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Keywords:

  • avanafil;
  • phosphodiesterase type 5 (PDE5) inhibitor;
  • erectile dysfunction (ED);
  • clinical study

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Study Type – Therapy (RCT)

Level of Evidence 1b

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

Avanafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for treating erectile dysfunction (ED). Preclinical and clinical phase I studies showed that avanafil had enhanced selectivity, faster onset of action and a favourable side-effect profile relative to currently available PDE5 inhibitors.

As the result of phase III clinical trial for the efficacy and safety of avanafil treatment (100 and 200 mg), taken as needed over a period of 12 weeks, in Korean patients with ED, avanafil is an effective and well-tolerated therapy for ED of broad-spectrum aetiology and severity.

OBJECTIVE

  • • 
    To evaluate the efficacy and safety of avanafil, a new potent selective phosphodiesterase type 5 (PDE5) inhibitor, in patients with erectile dysfunction (ED).

PATIENTS AND METHODS

  • • 
    The present study was a multicentre, randomized, double-blind, placebo-controlled, fix-dosed phase three clinical trial involving 200 patients with ED.
  • • 
    The subjects were treated with placebo or avanafil (100 or 200 mg) for 12 weeks and were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ).
  • • 
    The primary outcome variable was the change from baseline for IIEF erectile function domain (EFD) score.
  • • 
    The secondary outcome variables were SEP Q2 and Q3, the shift to normal rate (EFD ≥ 26), and response to the GAQ.

RESULTS

  • • 
    Compared with placebo, patients who took 100 or 200 mg of avanafil had significantly improved IIEF-EFD score.
  • • 
    There were similar results when comparing Q2 and Q3 in the SEP diary and the GAQ.
  • • 
    Flushing was the most common treatment-related adverse event.
  • • 
    Most adverse events were transient and mild or moderate in severity.

CONCLUSION

  • • 
    Avanafil is an effective and well-tolerated therapy for ED of broad-spectrum aetiology and severity.

Abbreviations
ED

erectile dysfunction

EFT

erectile function domain

GAQ

Global Assessment Questionnaire

IIEF

International Index of Erectile Function

PDE5

phosphodiesterase type 5

SEP

Sexual Encounter Profile

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Erectile dysfunction (ED), the persistent inability to achieve or maintain an erection for satisfactory sexual performance, affects more than 150 million men worldwide [1,2]. Oral phosphodiesterase type 5 (PDE5) inhibitors are recommended as first-line therapy for ED of varying aetiology and severity [3,4]. Clinical trials of available PDE5 inhibitors have shown that they are well tolerated and effective with a response rate of 60–80% [5,6]. However, many patients are dissatisfied with available therapies due to high cost, adverse events and perceived lack of efficacy [7]. Therefore, the development of novel PDE5 inhibitors with enhanced selectivity, faster onset of action, increased potency and improved tolerability is desirable [8].

Avanafil (4-[(3-chloro-4-methoxybenzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide) is a selective PDE5 inhibitor developed by Mitsubishi Tanabe Pharma Corporation (Osaka, Japan). Preclinical studies have reported that avanafil strongly inhibits PDE5 (half maximal inhibitory concentration, 5.2 nM) in a competitive manner and has higher selectivity against PDE1 and PDE6 [9,10]. Moreover, avanafil does not inhibit PDE11. Clinical kinetics data of phase I trials involving healthy male subjects showed that avanafil was well tolerated and rapidly absorbed, reaching a mean Tmax at 0.33–0.52 h after dosing and declining with a mean apparent T1/2 of 5.36–10.66 h. The area under the curve and Cmax were proportional to dose, and the mean accumulation index on day 7 after a single daily dose of avanafil was 0.98 [11]. Given this background, we investigated the efficacy and safety of oral avanafil treatment (100 and 200 mg), taken as needed over a period of 12 weeks, in Korean patients with ED of broad-spectrum aetiology and severity.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

This was a multicentre, double-blind, randomized, placebo-controlled, fixed-dose, parallel-group study conducted at 14 different centres in Korea in accordance with the Good Clinical Practice and the International Conference on Harmonization guidelines, and in conformity with the ethical principles of the Declaration of Helsinki. Patients were recruited prospectively and consecutively. Written informed consent was obtained from each patient before study entry.

