- Email: [email protected]
A Phase 3, Placebo Controlled Study of the Safety and Efficacy of Avanafil for the Treatment of Erectile Dysfunction After Nerve Sparing Radical Prostatectomy
A Phase 3, Placebo Controlled Study of the Safety and Efficacy of Avanafil for the Treatment of Erectile Dysfunction After Nerve Sparing Radical Prostatectomy John P. Mulhall,*,† Arthur L. Burnett,‡ Run Wang,§ Kevin T. McVary,储 Judd W. Moul,¶ Charles H. Bowden,** Karen DiDonato,** Winnie Shih** and Wesley W. Day** From Memorial Sloan-Kettering Cancer Center, New York, New York (JPM), The Johns Hopkins Medical Institutions, Baltimore, Maryland (ALB), University of Texas Medical School at Houston and MD Anderson Cancer Center, Houston, Texas (RW), Northwestern University/Feinberg School of Medicine, Chicago, Illinois (KTM), Division of Urology, Department of Surgery and Duke Cancer Institute, Durham, North Carolina (JWM), and VIVUS, Inc., Mountain View, California (CHB, KD, WS, WWD)
Abbreviations and Acronyms AE ⫽ adverse event ED ⫽ erectile dysfunction EF ⫽ erectile function IIEF ⫽ International Index of Erectile Function ITT ⫽ intent to treat PDE5i ⫽ phosphodiesterase type 5 inhibitor TEAE ⫽ treatment emergent adverse event
Purpose: We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy. Materials and Methods: This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy. Patients were randomized to 100 or 200 mg avanafil or placebo (taken 30 minutes before sexual activity) for 12 weeks. Primary end points included successful vaginal insertion (Sexual Encounter Profile [SEP] question 2), successful intercourse (SEP3) and change in score on the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire. Results: A total of 298 patients were randomized and 84.6% completed the study. At baseline 16.1% were age 65 years or older and 71.5% had severe erectile dysfunction (mean overall IIEF-EF domain score 9.2). After 12 weeks there were significantly greater increases in SEP2 and SEP3 and change in mean IIEF-EF domain score with 100 and 200 mg avanafil vs placebo (p ⬍0.01). Following dosing with avanafil 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs 4.5% (2 of 44) for placebo (p ⬍0.01). Avanafil was generally well tolerated. No serious adverse events were reported and fewer than 2% of patients discontinued the study due to an adverse event. Conclusions: Avanafil in 100 and 200 mg doses was effective and well tolerated in improving erectile function after prostatectomy. Results suggest a rapid onset of action and sustained duration of effect, with all 3 primary end points being achieved at both dose levels. Key Words: erectile dysfunction; prostatectomy; phosphodiesterase 5 inhibitors; clinical trial, phase III Accepted for publication November 29, 2012. Supported by VIVUS. Study received institutional review board approval. Clinical Trial Registration NCT00895011 (www.clinicaltrials.gov). * Correspondence: Sexual & Reproductive Medicine Program, Memorial Sloan-Kettering Cancer Center, Sidney Kimmel Center for Prostate & Urologic Cancers, 353 East 68th St. (Room 531), New York, New York 10065 (telephone: 646-422-4359; FAX: 212-988-0768; e-mail: [email protected]). † Financial interest and/or other relationship with Nexmed, Absorption Pharmaceuticals, AMS, Meda, Vivus Inc., Association of Peyronie’s Disease Advocates and Pfizer.
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0022-5347/13/1896-2230/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
http://dx.doi.org/10.1016/j.juro.2012.11.177 Vol. 189, 2230-2237, June 2013 RESEARCH, INC. Printed in U.S.A.
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‡ Financial interest and/or other relationship with Endo Pharmaceuticals, Abbott, Pfizer Inc., American Medical Systems Inc., Coloplast Corp., TIMM Medical, VIVUS Inc., Auxilium Inc., Shionogi Pharma, Reflexonic LLC, Medispec Ltd. and National Institutes of Health. § Financial interest and/or other relationship with American Medical Systems Inc., Coloplast Corp., TIMM Medical Technologies Inc., Augusta Medical System LLC and VIVUS Inc. 储 Financial interest and/or other relationship with Lilly/ICOS, Watson Pharmaceuticals, Allergan, GlaxoSmithKline, Allergan, Neotract, NIDDK, Johnson & Johnson and VIVUS Inc. ¶ Financial interest and/or other relationship with Sanofi Oncology, Dendreon, Ferring, Amgen, Medivation, Janssen, Bayer Oncology, Astellas, Theralogix and VIVUS Inc. ** Financial interest and/or other relationship with VIVUS Inc.
PROSTATE cancer treatment is frequently associated with the development of ED.1,2 Data from the Prostate Cancer Outcomes Study, a population based longitudinal cohort of 1,291 men, showed that 56% of men who underwent bilateral nerve sparing radical prostatectomy reported impotence at 18 months or more after surgery.3 Further data from a single center study (293) indicated that if left untreated, the rate of EF after recovery was only 36% (mean followup 27 months).4 Even lower rates of recovery have been reported for men older than 65 or older than 70 years.3–5 Currently first line treatment for most men with various causes of ED consists of oral PDE5i therapy including sildenafil, vardenafil, tadalafil and avanafil.6 –9 Overall, data show that treatment with a PDE5i improves sexual function in the majority of men with mild to moderate ED after nerve sparing radical prostatectomy. However, response rates are considerably lower in men with severe ED10,11 and men older than 65 years.5,10,12 Avanafil is a highly selective13,14 and potent (IC50 ⫽ 4.3 to 5.2 nM)15 PDE5i that has recently been approved for the treatment of men with ED.9 Data from phase 1, 2 and 3 clinical trials show that avanafil is rapidly absorbed (time to maximum plasma concentration 30 to 45 minutes) after oral administration, has a relatively short (3 to 5-hour) half-life15 and an onset of action of 15 minutes or less in some patients.16 –19 In phase 3 clinical trials avanafil improved EF in males with mild to severe ED with18 and without17 diabetes. In this study we evaluated the safety and efficacy of 100 and 200 mg avanafil in the treatment of adult males with ED after bilateral nerve sparing radical prostatectomy.
During a 4-week nontreatment run-in, patients maintained a diary of all attempts at sexual intercourse. Patients with a 50% or greater failure rate in maintaining an erection for a sufficient duration to allow successful intercourse, a score of 5 to 25 (inclusive) on the EF domain of the IIEF questionnaire,22,23 and who made at least 4 attempts at sexual intercourse during the run-in period were randomized (1:1:1) to 100 or 200 mg avanafil or placebo, and treated for 12 weeks (fig. 1). The study drug was taken approximately 30 minutes before initiation of sexual activity and results were recorded in a diary. Up to 2 doses could be taken within a 24-hour period if taken at least 12 hours apart. There were no restrictions on food or alcohol intake.
