3.6)
Asian2 (2.4)0 (0.0)1 (3.6)1 (3.6)
Other2 (2.4)0 (0.0)1 (3.6)1 (3.6)
Height, cm    
Mean (sd)177.8 (6.2)178.8 (6.7)176.9 (5.8)177.7 (6.1)
Median177.8180.3176.6178.5
Range163–191163–191164–188165–191
Weight, kg    
Mean (sd)92.3 (15.2)94.3 (15.6)90.2 (14.9)92.3 (15.4)
Median90.494.388.789.7
Range59–12870–12459–12864–127
Primary etiology, n (%)    
Organic50 (60.2)19 (70.4)15 (53.6)16 (57.1)
Psychological7 (8.4)1 (3.7)2 (7.1)4 (14.3)
Mixed26 (31.3)7 (25.9)11 (39.3)8 (28.6)
Duration of ED, months    
Mean (sd)58.1 (65.6)66.8 (75.4)62.3 (74.4)45.7 (42.3)
Median36.048.045.036.0
Minimum-maximum6–3846–3486–3846–186
Onset of ED, n (%)    
Gradual79 (95.2)25 (92.6)27 (96.4)27 (96.4)
Acute4 (4.8)2 (7.4)1 (3.6)1 (3.6)
Patient assessment of ED severity, n (%)    
Minimal14 (16.9)2 (7.4)6 (21.4)6 (21.4)
Moderate68 (81.9)24 (88.9)22 (78.6)22 (78.6)
Complete1 (1.2)1 (3.7)0 (0.0)0 (0.0)

The concomitant medications reported most frequently were dietary supplements (including vitamins), analgesics and anti-inflammatory agents, antihypertensives, hydroxymethylglutaryl-coenzyme reductase inhibitors, and proton pump inhibitors.

At baseline, there were no significant differences in International Index of Erectile Function–Erectile Function (IIEF-EF) domain scores and RigiScan readings between efficacy-safety patients in groups 1, 2 and 3 (P > 0.05). There was a significant difference, however, between groups in the measurement of time to last sexual activity (P < 0.05 [Table 2]). The majority of patients did not achieve ≥60% rigidity at baseline; because data were collected only for those patients who were screened under the original eligibility criteria, the number of patients achieving ≥60% rigidity was too low to be included in the data analysis at baseline.

Table 2. Baseline sexual function characteristics for the all-treated-patient population.
CharacteristicGroup 1: avanafil 50 mgGroup 2: avanafil 100 mgGroup 3: avanafil 200 mg
  1. *Erectile function domain score = Q1 + Q2 + Q3 + Q4 + Q5 + Q15 (baseline IIEF-EF domain scores were not used as part of the study inclusion criteria); No difference between groups existed (P > 0.05); Efficacy subjects (received all three doses and were evaluated for efficacy); §‘5’ is the lowest score possible for males attempting sexual activity; Difference between groups (P < 0.05).
IIEF-EF*, n (%)   
n262628
Severe (1–10)§1 (3.8)1 (3.8)0 (0.0)
Moderate (11–16)5 (19.2)8 (30.8)4 (14.3)
Mild to moderate (17–21)13 (50.0)11 (42.3)17 (60.7)
Mild (22–25)6 (23.1)5 (19.2)4 (14.3)
No ED (26–30)1 (3.8)1 (3.8)3 (10.7)
Mean (sd)19.0 (4.0)18.0 (4.3)19.4 (3.8)
Time since last sexual activity, days   
n262628
Mean (sd)4.6 (3.7)9.4 (10.8)4.7 (4.0)
Median3.65.0 3.73.7
Minimum-maximum1.1–17.20.5–46.00.6–20.0

Primary Efficacy Variables

Duration of ≥60% rigidity

While the peak response to sildenafil 50 mg occurred in the middle (60–80 min) or late (100–120 min) interval, the peak response to avanafil occurred in the early (20–40 min) interval for all (50–200 mg) doses. During the 20–40-min interval, the avanafil 200-mg and 100-mg treatments were superior to the sildenafil 50-mg treatment for duration of ≥60% rigidity for the tip and base of the penis (avanafil 200 mg) and tip of the penis (avanafil 100 mg [P < 0.05]), while sildenafil 50 mg was superior to avanafil 100 mg during the 100–120-min interval for the base of the penis (P < 0.05 [Table 3]).