The duration of the study was 16 weeks, and consisted of an initial 4-week treatment-free run-in period, followed by a 12-week treatment period. One follow-up telephone call was scheduled 6–7 days after the treatment period to ensure safety (Fig. 1). Patients were randomly assigned to receive placebo, 100 mg of avanafil, or 200 mg of avanafil. Based on previous avanafil clinical trials, patients were allowed to take the product under investigation (avanafil or placebo) when necessary, with water 30 min before sexual intercourse, but were not to exceed one dose per day [8,11].

image

Figure 1. Study design and data collection schedule. P/S call, post-survey call.

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The included patients were men with ED (as defined by the National Institutes of Health Consensus Development Panel on Impotence [12]) for at least 6 months, who were >20 years of age, in a stable heterosexual relationship for at least 6 months, and who made at least four attempts at sexual intercourse on four separate days during the run-in period, of which at least 50% of the attempts were unsuccessful.

Patients with the following conditions were excluded: penile anatomical defects; spinal cord injuries; previous radical prostatectomy or radical pelvic surgery; hyperprolactinaemia; a low total testosterone; poorly controlled diabetes (HbA1C > 12%) or proliferative diabetic retinopathy; major uncontrolled psychiatric disorder; history of active peptic ulcer disease within 1 year of screening; history of major haematological, renal or hepatic abnormalities; recent (within the previous 6 months) history of cardiovascular disease, stroke, myocardial infarction, cardiac failure, unstable angina or a life-threatening arrhythmia; or a history of alcoholism or substance abuse.

Patients were also ineligible if they were receiving regular treatment with nitrates, anticoagulants (except for aspirin), androgens, antiandrogens or trazodone. The use of erythromycin, cimetidine, ketoconazole, indinavir or grapefruit juice was avoided. Prior use of other PDE5 inhibitors was allowed, but patients who had not responded to other PDE5 inhibitors were excluded from the present study.

The primary efficacy variable was the change from baseline in erectile function domain (EFD) scores of the International Index of Erectile Dysfunction (IIEF) questionnaire. The change was calculated by comparing the sums of scores from questions 1–5 and 15 from the IIEF questionnaire assessed at baseline and after 12 weeks of avanafil or placebo treatment.

The secondary efficacy variables included patient responses to questions 2 and 3 of the Sexual Encounter Profile (SEP; Q2: Were you able to insert your penis into your partner's vagina?; Q3: Did your erection last long enough for you to complete intercourse with ejaculation?), which were assessed after each attempt at intercourse with avanafil or placebo therapy. Patient responses to the Global Assessment Question (GAQ: Has the treatment you have been taking during the study improved your erections?) was also assessed after 12 weeks of treatment. The percentage of patients exhibiting a ‘shift to normal’ (IIEF-EFD score ≥ 26) was analysed.

All adverse events were monitored and recorded. For each adverse event, the investigator assessed the seriousness, intensity (mild, moderate or severe) and relationship to the study drug (definitely, probably, possibly, probably not, definitely not or impossible to evaluate). Vital signs were evaluated at each visit and clinical laboratory variables and 12-lead ECGs were evaluated at the first and fifth visits.

Efficacy analysis was performed using the data from the intention-to-treat sample, which included all randomized patients who had received at least one dose of the study drug and at least one valid post-baseline evaluation. All comparisons were performed at a two-sided alpha level of 0.05. Assuming a standard deviation of 6.57 for the change from baseline in EFD scores, ≈ 45 patients per treatment group were required to achieve a 95% power to detect a response difference of 5 between the avanafil and placebo groups. Allowance of a 10% dropout rate required 50 randomized patients per group for efficacy analysis. The response rate of the GAQ and the percentage of shift to normal patients were assessed by chi-squared test. Other efficacy variables were analysed using an ANCOVA with baseline value as a covariate.

Safety analysis included all subjects who received at least one dose of the study drug. For safety analysis, 90% CIs were used in listing the number of adverse events that occurred and the rate of patients who experienced adverse events. In addition, an intergroup comparison was performed using a chi-squared test or Fisher's exact tests.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

In all, 200 patients who received at least one dose of double-blind treatment and who had adequate data for evaluation were eligible for the safety and efficacy population (66, 68, and 66 patients for placebo and avanafil [100 mg and 200 mg], respectively; Fig. 2). Demographic data and baseline characteristics of each group are shown in Table 1; 40% of the patients had prior PDE5 inhibitor use before entering the present study.

image

Figure 2. Disposition of subjects during the study. ITT, intention-to-treat; PP, per protocol; AEs, adverse events.