Key Inclusion and Exclusion Criteria Adult males age 18 to 70 years with a history of ED of 6 months or more after bilateral nerve sparing retropubic radical prostatectomy for localized carcinoma of the prostate (6 months or more before screening) and with staging of prostate carcinoma pT2 or less and Gleason score 7 (4 ⫹ 3) or less were included in the study. Patients were excluded for prior use of radiotherapy, chemotherapy, androgen deprivation therapy, cryotherapy, nonnerve sparing surgery and/or bladder or penile surgery, or if these were likely to be required during the study. Use of penile rehabilitation treatment (ie oral medications, intracavernous injections and/or intraurethral therapies) was not permitted before beginning the 4-week, nontreatment run-in period of the study or throughout the study. Patients with a history of diabetes or a history of dose limiting AEs during prior treatment with a PDE5i were excluded. Patients were also excluded if they experienced ED as a consequence of advanced neurological disease, spinal cord injury or diabetes, or had a history of severe ED requiring routine medical therapy before prostate surgery.
Study End Points Primary study end points were the change in percentage of sexual attempts in which patients are able to insert the
MATERIALS AND METHODS Study Design This randomized, double-blind, placebo controlled, parallel group study enrolled patients at 53 sites in the United States to assess the safety and efficacy of avanafil in the treatment of mild to severe ED in men following bilateral nerve sparing radical prostatectomy. All patients read and signed an institutional review board approved informed consent form and were assured that they could withdraw from the study at any time without jeopardizing medical care related to or required as a result of study participation. This study was conducted in accordance with the International Standard of Good Clinical Practice procedures (as defined by the International Conference on Harmonisation)20 and in accordance with the principles of the Declaration of Helsinki.21
Figure 1. Study design
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AVANAFIL FOR ERECTILE DYSFUNCTION AFTER PROSTATECTOMY
penis into the partner’s vagina (SEP2) and maintain an erection of sufficient duration to have successful intercourse (SEP3) between the run-in period and the end of the 12-week treatment period, as well as the change in domain score on the IIEF-EF questionnaire from baseline (visit 2) to end of treatment. Secondary end points included the change in response to individual questions and for other domains (orgasmic function, sexual desire, intercourse satisfaction, overall satisfaction) from the IIEF questionnaire between baseline and weeks 4, 8 and 12; responses to secondary subject diary questions; and the response to the Global Assessment Question on treatment effect and the Future Use question at week 12.
For patients who did not complete the trial, available diary data were used to calculate SEP2 and SEP3. The last observation carried forward convention was used to impute the end of treatment value for the IIEF-EF domain score. Treatment comparisons were assessed using an ANCOVA model with factors of treatment and stratification factors (severity of ED and baseline levels) as the covariate. A value of p ⬍0.05 denoted significance between avanafil and placebo. The study was designed to achieve 86% power with a sample size of 100 patients per arm to detect a mean difference of 25.7% (SD 57.4) for SEP2, 24.3% (SD 56.0) for SEP3 and 6.1 (SD 11.8) for the IIEF-EF domain score from baseline to end of treatment.
Safety Assessments AEs and vital signs were monitored at each study visit. Laboratory parameters, electrocardiograms and physical examinations were evaluated at screening and at the end of treatment.
Statistical Analysis All patients who were randomized, took 1 or more doses and had at least 1 post-dosing assessment were included in the ITT population. The evaluable population was defined as all patients in the ITT population who reported using at least 6 doses of the study drug and who made at least 4 sexual intercourse attempts during the run-in period. Safety analyses were performed on all patients who received 1 or more doses of study drug and for whom any safety data were available.
RESULTS Patient Disposition A total of 298 patients were randomized and 252 (84.6%) completed the study (fig. 2). A higher percentage of patients in the placebo group (24.0%) discontinued the study compared with the 100 mg (14.1%) or 200 mg (8.1%) avanafil treatment groups. Demographics and Baseline Characteristics Demographic and baseline characteristics including mean ED duration were similar among the groups (table 1). Of the patients 71.5% were severely impaired at baseline (mean overall IIEF-EF domain
Figure 2. Patient disposition (all enrolled patients). a indicates 230 persons in whom screening failed. Of those for whom reason was provided (210) the majority of failures were due to untreated hypogonadism or total testosterone less than 325 ng/dl (93, 44.3%); prostate carcinoma stage T2 or greater, or Gleason score 7 or greater (15, 7.1%); positive urine drug screen (11, 5.2%); and documented history of type 1 or type 2 diabetes (7, 3.3%). b indicates safety population included all patients who received 1 or more doses of study drug and had any safety data available. c indicates patients may have withdrawn consent for any reason, which did not have to be revealed to study site. d indicates ITT population included all patients who were randomized, reported taking 1 or more doses of study drug, and had 1 or more post-dose efficacy assessments. e indicates evaluable population included all ITT patients who reported using 6 or more doses of study drug during treatment period and had 4 or more attempts at intercourse during nontreatment run-in period.
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Table 1. Demographics and baseline characteristics (randomized population)
No. pts Mean pt age (SD) No. age category (%): Younger than 50 50–Younger than 65 65 or Older No. race (%): White Black Unknown Mean kg/m2 body mass index (SD) No. ED severity (%): Mild Moderate Severe No. mos ED (%):* 6 to Less than 12 12 to Less than 24 24 or More No. radical prostatectomy type (%):† Open Robotic Laparoscopic
Placebo
Avanafil 100 mg
Avanafil 200 mg
Overall
100 58.6 (5.87)
99 58.9 (5.88)
99 57.7 (6.60)
298 58.4 (6.13)
6 (6.0) 79 (79.0) 15 (15.0)
8 (8.1) 73 (73.7) 18 (18.2)
13 (13.1) 71 (71.7) 15 (15.2)
27 (9.1) 223 (74.8) 48 (16.1)
84 (84.0) 16 (16.0) 0 (0.0) 27.7 (3.42)
83 (83.8) 16 (16.2) 0 (0.0) 28.1 (3.93)
76 (76.8) 22 (22.2) 1 (1.0) 28.4 (3.94)
243 (81.5) 54 (18.1) 1 (0.3) 28.1 (3.77)
8 (8.0) 22 (22.0) 70 (70.0)
7 (7.1) 17 (17.2) 75 (75.8)
12 (12.1) 19 (19.2) 68 (68.7)
27 (9.1) 58 (19.5) 213 (71.5)
35 (35.0) 42 (42.0) 23 (23.0)
31 (31.3) 40 (40.4) 28 (28.3)
36 (36.4) 39 (39.4) 24 (24.2)
102 (34.2) 121 (40.6) 75 (25.2)
14 (14.0) 83 (83.0) 3 (3.0)
19 (19.2) 76 (76.8) 4 (4.0)
9 (9.1) 81 (81.8) 9 (9.1)
42 (14.1) 240 (80.5) 16 (5.4)
* Duration of ED is from after surgery to date of study enrollment. † Prostatectomies were performed by highly experienced surgeons, defined as having met the criteria of 1) 5 or more of years experience after residency, 2) performance of 250 or more radical prostatectomies using 1 technique (open vs laproscopic vs robotic), 3) performance of 50 or more radical prostatectomies in the last calendar year of study participation (approximately 5 to 10 per month), 4) having a dedicated researcher coordinator and 5) having an ED specialist in the practice.
score 9.2). Mean SEP3 success rate at baseline was less than 5% overall and the majority of patients (80.5%) had robotic surgical technique for radical prostatectomy. Medical History and Concomitant Medications (safety population) Except hypertension, which was reported by a lower proportion of patients in the 100 mg avanafil group, treatment groups were comparable with respect to medical history categories of special interest. Overall 125 (41.9%) patients reported a history of hypertension, 38 (12.8%) other cardiovascular disease, 35 (11.7%) depression, 15 (5.0%) anxiety, 7 (2.3%) coronary artery disease and 1 (0.3%) transurethral resection of the prostate. Concomitant medication use was similar between treatment groups. Overall 118 (39.6%) patients took antihypertensive medications, 28 (9.4%) took antidepressants and 4 (1.3%) took ␣-blockers. Treatment Compliance During each 4-week interval the proportion of patients who took the required number of doses of study drug was higher in the avanafil groups (83% to 93% [100 mg], 91% to 95% [200 mg]) than in the placebo group (76% to 90%). Mean time from dosing to sexual attempts was 58.1 (SD 50.43) minutes. Efficacy Primary End Points Total patient population. After 12 weeks of treatment 100 and 200 mg avanafil resulted in a signifi-
cantly greater increase in SEP2, SEP3 and change in mean IIEF-EF domain score compared with placebo (p ⬍0.01, fig. 3). Patients randomized to 100 and 200 mg avanafil had an improvement in IIEF-EF domain score of 3.6 (40%) and 5.2 (55%), respectively, compared with 0.1 (1%) for placebo. Stratification by severity at baseline. When SEP2, SEP3 and IIEF-EF domain scores were stratified by baseline ED severity, treatment with 200 mg avanafil resulted in improvement in all 3 co-primary end points vs placebo (fig. 4). Additional analysis was conducted to determine the proportion of patients who achieved a normalized IIEF-EF domain score (26 or greater) at the end of the treatment period. Regardless of baseline ED severity, higher proportions of patients in the 100 and 200 mg avanafil groups had a normalized IIEF-EF domain score compared with placebo (mild ED 4.3%, 7.3% and 2.1%; moderate ED 3.2%, 4.2% and 1.0%; severe ED 5.3%, 6.3% and 0.0%, respectively). Stratification by age. Regardless of age (younger than 50 years, 50 to less than 65 years and older than 65 years), treatment with 100 and 200 mg avanafil resulted in statistically significant changes from baseline in SEP3 (p ⬍0.01). Stratification by type of radical prostatectomy. When stratified by surgical technique (open, robotic or laparoscopic), treatment with 200 mg avanafil
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AVANAFIL FOR ERECTILE DYSFUNCTION AFTER PROSTATECTOMY
Figure 3. Change in co-primary end points (SEP2, SEP3 and IIEF-EF) from baseline to end of treatment (ITT population). difference compared with placebo (p ⬍0.01).
a
indicates
resulted in improvement in all 3 co-primary end points vs placebo for all types of radical prostatectomy surgery (p ⬍0.01 for all).
group (27.7%, p ⬍0.01) responded to the Future Use question that they would use the study treatment if it were available today.
Efficacy – Secondary End Points Treatment with 200 mg avanafil was associated with significant improvements in the IIEF orgasmic function domain score compared with placebo (p ⬍0.05). Treatment with 100 and 200 mg avanafil was associated with significant improvements in the intercourse satisfaction domain score (p ⫽ 0.01 and p ⬍0.01, respectively) and overall satisfaction score (p ⬍0.05 and p ⬍0.01, respectively) compared with placebo.
Subject diary responses by time interval from dose to attempt. For all time intervals from dose to sexual attempt (15 minutes or less through greater than 360 minutes), the 100 mg avanafil group had significantly higher proportions of successful or satisfied responses regarding vaginal penetration (SEP2), intercourse (SEP3) and overall sexual experience vs placebo (p ⬍0.1 for all intervals except for the 120 to 240-minute interval [p ⬍0.05]). Significantly higher responses compared with placebo were also achieved in the 200 mg avanafil group for all intervals up to 240 minutes (p ⬍0.01) but not beyond that point (p ⬎0.05). After dosing with 100 or 200 mg avanafil, 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs 4.5% (2 of 44) for placebo (p ⬍0.01). Of all attempts made from 16 to 30 minutes, and from 31 to 60 minutes after dosing, SEP3 success rates for patients randomized to 100 or 200 mg avanafil were 30.2% (281 of 932) and 29.5% (456 of 1,544) vs 7.7% (34 of 439) and 11.3% (84 of 744) for placebo, respectively (p ⬍0.01).
Secondary subject diary responses. Compared with placebo, secondary subject diary responses were significantly greater for the 100 and 200 mg avanafil groups, including changes in the percentages of sexual attempts in which patients were able to achieve an erection (p ⬍0.01), and were satisfied with their erection (p ⬍0.01) and sexual experience (p ⬍0.05 and p ⬍0.01, respectively). Global assessment questions. At the end of treatment significantly higher proportions of patients in the 100 mg (31.3%) and 200 mg (41.3%) avanafil groups compared with placebo (10.7%) responded that study treatment improved their erections (p ⬍0.01). A significantly higher proportion of patients in the 200 mg avanafil group (57.6%) compared with the 100 mg avanafil group (39.8%, p ⬍0.05) and the placebo
Safety Study drug tolerability and AEs. Treatment with avanafil was generally well tolerated and 2% of pa-
Figure 4. Co-primary end points (SEP2, SEP3 and IIEF-EF) at end of treatment by baseline (BL) severity of ED (ITT population). a indicates change from baseline not significant (p ⬎0.05). b indicates change from baseline (p ⬍0.01).
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Table 2. All TEAEs reported in 1% or more of patients (safety population)
Headache Flushing Nasopharyngitis Back pain Nasal congestion Upper respiratory tract infection Abnormal electrocardiogram Bronchitis Dizziness Blood cholesterol increased Nausea
No. Placebo (%)
No. Avanafil 100 mg (%)
No. Avanafil 200 mg (%)
No. Totals (%)
1 (1.0) 0 (0.0) 0 (0.0) 1 (1.0) 1 (1.0) 0 (0.0) 0 (0.0) 4 (4.0) 0 (0.0) 1 (1.0) 1 (1.0)
8 (8.1) 5 (5.1) 3 (3.0) 3 (3.0) 3 (3.0) 2 (2.0) 1 (1.0) 0 (0.0) 1 (1.0) 2 (2.0) 1 (1.0)
12 (12.1) 10 (10.1) 5 (5.1) 2 (2.0) 1 (1.0) 3 (3.0) 3 (3.0) 0 (0.0) 2 (2.0) 0 (0.0) 1 (1.0)
21 (7.0) 15 (5.0) 8 (2.7) 6 (2.0) 5 (1.7) 5 (1.7) 4 (1.3) 4 (1.3) 3 (1.0) 3 (1.0) 3 (1.0)
TEAEs were defined as AEs occurring after the first dose of study drug or after the first dispense date, if missing, and before the last visit.
tients discontinued from the study drug due to an AE. TEAEs were reported in 23 (23.0%), 38 (38.4%) and 45 (45.5%) patients in the placebo and 100 and 200 mg avanafil groups, respectively. There were no increased safety concerns with the 200 vs 100 mg avanafil dose. The most frequently reported AEs were headache, flushing and nasopharyngitis (table 2). Dyspepsia was reported in 1 patient each in the 100 mg avanafil group and placebo group (0.7% overall). Syncope, a hemodynamic AE, was reported in less than 2% of patients overall. The incidence of headache, flushing, nasopharyngitis, abnormal electrocardiogram upper respiratory tract infection and dizziness was higher in the avanafil groups, the severity of which was dose dependent. No patient had a TEAE categorized as priapism or major cardiac events, and no patient died or had a serious AE during the study. Study discontinuation. Overall 5 (1.7%) patients discontinued due to an AE (1 in the placebo group, 2 in the 100 mg avanafil group and 2 in the 200 mg avanafil group). For 2% (2) and 1% (1) of patients in the 100 and 200 mg avanafil groups, respectively, AEs that led to discontinuation were considered related to study drug. Other relevant safety parameters. No clinically important differences among treatment groups in mean changes in safety laboratory parameters or electrocardiogram parameters or physical examination findings were noted. For all treatment groups mean blood pressure (systolic and diastolic) and heart rate values at the end of treatment were similar to those at randomization.
ing by age, baseline ED severity and by type of radical prostatectomy surgical technique. Definitive conclusions about the magnitude of treatment effect for other subgroups could not be determined because of insufficient sample size. A higher proportion of patients in the 100 and 200 mg avanafil groups had a normalized IIEF-EF domain score compared with placebo. Because of the small sample size, no tests of statistical significance were performed. Nonetheless, avanafil was numerically superior to placebo in the proportion of men achieving normalized EF in this difficult to treat, postoperative population. An ad hoc analysis was performed to determine clinically important differences for the 3 co-primary end points. Minimum clinically important differences24 were defined as 23%, 21% and 4 or more points for SEP3, SEP225 and IIEF-EF,26 respectively. Clinically relevant improvements were demonstrated across all 3 co-primary efficacy end points, and statistical significance was demonstrated for SEP3, SEP2 and IIEF-EF compared with placebo (table 3). On the basis of the responder analysis and the use of a generally recognized definition of a clinically relevant change, the observed changes in Table 3. Responder analysis: change from baseline scores (ITT population) Placebo 96
Avanafil 100 mg
DISCUSSION
No. pts SEP3: No. (%)* p Value SEP2: No. (%)† p Value IIEF-EF: No. (%)‡ p Value
94
In the current study 100 and 200 mg avanafil significantly improved EF compared with placebo in men with all levels of ED severity. The effects of treatment were observed across subgroups, includ-
* Responders with a change from baseline of 23% or greater. † Responders with a change from baseline of 21% or greater. ‡ Responders with a change from baseline of 4% or greater. § Statistically significant difference from placebo.
Avanafil 200 mg 96
14 (14.6) Not applicable
26 (27.7) 0.5
36 (37.5) ⬍0.01§
7 (7.3) Not applicable
29 (30.9) 0.01§
37 (38.5) ⬍0.01§
13 (13.7) Not applicable
33 (35.1) ⬍0.01§
48 (50.0) ⬍0.01§
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AVANAFIL FOR ERECTILE DYSFUNCTION AFTER PROSTATECTOMY
the 3 co-primary end points in response to treatment with avanafil at the 100 mg and 200 mg doses were statistically significant and clinically meaningful in this population. The effects of avanafil on improvements in EF were observed rapidly after administration, as early as 15 to 30 minutes in some patients. This early onset of action is consistent with the rapid absorption of avanafil,15 and results from a phase 3 clinical trial of men with mild to severe ED (nonprostatectomy population) in which avanafil was associated with a significant treatment response (SEP3) in some patients as early as 15 minutes after dosing.17 Avanafil treatment was well tolerated with no major differences in the incidence of AEs leading to discontinuation between the avanafil and placebo groups. Consistent with the known effects of PDE5is, the incidence of headache and flushing was higher with avanafil than placebo, and increased in a dose related manner. These AEs were manageable and well tolerated. Two patients on avanafil discontinued the study drug due to headache. It should be noted that a greater proportion of patients in the placebo group discontinued the study (24%, 24 of 100) compared with patients randomized to 100 or 200 mg avanafil (11%, 22 of 198). The primary reason was withdrawn consent for the placebo (14 of 24, 58%) and avanafil (9 of 22, 41%) groups. As per study protocol, patients may have
withdrawn consent for any reason, which may or may not be revealed to the study site, so that the possibility of self-selection for any reason (including perceived lack of efficacy) cannot be discounted.
CONCLUSIONS In men with mild to severe ED after bilateral nerve sparing radical prostatectomy, 100 mg and 200 mg avanafil were effective and well tolerated in improving EF. The time to efficacy for both doses of avanafil was rapid and for all intervals from dose to sexual attempt (15 or less to greater than 360 minutes), both avanafil groups had a higher proportion of successful or satisfied responses compared with placebo. Results suggest a rapid onset of action and sustained duration of effect, with all 3 primary end points being achieved at both dose levels. While patients with ED after prostatectomy may respond less robustly to PDE5i therapy than their counterparts in the general population, avanafil offers these patients an oral treatment option that demonstrates clinically meaningful efficacy.
ACKNOWLEDGMENTS KnowledgePoint360 provided writing, editorial and graphics support for the development of the manuscript, and their participation was funded by VIVUS, Inc.
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AVANAFIL FOR ERECTILE DYSFUNCTION AFTER PROSTATECTOMY
20. International Conference on Harmonisation: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Available at www. ich.org/products/guidelines.html. Accessed June 19, 2012.
Guidelines: Management of erectile dysfunction (’05/Updated ’06). Chapter 1 (Appendix 1-A) and Chapter 2 (Appendix 2-C). Available at www. auanet.org/content/clinical-practice-guidelines/ clinical-guidelines.cfm?sub⫽ed. Accessed September 19, 2012.
21. World Medical Association General Assembly. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Available at www.wma.net/en/30publications/ 10policies/b3/. Accessed September 19, 2012.
23. Rosen RC, Riley A, Wagner G et al: The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822.
22. Montague DK, Jarow JP, Broderick GA et al: American Urological Association (AUA) Practice
24. Jaeschke R, Singer J and Guyatt GH: Measurement of health status. Ascertaining the minimal
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clinically important difference. Control Clin Trials 1989; 10: 407. 25. Araujo AB, Allen KR and Rosen RC: Minimal clinically important differences in the vaginal insertion and successful intercourse items of the sexual encounter profile. J Sex Med 2012; 9: 169. 26. Rosen RC, Allen KR, Ni X et al: Minimal clinically important differences in the erectile function domain of the International Index of Erectile Function scale. Eur Urol 2011; 60: 1010.
Abbreviations and Acronyms AE ⫽ adverse event ED ⫽ erectile dysfunction EF ⫽ erectile function IIEF ⫽ International Index of Erectile Function ITT ⫽ intent to treat PDE5i ⫽ phosphodiesterase type 5 inhibitor TEAE ⫽ treatment emergent adverse event
Purpose: We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy. Materials and Methods: This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy. Patients were randomized to 100 or 200 mg avanafil or placebo (taken 30 minutes before sexual activity) for 12 weeks. Primary end points included successful vaginal insertion (Sexual Encounter Profile [SEP] question 2), successful intercourse (SEP3) and change in score on the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire. Results: A total of 298 patients were randomized and 84.6% completed the study. At baseline 16.1% were age 65 years or older and 71.5% had severe erectile dysfunction (mean overall IIEF-EF domain score 9.2). After 12 weeks there were significantly greater increases in SEP2 and SEP3 and change in mean IIEF-EF domain score with 100 and 200 mg avanafil vs placebo (p ⬍0.01). Following dosing with avanafil 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs 4.5% (2 of 44) for placebo (p ⬍0.01). Avanafil was generally well tolerated. No serious adverse events were reported and fewer than 2% of patients discontinued the study due to an adverse event. Conclusions: Avanafil in 100 and 200 mg doses was effective and well tolerated in improving erectile function after prostatectomy. Results suggest a rapid onset of action and sustained duration of effect, with all 3 primary end points being achieved at both dose levels. Key Words: erectile dysfunction; prostatectomy; phosphodiesterase 5 inhibitors; clinical trial, phase III Accepted for publication November 29, 2012. Supported by VIVUS. Study received institutional review board approval. Clinical Trial Registration NCT00895011 (www.clinicaltrials.gov). * Correspondence: Sexual & Reproductive Medicine Program, Memorial Sloan-Kettering Cancer Center, Sidney Kimmel Center for Prostate & Urologic Cancers, 353 East 68th St. (Room 531), New York, New York 10065 (telephone: 646-422-4359; FAX: 212-988-0768; e-mail: [email protected]). † Financial interest and/or other relationship with Nexmed, Absorption Pharmaceuticals, AMS, Meda, Vivus Inc., Association of Peyronie’s Disease Advocates and Pfizer.
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www.jurology.com
0022-5347/13/1896-2230/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
http://dx.doi.org/10.1016/j.juro.2012.11.177 Vol. 189, 2230-2237, June 2013 RESEARCH, INC. Printed in U.S.A.
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‡ Financial interest and/or other relationship with Endo Pharmaceuticals, Abbott, Pfizer Inc., American Medical Systems Inc., Coloplast Corp., TIMM Medical, VIVUS Inc., Auxilium Inc., Shionogi Pharma, Reflexonic LLC, Medispec Ltd. and National Institutes of Health. § Financial interest and/or other relationship with American Medical Systems Inc., Coloplast Corp., TIMM Medical Technologies Inc., Augusta Medical System LLC and VIVUS Inc. 储 Financial interest and/or other relationship with Lilly/ICOS, Watson Pharmaceuticals, Allergan, GlaxoSmithKline, Allergan, Neotract, NIDDK, Johnson & Johnson and VIVUS Inc. ¶ Financial interest and/or other relationship with Sanofi Oncology, Dendreon, Ferring, Amgen, Medivation, Janssen, Bayer Oncology, Astellas, Theralogix and VIVUS Inc. ** Financial interest and/or other relationship with VIVUS Inc.
PROSTATE cancer treatment is frequently associated with the development of ED.1,2 Data from the Prostate Cancer Outcomes Study, a population based longitudinal cohort of 1,291 men, showed that 56% of men who underwent bilateral nerve sparing radical prostatectomy reported impotence at 18 months or more after surgery.3 Further data from a single center study (293) indicated that if left untreated, the rate of EF after recovery was only 36% (mean followup 27 months).4 Even lower rates of recovery have been reported for men older than 65 or older than 70 years.3–5 Currently first line treatment for most men with various causes of ED consists of oral PDE5i therapy including sildenafil, vardenafil, tadalafil and avanafil.6 –9 Overall, data show that treatment with a PDE5i improves sexual function in the majority of men with mild to moderate ED after nerve sparing radical prostatectomy. However, response rates are considerably lower in men with severe ED10,11 and men older than 65 years.5,10,12 Avanafil is a highly selective13,14 and potent (IC50 ⫽ 4.3 to 5.2 nM)15 PDE5i that has recently been approved for the treatment of men with ED.9 Data from phase 1, 2 and 3 clinical trials show that avanafil is rapidly absorbed (time to maximum plasma concentration 30 to 45 minutes) after oral administration, has a relatively short (3 to 5-hour) half-life15 and an onset of action of 15 minutes or less in some patients.16 –19 In phase 3 clinical trials avanafil improved EF in males with mild to severe ED with18 and without17 diabetes. In this study we evaluated the safety and efficacy of 100 and 200 mg avanafil in the treatment of adult males with ED after bilateral nerve sparing radical prostatectomy.
During a 4-week nontreatment run-in, patients maintained a diary of all attempts at sexual intercourse. Patients with a 50% or greater failure rate in maintaining an erection for a sufficient duration to allow successful intercourse, a score of 5 to 25 (inclusive) on the EF domain of the IIEF questionnaire,22,23 and who made at least 4 attempts at sexual intercourse during the run-in period were randomized (1:1:1) to 100 or 200 mg avanafil or placebo, and treated for 12 weeks (fig. 1). The study drug was taken approximately 30 minutes before initiation of sexual activity and results were recorded in a diary. Up to 2 doses could be taken within a 24-hour period if taken at least 12 hours apart. There were no restrictions on food or alcohol intake.
Key Inclusion and Exclusion Criteria Adult males age 18 to 70 years with a history of ED of 6 months or more after bilateral nerve sparing retropubic radical prostatectomy for localized carcinoma of the prostate (6 months or more before screening) and with staging of prostate carcinoma pT2 or less and Gleason score 7 (4 ⫹ 3) or less were included in the study. Patients were excluded for prior use of radiotherapy, chemotherapy, androgen deprivation therapy, cryotherapy, nonnerve sparing surgery and/or bladder or penile surgery, or if these were likely to be required during the study. Use of penile rehabilitation treatment (ie oral medications, intracavernous injections and/or intraurethral therapies) was not permitted before beginning the 4-week, nontreatment run-in period of the study or throughout the study. Patients with a history of diabetes or a history of dose limiting AEs during prior treatment with a PDE5i were excluded. Patients were also excluded if they experienced ED as a consequence of advanced neurological disease, spinal cord injury or diabetes, or had a history of severe ED requiring routine medical therapy before prostate surgery.
Study End Points Primary study end points were the change in percentage of sexual attempts in which patients are able to insert the
MATERIALS AND METHODS Study Design This randomized, double-blind, placebo controlled, parallel group study enrolled patients at 53 sites in the United States to assess the safety and efficacy of avanafil in the treatment of mild to severe ED in men following bilateral nerve sparing radical prostatectomy. All patients read and signed an institutional review board approved informed consent form and were assured that they could withdraw from the study at any time without jeopardizing medical care related to or required as a result of study participation. This study was conducted in accordance with the International Standard of Good Clinical Practice procedures (as defined by the International Conference on Harmonisation)20 and in accordance with the principles of the Declaration of Helsinki.21
Figure 1. Study design
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penis into the partner’s vagina (SEP2) and maintain an erection of sufficient duration to have successful intercourse (SEP3) between the run-in period and the end of the 12-week treatment period, as well as the change in domain score on the IIEF-EF questionnaire from baseline (visit 2) to end of treatment. Secondary end points included the change in response to individual questions and for other domains (orgasmic function, sexual desire, intercourse satisfaction, overall satisfaction) from the IIEF questionnaire between baseline and weeks 4, 8 and 12; responses to secondary subject diary questions; and the response to the Global Assessment Question on treatment effect and the Future Use question at week 12.
For patients who did not complete the trial, available diary data were used to calculate SEP2 and SEP3. The last observation carried forward convention was used to impute the end of treatment value for the IIEF-EF domain score. Treatment comparisons were assessed using an ANCOVA model with factors of treatment and stratification factors (severity of ED and baseline levels) as the covariate. A value of p ⬍0.05 denoted significance between avanafil and placebo. The study was designed to achieve 86% power with a sample size of 100 patients per arm to detect a mean difference of 25.7% (SD 57.4) for SEP2, 24.3% (SD 56.0) for SEP3 and 6.1 (SD 11.8) for the IIEF-EF domain score from baseline to end of treatment.
Safety Assessments AEs and vital signs were monitored at each study visit. Laboratory parameters, electrocardiograms and physical examinations were evaluated at screening and at the end of treatment.
Statistical Analysis All patients who were randomized, took 1 or more doses and had at least 1 post-dosing assessment were included in the ITT population. The evaluable population was defined as all patients in the ITT population who reported using at least 6 doses of the study drug and who made at least 4 sexual intercourse attempts during the run-in period. Safety analyses were performed on all patients who received 1 or more doses of study drug and for whom any safety data were available.
RESULTS Patient Disposition A total of 298 patients were randomized and 252 (84.6%) completed the study (fig. 2). A higher percentage of patients in the placebo group (24.0%) discontinued the study compared with the 100 mg (14.1%) or 200 mg (8.1%) avanafil treatment groups. Demographics and Baseline Characteristics Demographic and baseline characteristics including mean ED duration were similar among the groups (table 1). Of the patients 71.5% were severely impaired at baseline (mean overall IIEF-EF domain
Figure 2. Patient disposition (all enrolled patients). a indicates 230 persons in whom screening failed. Of those for whom reason was provided (210) the majority of failures were due to untreated hypogonadism or total testosterone less than 325 ng/dl (93, 44.3%); prostate carcinoma stage T2 or greater, or Gleason score 7 or greater (15, 7.1%); positive urine drug screen (11, 5.2%); and documented history of type 1 or type 2 diabetes (7, 3.3%). b indicates safety population included all patients who received 1 or more doses of study drug and had any safety data available. c indicates patients may have withdrawn consent for any reason, which did not have to be revealed to study site. d indicates ITT population included all patients who were randomized, reported taking 1 or more doses of study drug, and had 1 or more post-dose efficacy assessments. e indicates evaluable population included all ITT patients who reported using 6 or more doses of study drug during treatment period and had 4 or more attempts at intercourse during nontreatment run-in period.
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Table 1. Demographics and baseline characteristics (randomized population)
No. pts Mean pt age (SD) No. age category (%): Younger than 50 50–Younger than 65 65 or Older No. race (%): White Black Unknown Mean kg/m2 body mass index (SD) No. ED severity (%): Mild Moderate Severe No. mos ED (%):* 6 to Less than 12 12 to Less than 24 24 or More No. radical prostatectomy type (%):† Open Robotic Laparoscopic
Placebo
Avanafil 100 mg
Avanafil 200 mg
Overall
100 58.6 (5.87)
99 58.9 (5.88)
99 57.7 (6.60)
298 58.4 (6.13)
6 (6.0) 79 (79.0) 15 (15.0)
8 (8.1) 73 (73.7) 18 (18.2)
13 (13.1) 71 (71.7) 15 (15.2)
27 (9.1) 223 (74.8) 48 (16.1)
84 (84.0) 16 (16.0) 0 (0.0) 27.7 (3.42)
83 (83.8) 16 (16.2) 0 (0.0) 28.1 (3.93)
76 (76.8) 22 (22.2) 1 (1.0) 28.4 (3.94)
243 (81.5) 54 (18.1) 1 (0.3) 28.1 (3.77)
8 (8.0) 22 (22.0) 70 (70.0)
7 (7.1) 17 (17.2) 75 (75.8)
12 (12.1) 19 (19.2) 68 (68.7)
27 (9.1) 58 (19.5) 213 (71.5)
35 (35.0) 42 (42.0) 23 (23.0)
31 (31.3) 40 (40.4) 28 (28.3)
36 (36.4) 39 (39.4) 24 (24.2)
102 (34.2) 121 (40.6) 75 (25.2)
14 (14.0) 83 (83.0) 3 (3.0)
19 (19.2) 76 (76.8) 4 (4.0)
9 (9.1) 81 (81.8) 9 (9.1)
42 (14.1) 240 (80.5) 16 (5.4)
* Duration of ED is from after surgery to date of study enrollment. † Prostatectomies were performed by highly experienced surgeons, defined as having met the criteria of 1) 5 or more of years experience after residency, 2) performance of 250 or more radical prostatectomies using 1 technique (open vs laproscopic vs robotic), 3) performance of 50 or more radical prostatectomies in the last calendar year of study participation (approximately 5 to 10 per month), 4) having a dedicated researcher coordinator and 5) having an ED specialist in the practice.
score 9.2). Mean SEP3 success rate at baseline was less than 5% overall and the majority of patients (80.5%) had robotic surgical technique for radical prostatectomy. Medical History and Concomitant Medications (safety population) Except hypertension, which was reported by a lower proportion of patients in the 100 mg avanafil group, treatment groups were comparable with respect to medical history categories of special interest. Overall 125 (41.9%) patients reported a history of hypertension, 38 (12.8%) other cardiovascular disease, 35 (11.7%) depression, 15 (5.0%) anxiety, 7 (2.3%) coronary artery disease and 1 (0.3%) transurethral resection of the prostate. Concomitant medication use was similar between treatment groups. Overall 118 (39.6%) patients took antihypertensive medications, 28 (9.4%) took antidepressants and 4 (1.3%) took ␣-blockers. Treatment Compliance During each 4-week interval the proportion of patients who took the required number of doses of study drug was higher in the avanafil groups (83% to 93% [100 mg], 91% to 95% [200 mg]) than in the placebo group (76% to 90%). Mean time from dosing to sexual attempts was 58.1 (SD 50.43) minutes. Efficacy Primary End Points Total patient population. After 12 weeks of treatment 100 and 200 mg avanafil resulted in a signifi-
cantly greater increase in SEP2, SEP3 and change in mean IIEF-EF domain score compared with placebo (p ⬍0.01, fig. 3). Patients randomized to 100 and 200 mg avanafil had an improvement in IIEF-EF domain score of 3.6 (40%) and 5.2 (55%), respectively, compared with 0.1 (1%) for placebo. Stratification by severity at baseline. When SEP2, SEP3 and IIEF-EF domain scores were stratified by baseline ED severity, treatment with 200 mg avanafil resulted in improvement in all 3 co-primary end points vs placebo (fig. 4). Additional analysis was conducted to determine the proportion of patients who achieved a normalized IIEF-EF domain score (26 or greater) at the end of the treatment period. Regardless of baseline ED severity, higher proportions of patients in the 100 and 200 mg avanafil groups had a normalized IIEF-EF domain score compared with placebo (mild ED 4.3%, 7.3% and 2.1%; moderate ED 3.2%, 4.2% and 1.0%; severe ED 5.3%, 6.3% and 0.0%, respectively). Stratification by age. Regardless of age (younger than 50 years, 50 to less than 65 years and older than 65 years), treatment with 100 and 200 mg avanafil resulted in statistically significant changes from baseline in SEP3 (p ⬍0.01). Stratification by type of radical prostatectomy. When stratified by surgical technique (open, robotic or laparoscopic), treatment with 200 mg avanafil
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AVANAFIL FOR ERECTILE DYSFUNCTION AFTER PROSTATECTOMY
Figure 3. Change in co-primary end points (SEP2, SEP3 and IIEF-EF) from baseline to end of treatment (ITT population). difference compared with placebo (p ⬍0.01).
a
indicates
resulted in improvement in all 3 co-primary end points vs placebo for all types of radical prostatectomy surgery (p ⬍0.01 for all).
group (27.7%, p ⬍0.01) responded to the Future Use question that they would use the study treatment if it were available today.
Efficacy – Secondary End Points Treatment with 200 mg avanafil was associated with significant improvements in the IIEF orgasmic function domain score compared with placebo (p ⬍0.05). Treatment with 100 and 200 mg avanafil was associated with significant improvements in the intercourse satisfaction domain score (p ⫽ 0.01 and p ⬍0.01, respectively) and overall satisfaction score (p ⬍0.05 and p ⬍0.01, respectively) compared with placebo.
Subject diary responses by time interval from dose to attempt. For all time intervals from dose to sexual attempt (15 minutes or less through greater than 360 minutes), the 100 mg avanafil group had significantly higher proportions of successful or satisfied responses regarding vaginal penetration (SEP2), intercourse (SEP3) and overall sexual experience vs placebo (p ⬍0.1 for all intervals except for the 120 to 240-minute interval [p ⬍0.05]). Significantly higher responses compared with placebo were also achieved in the 200 mg avanafil group for all intervals up to 240 minutes (p ⬍0.01) but not beyond that point (p ⬎0.05). After dosing with 100 or 200 mg avanafil, 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs 4.5% (2 of 44) for placebo (p ⬍0.01). Of all attempts made from 16 to 30 minutes, and from 31 to 60 minutes after dosing, SEP3 success rates for patients randomized to 100 or 200 mg avanafil were 30.2% (281 of 932) and 29.5% (456 of 1,544) vs 7.7% (34 of 439) and 11.3% (84 of 744) for placebo, respectively (p ⬍0.01).
Secondary subject diary responses. Compared with placebo, secondary subject diary responses were significantly greater for the 100 and 200 mg avanafil groups, including changes in the percentages of sexual attempts in which patients were able to achieve an erection (p ⬍0.01), and were satisfied with their erection (p ⬍0.01) and sexual experience (p ⬍0.05 and p ⬍0.01, respectively). Global assessment questions. At the end of treatment significantly higher proportions of patients in the 100 mg (31.3%) and 200 mg (41.3%) avanafil groups compared with placebo (10.7%) responded that study treatment improved their erections (p ⬍0.01). A significantly higher proportion of patients in the 200 mg avanafil group (57.6%) compared with the 100 mg avanafil group (39.8%, p ⬍0.05) and the placebo
Safety Study drug tolerability and AEs. Treatment with avanafil was generally well tolerated and 2% of pa-
Figure 4. Co-primary end points (SEP2, SEP3 and IIEF-EF) at end of treatment by baseline (BL) severity of ED (ITT population). a indicates change from baseline not significant (p ⬎0.05). b indicates change from baseline (p ⬍0.01).
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Table 2. All TEAEs reported in 1% or more of patients (safety population)
Headache Flushing Nasopharyngitis Back pain Nasal congestion Upper respiratory tract infection Abnormal electrocardiogram Bronchitis Dizziness Blood cholesterol increased Nausea
No. Placebo (%)
No. Avanafil 100 mg (%)
No. Avanafil 200 mg (%)
No. Totals (%)
1 (1.0) 0 (0.0) 0 (0.0) 1 (1.0) 1 (1.0) 0 (0.0) 0 (0.0) 4 (4.0) 0 (0.0) 1 (1.0) 1 (1.0)
8 (8.1) 5 (5.1) 3 (3.0) 3 (3.0) 3 (3.0) 2 (2.0) 1 (1.0) 0 (0.0) 1 (1.0) 2 (2.0) 1 (1.0)
12 (12.1) 10 (10.1) 5 (5.1) 2 (2.0) 1 (1.0) 3 (3.0) 3 (3.0) 0 (0.0) 2 (2.0) 0 (0.0) 1 (1.0)
21 (7.0) 15 (5.0) 8 (2.7) 6 (2.0) 5 (1.7) 5 (1.7) 4 (1.3) 4 (1.3) 3 (1.0) 3 (1.0) 3 (1.0)
TEAEs were defined as AEs occurring after the first dose of study drug or after the first dispense date, if missing, and before the last visit.
tients discontinued from the study drug due to an AE. TEAEs were reported in 23 (23.0%), 38 (38.4%) and 45 (45.5%) patients in the placebo and 100 and 200 mg avanafil groups, respectively. There were no increased safety concerns with the 200 vs 100 mg avanafil dose. The most frequently reported AEs were headache, flushing and nasopharyngitis (table 2). Dyspepsia was reported in 1 patient each in the 100 mg avanafil group and placebo group (0.7% overall). Syncope, a hemodynamic AE, was reported in less than 2% of patients overall. The incidence of headache, flushing, nasopharyngitis, abnormal electrocardiogram upper respiratory tract infection and dizziness was higher in the avanafil groups, the severity of which was dose dependent. No patient had a TEAE categorized as priapism or major cardiac events, and no patient died or had a serious AE during the study. Study discontinuation. Overall 5 (1.7%) patients discontinued due to an AE (1 in the placebo group, 2 in the 100 mg avanafil group and 2 in the 200 mg avanafil group). For 2% (2) and 1% (1) of patients in the 100 and 200 mg avanafil groups, respectively, AEs that led to discontinuation were considered related to study drug. Other relevant safety parameters. No clinically important differences among treatment groups in mean changes in safety laboratory parameters or electrocardiogram parameters or physical examination findings were noted. For all treatment groups mean blood pressure (systolic and diastolic) and heart rate values at the end of treatment were similar to those at randomization.
ing by age, baseline ED severity and by type of radical prostatectomy surgical technique. Definitive conclusions about the magnitude of treatment effect for other subgroups could not be determined because of insufficient sample size. A higher proportion of patients in the 100 and 200 mg avanafil groups had a normalized IIEF-EF domain score compared with placebo. Because of the small sample size, no tests of statistical significance were performed. Nonetheless, avanafil was numerically superior to placebo in the proportion of men achieving normalized EF in this difficult to treat, postoperative population. An ad hoc analysis was performed to determine clinically important differences for the 3 co-primary end points. Minimum clinically important differences24 were defined as 23%, 21% and 4 or more points for SEP3, SEP225 and IIEF-EF,26 respectively. Clinically relevant improvements were demonstrated across all 3 co-primary efficacy end points, and statistical significance was demonstrated for SEP3, SEP2 and IIEF-EF compared with placebo (table 3). On the basis of the responder analysis and the use of a generally recognized definition of a clinically relevant change, the observed changes in Table 3. Responder analysis: change from baseline scores (ITT population) Placebo 96
Avanafil 100 mg
DISCUSSION
No. pts SEP3: No. (%)* p Value SEP2: No. (%)† p Value IIEF-EF: No. (%)‡ p Value
94
In the current study 100 and 200 mg avanafil significantly improved EF compared with placebo in men with all levels of ED severity. The effects of treatment were observed across subgroups, includ-
* Responders with a change from baseline of 23% or greater. † Responders with a change from baseline of 21% or greater. ‡ Responders with a change from baseline of 4% or greater. § Statistically significant difference from placebo.
Avanafil 200 mg 96
14 (14.6) Not applicable
26 (27.7) 0.5
36 (37.5) ⬍0.01§
7 (7.3) Not applicable
29 (30.9) 0.01§
37 (38.5) ⬍0.01§
13 (13.7) Not applicable
33 (35.1) ⬍0.01§
48 (50.0) ⬍0.01§
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AVANAFIL FOR ERECTILE DYSFUNCTION AFTER PROSTATECTOMY
the 3 co-primary end points in response to treatment with avanafil at the 100 mg and 200 mg doses were statistically significant and clinically meaningful in this population. The effects of avanafil on improvements in EF were observed rapidly after administration, as early as 15 to 30 minutes in some patients. This early onset of action is consistent with the rapid absorption of avanafil,15 and results from a phase 3 clinical trial of men with mild to severe ED (nonprostatectomy population) in which avanafil was associated with a significant treatment response (SEP3) in some patients as early as 15 minutes after dosing.17 Avanafil treatment was well tolerated with no major differences in the incidence of AEs leading to discontinuation between the avanafil and placebo groups. Consistent with the known effects of PDE5is, the incidence of headache and flushing was higher with avanafil than placebo, and increased in a dose related manner. These AEs were manageable and well tolerated. Two patients on avanafil discontinued the study drug due to headache. It should be noted that a greater proportion of patients in the placebo group discontinued the study (24%, 24 of 100) compared with patients randomized to 100 or 200 mg avanafil (11%, 22 of 198). The primary reason was withdrawn consent for the placebo (14 of 24, 58%) and avanafil (9 of 22, 41%) groups. As per study protocol, patients may have
withdrawn consent for any reason, which may or may not be revealed to the study site, so that the possibility of self-selection for any reason (including perceived lack of efficacy) cannot be discounted.
CONCLUSIONS In men with mild to severe ED after bilateral nerve sparing radical prostatectomy, 100 mg and 200 mg avanafil were effective and well tolerated in improving EF. The time to efficacy for both doses of avanafil was rapid and for all intervals from dose to sexual attempt (15 or less to greater than 360 minutes), both avanafil groups had a higher proportion of successful or satisfied responses compared with placebo. Results suggest a rapid onset of action and sustained duration of effect, with all 3 primary end points being achieved at both dose levels. While patients with ED after prostatectomy may respond less robustly to PDE5i therapy than their counterparts in the general population, avanafil offers these patients an oral treatment option that demonstrates clinically meaningful efficacy.
ACKNOWLEDGMENTS KnowledgePoint360 provided writing, editorial and graphics support for the development of the manuscript, and their participation was funded by VIVUS, Inc.
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