Table 3. Mean* and median duration of ≥60% rigidity following 20-minute VSS at three different time points post-dosing, min.
Study group20–40 min60–80 min100–120 min
TipBaseTipBaseTipBase
  1. *Mean = efficacy patients; Median = all treated patients; P < 0.05: pairwise P values test for differences between active treatments and placebo by Wilcoxon signed-rank test; §P < 0.05: pairwise P value test for differences between sildenafil and avanafil by Wilcoxon signed-rank test.
Group 1, mean (median)      
Placebo1.0 (0.0)2.7 (0.0)1.0 (0.0)1.9 (0.0)1.3 (0.0)1.8 (0.0)
Sildenafil2.3 (0.0)3.9 (0.0)2.7 (0.0)4.9 (2.0)1.7 (0.0)3.2 (0.0)
Avanafil, 50 mg3.2 (1.0)6.0 (4.0)2.2 (0.0)4.9 (2.0)0.9 (0.0)3.0 (0.0)
Group 2, mean (median)      
Placebo1.4 (0.0)1.2 (0.0)0.6 (0.0)0.9 (0.0)2.5 (0.0)1.3 (0.0)
Sildenafil4.0 (2.0)4.3 (1.0)5.4 (3.0)4.7 (0.0)6.7 (3.0)5.2 (1.0)
Avanafil, 100 mg6.2 (3.0)§5.2 (2.0)5.0 (2.0)3.0 (1.0)4.5 (2.0)2.3 (0.0)§
Group 3, mean (median)      
Placebo3.6 (1.0)3.9 (3.0)2.6 (0.0)3.1 (1.5)2.3 (0.0)2.2 (1.0)
Sildenafil4.4 (1.5)5.5 (3.0)6.7 (6.0)7.2 (7.5)7.3 (6.5)7.7 (7.5)
Avanafil, 200 mg8.5 (8.5)§9.5 (10.5)§7.5 (6.5)7.5 (7.0)5.2 (2.0)6.3 (3.5)

Time to ≥60% rigidity

The cumulative time for all three time intervals to ≥60% rigidity was significantly shorter with avanafil 100-mg and 200-mg treatments (for the tip of the penis) or with avanafil 200-mg treatment (for the base of the penis) compared with treatment with placebo (P < 0.05). Of the sildenafil 50-mg treatments, only the cumulative time for all three intervals to ≥60% rigidity for group 2 (tip of the penis) was significantly shorter than for placebo treatment (P < 0.05).

Maximum penile rigidity, TAU, RAU and EAS

Significant differences in maximum penile rigidity between avanafil treatments and placebo and between sildenafil treatment and placebo were noted. A consistent pattern of response (i.e. dose-related response; response to sildenafil between groups) was not apparent, however, which may be a reflection of the lower number of patients per avanafil group (compared with placebo), as well as differing baseline or placebo response levels across the three groups.

During the 20–40-min interval, the majority of values for TAU and RAU with the avanafil 50-mg, 100-mg and 200-mg treatments were significantly superior to placebo (P < 0.05). Significant differences between avanafil treatments and placebo for TAU were noted most frequently during the early (20–40 min) and middle (60–80 min) intervals (P < 0.05). During the 100–120-min interval, only the 200-mg treatment was superior to placebo for TAU (P < 0.05). Significant differences in TAU between sildenafil 50-mg treatments and placebo were noted most frequently during the 60–80-min and 100–120-min intervals (P < 0.05). Sildenafil 50 mg was superior to avanafil 100 mg for TAU during the 100–120-min interval (P < 0.05).

Similar to that which was observed for the objective efficacy endpoints, significant differences between avanafil treatments and placebo for EAS ≥3 were noted most frequently at the early time point (20–40 min [P < 0.05]).

Safety

All reported treatment-emergent AEs for patients with avanafil treatment were considered mild in severity (Table 4) and consistent with those AEs observed with other PDE5 inhibitors. No severe AEs or deaths were reported during the study, and no patient dropped out of the study because of an AE.