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Table 1.  Demographic and erectile dysfunction characteristics of study subjects
 Placebo (N= 66)Avanafil
100 mg (N= 68)200 mg (N= 66) P
  1. Values are means ±sd or n (%). P values were calculated using chi-squared or Fisher's exact tests for comparison of subject numbers and anova for comparison of mean values.

Age, years54.90 ± 8.9055.80 ± 8.2056.60 ± .300.5321
Height, cm169.60 ± 6.10170.00 ± 5.20169.00 ± 5.700.6094
Weight, kg71.70 ± 8.5072.00 ± 7.8070.40 ± 6.700.4846
Aetiology [n (%)]    
 Organic33 (50.00)36 (52.94)33 (50.00) 
 Psychogenic2 (3.03)4 (5.88)4 (6.06)0.9043
 Mixed31 (46.97)28 (41.18)29 (43.94) 
Severity (EFD score) [n (%)]    
 Severe (<11)13 (19.70)11 (16.18)16 (24.24) 
 Moderate (11–16)34 (51.52)34 (50.00)28 (42.42)0.7232
 Mild (17–25)19 (28.79)23 (33.82)22 (33.33) 
Prior PDE5 inhibitor users [n (%)]28 (42.42)23 (33.82)29 (43.94)0.4340

All efficacy analyses reported here were performed on the intention-to-treat population. However, data from the per protocol population were very similar. Analyses of intervisit differences in each group revealed that all groups, except for the placebo group, showed statistically significant improvement with regard to the change from baseline in EFD scores of the IIEF (P < 0.001). When the difference from the baseline value was compared between visits, there were statistically significant improvements in the 100 and 200 mg avanafil treatment groups (P < 0.001), but there were no significant improvements in the placebo group (Fig. 3a).

image

Figure 3. Primary efficacy outcome variable. (A) International Index of Erectile Function-erectile function domain (IIEF-EFD) scores at each visit; (B) Mean changes from baseline to endpoint at 12 weeks for IIEF-EFD scores (*P < 0.001).

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After 12 weeks of treatment with on-demand avanafil, mean changes from baseline in EFD of the IIEF were 8.5 for the 100 mg group and 8.8 for the 200 mg group, which were significantly greater than for the placebo group (3.5, P < 0.001, Fig. 3b). Final IIEF-EFD scores were as high as 18 for placebo, 23.7 for 100 mg avanafil, and 22.9 for 200 mg avanafil. No significant differences were observed between the two avanafil groups.

The change from baseline in each domain of the IIEF showed significant changes in avanafil groups compared with placebo (P < 0.001, Fig. 4). In comparing the rates of response to SEP Q2 and Q3, the proportion of ‘yes’ responses to the GAQ, and the percentage of patients achieving normal EFD scores (≥26), all patients in the avanafil groups had a significant difference compared with patients in the placebo group (P < 0.001, Table 2).

image

Figure 4. Mean changes from baseline to endpoint at 12 weeks for each domain of the IIEF (*P < 0.001).

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Table 2.  Changes in secondary efficacy outcome variables after 12 weeks
 Placebo (N= 66)Avanafil
100 mg (N= 68)200 mg (N= 66)
  1. Values are changes of percentage of positive responses from baseline to 12 weeks. P values were calculated using chi-squared or Fisher's exact tests for comparison of subject numbers and anova for comparison of mean values. *P < 0.001.

SEP Q215.70%27%*29.2%*
SEP Q325.80%54.3%*55.3%*
GAQ25.00%53%*46%*
Shift to normal rate (EFD ≥ 26)16.70%45.6%*39.39%*

In general, avanafil was safe and well tolerated. Most adverse events were mild or moderate in severity. The most commonly reported treatment-related adverse event was flushing, as shown in Table 3. No clinically significant changes in laboratory tests, electrocardiograms or blood pressure were observed in the avanafil groups.