Table 4. Patients reporting ≥1 treatment-emergent AE for the all-treated-patients population.
Variable, by groupPlaceboSildenafilAvanafil
  1. *AEs were assigned to the treatment received before the occurrence (including treatments that were designated as non-analysis treatments); AEs were counted once per patient per treatment period as the most severe that was reported; AEs were counted once per patient per treatment period as the most close relationship to trial therapy that was reported; §‘Related’ includes missing values and AEs reported as having ‘Probably,’ ‘Possibly,’ or ‘Unknown’ relationship to study drug.
Group 1 (avanafil 50 mg)   
n272727
Treatment-emergent AEs*, n (%)2 (7.4)4 (14.8)4 (14.8)
Severity of treatment-emergent AE, n (%)   
Mild2 (7.4)4 (14.8)4 (14.8)
Moderate0 (0.0)0 (0.0)0 (0.0)
Severe0 (0.0)0 (0.0)0 (0.0)
Treatment-emergent AEs related to study drug‡§, n (%)2 (7.4)3 (11.1)4 (14.8)
Serious AEs*, n (%)0 (0.0)0 (0.0)0 (0.0)
Discontinuation owing to an AE, n (%)0 (0.0)0 (0.0)0 (0.0)
Group 2 (avanafil 100 mg)   
n272827
Treatment-emergent AEs*, n (%)1 (3.7)1 (3.7)3 (11.1)
Severity of treatment-emergent AEs, n (%)   
Mild0 (0.0)2 (7.1)3 (11.1)
Moderate1 (3.7)0 (0.0)0 (0.0)
Severe0 (0.0)0 (0.0)0 (0.0)
Treatment-emergent AEs related to study drug‡§, n (%)0 (0.0)1 (3.6)2 (7.4)
Serious AEs*, n (%)0 (0.0)0 (0.0)0 (0.0)
Discontinuation due to an AE, n (%)0 (0.0)0 (0.0)0 (0.0)
Group 3 (avanafil 200 mg)   
n282828
Treatment-emergent AEs*, n (%)2 (7.1)4 (14.3)4 (14.3)
Severity of treatment emergent AEs, n (%)   
Mild2 (7.1)2 (7.1)4 (14.3)
Moderate0 (0.0)2 (7.1)0 (0.0)
Severe0 (0.0)0 (0.0)0 (0.0)
Treatment emergent AEs related to study drug‡§, n (%)2 (7.1)3 (10.7)4 (14.3)
Serious AEs*, n (%)0 (0.0)0 (0.0)0 (0.0)
Discontinuation owing to an AE, n (%)0 (0.0)0 (0.0)0 (0.0)

The most frequently reported AE was flushing, which occurred at a similar incidence with each of the avanafil treatments, did not appear to be dose-related (Table 5), and was considered to be related to treatment. There were no reports of visual impairment in any patient treated with avanafil or placebo. Visual impairment was reported in one (3.7%) patient in group 1 who was treated with sildenafil 50 mg.

Table 5. Incidence of all treatment-emergent AEs.
AEa, by group, n (%)PlaceboSildenafilAvanafil
  1. aAEs were counted once per patient per treatment period. AEs were assigned to the treatment received before the occurrence (including treatments that were designated as non-analysis treatments).
Group 1 (avanafil 50 mg)   
n272727
Flushing1 (3.7)2 (7.4)4 (14.8)
Diarrhoea1 (3.7)0 (0.0)0 (0.0)
Headache0 (0.0)0 (0.0)1 (3.7)
UTI0 (0.0)1 (3.7)0 (0.0)
Visual impairment0 (0.0)1 (3.7)0 (0.0)
Group 2 (avanafil 100 mg)   
n272827
Flushing0 (0.0)1 (3.6)2 (7.4)
Dermatitis contact0 (0.0)0 (0.0)1 (3.7)
Palpitations0 (0.0)1 (3.6)0 (0.0)
Pneumonia1 (3.7)0 (0.0)0 (0.0)
Group 3 (avanafil 200 mg)   
n282828
Flushing0 (0.0)1 (3.6)2 (7.1)
Headache1 (3.6)1 (3.6)1 (3.6)
Dry mouth0 (0.0)1 (3.6)1 (3.6)
Blood pressure increased0 (0.0)0 (0.0)1 (3.6)
Cardiac flutter0 (0.0)0 (0.0)1 (3.6)
Migraine0 (0.0)1 (3.6)0 (0.0)
Nausea0 (0.0)1 (3.6)0 (0.0)
Sinusitis0 (0.0)1 (3.6)0 (0.0)
Stomach discomfort1 (3.6)0 (0.0)0 (0.0)

Discussion

In this phase II study, avanafil was associated with a rapid onset of action and significant improvements in erectile response to VSS. The primary endpoints of treatment response (duration of ≥60% rigidity, time to ≥60% rigidity, maximum rigidity, TAU, RAU, and responses to the five-point EAS) were met, supporting the efficacy of avanafil for the treatment of mild to moderate ED.

Avanafil treatments compared with placebo were, in general, associated most frequently with the earliest time interval (20–40 min after dosing). During this interval, the majority of efficacy endpoints for the 50-mg, 100-mg, and 200-mg avanafil treatments were significantly greater compared with placebo (P < 0.05).

While all avanafil treatments showed some degree of efficacy during the middle (60–80 min) interval, avanafil 200 mg continued to show a high level of efficacy during the latest (100–120 min) interval. Whereas efficacy was greatest with avanafil during the early interval, the response to sildenafil 50 mg was, in general, greatest at the late interval (100–120 min). Significant improvements with avanafil treatments compared with sildenafil 50 mg were noted during the early interval for time to ≥60% rigidity, duration of ≥60% rigidity, maximum rigidity and TAU.

Avanafil also presented a favourable safety profile, and reports of AEs were generally low and mild in severity. These results are consistent with those reported in phase III safety and efficacy trials that showed that avanafil is well tolerated and effective for the treatment of ED in males with mild to severe ED, with and without diabetes, and following nerve-sparing radical prostatectomy. Results of the placebo-controlled trials were also confirmed in the long-term, open-label TA-314 study [37]. In that population, in which 32% of patients had diabetes, improvements in erectile function were observed for up to 1 year and avanafil was generally well tolerated over 52 weeks, with a low discontinuation rate attributable to AEs (<3%).

In the phase III clinical trials, avanafil was also associated with a rapid onset of action and durability of effect [37-40]. In some patients, there was a significant treatment response as early as 15 min after dosing, which may extend to 6 h. In study TA-301, in males with mild to severe ED and without diabetes, after avanafil treatment, 66.7% and 69.4% of patients making sexual attempts within ≤15 min and >6 h were successful compared with 48.1% and 50% for placebo, respectively for both [41].

In the phase III studies, the most commonly reported AEs were generally consistent with those observed with other PDE5 inhibitors [22-24, 35, 42-44] and included headache, flushing, and nasal congestion [37-40]. In the present study, there were no reports of visual disturbances, such as so-called blue vision (cyanopsia), hearing loss, or priapism with any dose of avanafil. And these results are consistent with results of avanafil phase III (TA-301, TA-302, and TA-303) studies of more than 1300 males with mild to severe ED in which no occurrences of blue vision were reported with any dose of avanafil (50–200 mg) [38, 39, 45]; however, in the long-term (52-week), open-label safety, efficacy, and tolerability study (TA-314) of avanafil 50–200 mg in 712 males with or without diabetes and mild to severe ED, one patient (N = 712) in the avanafil 100-mg group reported cyanopsia [37].

Overall, the results of the present study in patients with mild to moderate ED suggest that avanafil is efficacious, well tolerated, and has a rapid onset of action. These findings are consistent with the rapid absorption and early Tmax of avanafil, which also suggest that the pharmacodynamic effect of avanafil persists for 6 h. The results of this phase II study supported the initiation of the avanafil phase III clinical trials.

The present study has some limitations. We used a sildenafil 50-mg dose for comparison, and although this is the dose recommended by the manufacturer for the majority of patients with ED, usage in actual practice may differ. The maximum recommended dose of sildenafil (100 mg) [24] was not compared in the present study. It is, therefore, not known whether a higher dose of sildenafil would have shown greater efficacy at the earlier (i.e. 20–40 min) interval. Despite these limitations, avanafil was found to have a consistent time course of action across all three dose levels tested in the present study, with the peak response occurring within 20–40 min after dosing; therefore, it is likely that, had the maximum dose of sildenafil been included, the peak response to that dose would have occurred in the same interval (60–120 min) as was observed for the 50-mg dose.

In conclusion, the safety and tolerability, and improvement in sexual function, coupled with the rapid onset of action and duration of effect, make avanafil an attractive new option for males with ED, especially in the setting of on-demand treatment.

Acknowledgment

VIVUS designed and funded the study. VIVUS also wrote the study protocol and funded the data analysis.

KnowledgePoint360 Group, LLC provided writing, editorial and graphics support for the development of this manuscript; their participation was funded by VIVUS, Inc.

Conflict of Interest

Wayne J. G. Hellstrom has served as a Consultant or Advisor for Absorption Pharmaceuticals, Auxilium, Coloplast, Endo, Lilly, Cook, American Medical Systems, Ferring, Abbott, Thorologix, NIH, and Slate. Matthew T. Freier and Ege Can Serefoglu have no conflicts to declare. Ronald W. Lewis has served as a member of physician advisory boards for Pfizer and Lilly. Craig A. Peterson and Karen DiDonato are employees of VIVUS, Inc.

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