Table 3.  Incidence of drug-related adverse events. Values are n (%).
Drug-related adverse eventsPlacebo (N= 68)Avanafil
100 mg (N= 70)200 mg (N= 69)
Chest discomfort  1 (1.45%)
Chest pain 1 (1.43%) 
Fatigue 1 (1.43%) 
Dizziness1 (1.47%)1 (1.43%)1 (1.45%)
Headache 3 (4.29%)7 (10.14%)
Diarrhoea 1 (1.43%) 
Dyspepsia 1 (1.43%) 
Heart burn  1 (1.45%)
Nausea 2 (2.86%)1 (1.45%)
Palpitation 3 (4.29%)1 (1.45%)
Nose congestion 1 (1.43%)1 (1.45%)
Urticaria 1 (1.43%) 
Flushing2 (2.94%)8 (11.43%)9 (13.0%)
Conjunctivitis 1 (1.43%) 
Vision abnormal 1 (1.43%) 
Total3 (4.41%)25 (35.71%)22 (31.88%)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

This multicentre, randomized, double-blind, placebo-controlled, fixed-dose clinical study compared the efficacy and safety of 100 and 200 mg avanafil with placebo over 12 weeks of treatment. This is the first report of a phase III clinical trial of avanafil anywhere in the world.

Avanafil therapy was be significantly superior to placebo for all primary and secondary efficacy variables. IIEF-EFD score, the primary efficacy variable, showed improvements of 8.5 and 8.8 points after 12 weeks of 100 and 200 mg avanafil treatments, respectively, which were significantly greater than placebo (3.5 points). With respect to secondary efficacy variables, statistically significant improvements were also observed for all endpoints. Scores from all domains of the IIEF were significantly improved in the avanafil groups. Furthermore, the responses to SEP Q2 and Q3, as well as GAQ, were similar to those associated with other PDE5 inhibitors [13–16]. The proportion of patients achieving normal EFD scores (≥26) has been widely used to evaluate the efficacy of PDE5 inhibitors [17]. For avanafil, the proportions of patients achieving normal EFD scores after 12 weeks were 16.7%, 45.6% and 39.39% in the placebo group, 100 and 200 mg avanafil treatment groups, respectively. There were no statistically significant differences between the two avanafil groups. The mean rates of positive response to GAQ and patients achieving normal EFD scores after 12 weeks were higher in the 100 mg group, probably because of the small number of subjects. Admittedly, the higher dosage could have resulted in significantly greater efficacy with a larger cohort of subjects.

The adverse events associated with avanafil were similar to those commonly observed in other studies involving PDE5 inhibitors. In the present study, the most frequently reported adverse events were flushing and headache of mild to moderate severity. Only one patient discontinued treatment due to adverse events. Most treatment-related adverse events were attenuated without treatment. Avanafil did not induce myalgia, as is sometimes reported for tadalafil [18]. Ther was only one case of vision abnormality in the present study. The rate was much lower than for sidenafil [19]. This observed adverse event data for avanafil might be correlated with the favourable pharmacokinetic profile and greater selectivity for PDE5. Avanafil has higher selectivity (120-fold) against PDE6 than sildenafil (16-fold) and vardenafil (21-fold), and higher selectivity (>10 000-fold) against PDE1 than sildenafil (380-fold) and vardenafil (1000-fold). Avanafil does not inhibit PDE11. Colour vision disturbances are believed to be attributable to non-specific inhibition of some PDE inhibitors, specifically PDE6 [20].

In the present study, 60% of patients had no previous PDE5 inhibitor experience. No significant differences in the efficacy and adverse events were observed between patients with previous PDE5 inhibitor experience and those who were PDE5 inhibitor-naive. These results suggest that exclusion of non-responders might not have significantly affected the observed outcomes.

From the results evaluated thus far, avanafil treatments in doses of 100 and 200 mg were well tolerated and effective in treating patients with mild to severe ED. However, no statistically significant differences were observed between the 100 and 200 mg avanafil groups. Thus, larger clinical trials with longer treatment duration, applying a flexible dosing of avanafil in a more diverse group of patients, are needed in the future. The unique clinical properties (higher selectivity and faster onset) of avanafil will provide a welcome addition to current ED management.

In conclusion, avanafil resulted in significant improvements in EF as measured by the IIEF, SEP and GAQ among patients with ED in doses of 100 or 200 mg as needed for 12 weeks. The frequency of adverse events was low, indicating that avanafil is safe and well tolerated. Based upon these data, avanafil will provide another reliable treatment option for ED patients.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

None declared. Source of funding: JW Pharmaceutical Co. (study no: CWP-AVA-301).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES