International Journal of Impotence Research (2002) 14, 54–60 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir
Combination therapy for erectile dysfunction: a randomized, double blind, unblinded active-controlled, cross-over study of the pharmacodynamics and safety of combined oral formulations of apomorphine hydrochloride, phentolamine mesylate and papaverine hydrochloride in men with moderate to severe erectile dysfunction
PI Lammers1*, E Rubio-Aurioles2, R Castell3, J Castaneda3, R Ponce de Leon4, D Hurley4, M Lipezker4, LA Loehr1 and F Lowrey1
1Zonagen, Inc., USA; 2Asociacio´n Mexicana para la Salud Sexual Me´xico; 3Hospital General de Me´xico; and 4Estadisticos y Clinicos Asociados, Mexico
Oral therapy has become first line treatment for patients with mild to moderate erectile dysfunction (ED). Studies have shown that sildenafil may not be effective in all patients, and has been associated with a variety of adverse effects and an adverse interaction with nitrates and inhibitors of cytochrome P450 enzymes. The objective was to compare the efficacy and safety of three different oral combinations with the highest dose of sildenafil in men with moderate to severe ED. Randomized, double blind, unblinded active-controlled, Phase II study was carried out at three sites in Mexico. After a 4-week placebo run-in period, patients received all four of the following treatments using a 4-way cross-over design: 40 mg phentolamine (PM) þ 6mg apomorphine (Apo); 40 mg PM þ 150 mg papaverine (Pap); 40 mg PM þ 6 mg Apo þ 150 mg Pap (Tricombo); 100 mg sildenafil (SC). With the exception of sildenafil tablets, all study medication was blinded. Moderate to severe ED was defined as a less than 50% vaginal penetration success rate during the placebo run-in period. A total of 44 patients were enrolled, of whom 36 completed all four treatment periods. All treatments produced a significant effect in primary efficacy variable (Sexual Encounter Profile) compared to baseline, however, no statistically significant differences were found between treatments. A significant period effect was observed. Also, the four treatments were found not to differ significantly in five out of six secondary efficacy variables. The lowest incidence of treatment-related adverse events (AE) occurred in the 40 mg PM þ 6 mg Apo group (9.8%), followed by 100 mg SC (15%), and the other two combinations (16.7 and 17.5%, respectively). Nasocongestion and headache were the most frequently reported AE. An oral combination of vasoactive agents may provide an alternative approach to sildenafil. Based on these results a combination of phentolamine and apomorphine warrants further clinical investigation. International Journal of Impotence Research (2002) 14, 54–60. DOI: 10.1038=sj=ijir=3900816
Keywords: erectile dysfunction; impotence; pharmacodynamics; safety; oral combination; apomorphine; phentolamine; papaverine
Introduction and complete impotence in non-institutionalized men between the ages of 40 and 70 y.1 A wide variety of etiologies have been described for this The Massachusetts Male Aging Study reported a condition, however, the most frequently reported is combined prevalence of 52% for minimal, moderate, arterial insufficiency associated with cardiovascular disease. Also, studies have shown that the etiology of this condition is not predictive of response to *Correspondence: PI Lammers, MD; Zonagen, Inc.; 2408 treatment, and choice of therapy depends on under- Timberloch Place, Suite B-4; The Woodlands, TX 77380, USA. lying etiology, severity of disease, physician’s pre- E-mail: [email protected] ference, and treatment success and tolerance by Received 5 April 2001; accepted 20 September 2001 individual patients.2–4 Combination therapy for ED PI Lammers et al 55 Currently, there are several single pharmacologi- or uncontrolled hypertension (systolic > 160, dia- cal agents approved for the treatment of erectile stolic > 90 mmHg); significant penile pathology dysfunction (ED), including oral, intraurethral and (curvature, fibrosis, implants, etc.); history of clini- intracavernosal applications. Other oral vasoactive cally significant hepatic or renal disease, coronary agents are currently undergoing clinical testing or artery disease, nervous system diseases, radical regulatory review. prostatectomy, or uncontrolled psychiatric Oral sildenafil has been reported as a safe and condition; known intolerance to papaverine, phen- efficacious treatment for ED, however, it is ineffec- tolamine, apomorphine or sildenafil; concomitant tive in approximately 27% of the population, and use of organic nitrates; regular use of sympathetic- has been associated with a variety of adverse effects mimetic medication; use of antiemetics that are including headache, flushing, dyspepsia, and ad- central nervous system depressors; blood donations; verse interaction with nitrates and inhibitors of planned or ongoing participation in another study; cytochrome P450 enzymes.5 – 9 any condition which would interfere with the In an attempt to improve effectiveness in ED patient’s ability to provide informed consent, to patients dissatisfied with single agent therapy, comply with study instructions, or which might combinations of different pharmacological agents confound the interpretation of the study results; have been explored. Intracavernosal injection and, any condition, which in the opinion of the combinations of papaverine, phentolamine and principal investigator could endanger the health or alprostadil (prostaglandin-E1) are frequently used wellbeing of the patient. off-label, whereas combinations of oral and local (intraurethral) formulations have also shown 10 – 14 promise. Study design and methodology These findings triggered interest in evaluating an oral combination of phentolamine, papaverine and apomorphine. This combination was chosen to The study was conducted at three sites in Mexico. couple a central acting agent (apomorphine, dopa- The institutional review board of each participating mine receptor agonist) with the predominantly institution approved the protocol. peripheral activities of phentolamine (non-selective After an initial 4-week placebo run-in period to alpha-adrenoceptor antagonist) and papaverine determine study eligibility, subjects received all (non-specific phosphodiesterase inhibitor).15 – 18 four of the following treatment options during the In an initial Phase I study, three oral combina- treatment period using a 4-way randomized, cross- tions of 40 mg phentolamine mesylate, 150 mg over design: 40 mg phentolamine plus 6 mg apomor- papaverine hydrochloride, and 2, 4 or 6 mg of oral phine (Ph40 þ Apo6); 40 mg phentolamine þ 150 mg apomorphine, respectively, were safely adminis- papaverine (Ph40 þ Pap150); 40 mg phentolamine tered to 10 male volunteers.19 plus 150 mg papaverine and 6 mg apomorphine The primary objective of the present Phase II, (Tricombo); 100 mg sildenafil (SC100). Combination Proof-of-Concept study was to compare pharmaco- tablets were blinded, whereas for logistical reasons dynamics and safety of different oral tablet combi- no blinding was used for sildenafil. nations of apomorphine, phentolamine and At the start of each of the four treatment periods, papaverine, with those of 100 mg sildenafil in men the subject received an in-office dose of the with moderate to severe ED. randomized treatment followed by an observation period of 60 min to evaluate safety. Subjects with a decrease of 30% or greater in their diastolic or Methods systolic blood pressure, or an increase of 30% or greater in heart rate from their baseline value were withdrawn from the study. Patients During the treatment periods, subjects recorded the outcome of an attempt at sexual intercourse in a Sexual Encounter Profile (SEP) diary. Men returned Men who were enrolled in this study were aged 40 – diary cards and received replacement medication at 75 inclusive, had a history of ED of at least 6 months each subsequent visit. At each of these visits, drug duration, and were engaged in a stable, monoga- accountability was performed, and adverse events mous heterosexual relationship. All men provided (AE) and concomitant medications since last visit written informed consent and had to inform their were reviewed and recorded. Also, the investigator partners of study participation. Moderate to severe evaluated the global assessment question (GAQ). ED was defined as a less than 50% vaginal At the last visit, upon completion of all study penetration success rate in a 4-week placebo run-in procedures, the investigator evaluated the GAQ, and period. recorded subject’s response to the following ques- Exclusion criteria included ED caused by an tion: ‘Which of the four treatments did you prefer or untreated endocrine disease; postural hypotension liked best?’
International Journal of Impotence Research Combination therapy for ED PI Lammers et al 56 Statistical methods A similar analysis was performed for the second- ary analysis variables, except for the GAQ. A corresponding ordinal analogue of the model appro- No power-based sample size could be determined priate for a 464 Latin Square Design was employed accurately since response rates for sildenafiland for the GAQ secondary efficacy variable. two of the three experimental drug treatments for All of the two-group efficacy statistical tests the study-specificefficacy parameters were not fully performed were one-sided, controlling for the type known. However, it was determined that approxi- I error level at 0.10. The statistical test(s) conducted mately 48 patients had to be enrolled and no more for the primary efficacy analyses were under the null than a 8.33% dropout=non-evaluable rate to reach hypothesis of ‘not as good as’ vs the alternative 44 evaluable patients.20 hypothesis of ‘at least as good as’ for at least one of The mean SEP attempt score was the primary the three combination treatment groups compared to efficacy variable. The SEP score is a numerical rating sildenafil. scale used to objectively rate the patients’ erectile response (self-assessment) in a stepped fashion during three sexual encounters. The SEP included Results questions regarding: (1) attempts at sexual activity; (2) patients’ ability to achieve at least some erection; (3) the ability to achieve vaginal penetration; (4) A total of 68 patients were included in the 4-week erectile duration sufficient for ejaculation; (5) satis- run-in period, of whom 25 were not randomized faction with the hardness of the erection; and (6) (vaginal penetration success rate greater than 50%, overall satisfaction with the sexual experience. A or lost to follow-up). Of the 43 randomized patients, positive answer to each question in the SEP was one was lost to follow-up after randomization and scored as a one, thus allowing a maximum of six the remaining 42 patients received at least one dose points for each sexual encounter. A six-point SEP of the study drug. Thirty-six (36) patients completed mean was calculated for the (maximum of) 12 sexual all four treatment periods with at least two tablets encounters per treatment. per period (almost all of these patients took four or Secondary efficacy variables were: percentage of more tablets per period). No patient was withdrawn vaginal penetrations; percentage of penetrations during the 60 min observation period after receiving leading to ejaculations; mean erection rigidity as the in-office dose of each of the randomized determined on a Visual Analogue Scale (scale 0 – treatments. 100; VAS); mean VAS for duration of erection; mean VAS for satisfaction with sexual experience, and the Global Assessment Question (GAQ). Efficacy The efficacy population was defined as the set of all subjects randomized to treatment sequence, who had received all four treatments in their assigned Results for the primary efficacy variable, the mean sequence, had no major protocol violations, and had six-point SEP score are listed in Table 1. Differences efficacy data for two or more tablets to calculate the between all four treatments were not large numeri- primary efficacy variable (SEP attempt mean) for cally and did not reach statistical significance. each of the four treatments dispensed. However, all four treatments produced highly sig- Monitoring AE assessed safety. The safety popu- nificant increases (P < 0.001) in mean SEP response lation was defined as all subjects who received at compared to baseline (Table 2). The mean increase least one dose of study medication. The incidence from baseline was 1.84 points for SC100, 1.88 for of AE was summarized overall, by COSTART PM40 þ Apo6, 1.68 for Tricombo and 1.63 for body system and by preferred term for each treat- PM40 þ Pap150, respectively. ment group. Further summarizations based on There was a statistically significant overall period severity (mild, moderate, severe), and relation to effect (P ¼ 0.0111, 3 d.f.). Patients showed improved study treatment (related, not related) were performed. scores in the last two treatment periods, indepen- The SEP mean attempt score at each visit dently of the type of treatment they received. It was analyzed using a model appropriate for a should be noted that the third and fourth period 464 Latin square design. The model included terms effects were larger than the largest treatment effect, for treatment and treatment by site interaction, for example, SC100 7 Ph40 þ Apo6 ¼ 0.22 points on if there were sufficient degrees of freedom. In six-point SEP scale. addition, Gould’s method was used to account Previous sildenafil users had a slightly lower for patients who chose not to continue with a mean placebo lead-in baseline score than naive particular treatment due to lack of efficacy or sildenafil users (mean SEP score 1.45 vs 1.67, unacceptable side effects. A subgroup analysis respectively; Table 1). In the active treatment was performed stratifying by patient’s previous period, the two strata differed in treatment effect, sildenafiluse.21 but this did not reach statistical significance which
International Journal of Impotence Research Combination therapy for ED PI Lammers et al 57 Table 1 Primary and secondary efficacy variables with four different oral treatments for erectile dysfunction (LS-means)
P-values (1-sided)*
PM40 þ PM40 þ PM40 þ SC100 vs SC100 vs SC 100 SC100 Apo6 Pap150 Apo6 þ Pap150 PM40 þ Ph40 þ vs Response variable Baseline (n ¼ 36) (n ¼ 36) (n ¼ 36) (n ¼ 36) Apo6 Pap150 Tricombo
Mean six-point SEP: 1. Overall 1.63 3.50 3.43 3.23 3.37 0.38 0.17 0.32 2. Previous SC100 users (n ¼ 7) 1.45 2.53 3.20 2.41 2.86 0.16 0.42 0.31 3. Non-previous SC100 users (n ¼ 29) 1.67 3.69 3.60 3.45 3.42 0.38 0.22 0.19 Mean VAS rigidity scale (0 – 100) 16.61 46.12 44.53 43.98 44.63 0.36 0.32 0.37 Mean VAS duration scale (0 – 100) 13.59 42.46 39.44 39.99 40.53 0.27 0.31 0.35 Mean VAS satisfaction scale (0 – 100) 11.61 40.30 36.10 36.80 36.83 0.20 0.25 0.25 Mean proportion of successful 0.13 0.58 0.58 0.55 0.59 0.45 0.36 0.41 vaginal penetration Mean proportion of vaginal intercourse 0.06 0.44 0.46 0.42 0.45 0.41 0.37 0.45 leading to orgasm GAQ (1 ¼ very satisfied, 5 ¼ very — 2.50 2.92 2.98 2.92 0.06 0.04 0.07 dissatisfied)
*Protocol defined significance level is set at 0.10 with 1-sided testing; SEP: Sexual Encounter Profile, VAS: Visual Analogue Scale; GAQ: Global Assessment Question.
Table 2 Change from baseline in mean six-point SEP score by treatment
SC100 PM40 þ Apo6 PM40 þ Pap150 PM40 þ Apo6 þ Treatment (n ¼ 36) (n ¼ 36) (n ¼ 36) Pap150 (n ¼ 36)
Half length of 95% CI for mean six-point SEP scale 0.66 0.62 0.58 0.61 Change from baseline 1.84 1.88 1.63 1.68 P-value < 0.001 < 0.001 < 0.001 < 0.001 may be due to the small sample size in the previous Nasocongestion (rhinitis) and headache were the sildenafil user group (n ¼ 7). most frequently reported treatment-related AE Results for five of the six secondary response (ranges 4.8 – 15%, and 2.4 – 5%, respectively). variables (3 VAS, proportion of vaginal penetration Only two patients reported a cardiovascular AE: and proportion of orgasms) were similar to SEP; that one patient with palpitations and tachycardia on is the four treatment means were found not to differ Tricombo, the other tachycardia and coronary artery significantly (Table 1). The only significant differ- disorder while taking 100 mg sildenafil. ence was found for the GAQ (five-point ordinal scale Only one patient reported a serious AE: hospita- ranging from 1 ¼ very satisfied to 5 ¼ very dissatis- lization for a right nephrectomy not related to fied), where sildenafil showed a statistically sig- treatment. All treatment-related AE were mild or nificant lower score than the other three treatments. moderate in severity. The percentage of succesful vaginal penetrations, penetrations leading to orgasm, and of the patients’ preference for a specific treatment at the end of the study was similar among all four treatment groups Discussion (Figure 1).
This was a multi-center, randomized, partly double blind, phase II proof-of-concept study to determine Safety whether pharmacodynamics and safety of different oral combinations of vasoactive agents were at least as good as those of 100 mg sildenafil in the treatment The safety population consisted of 42 patients. of moderate to severe ED. Overall, 19 patients reported a total of 150 AE Thirty-six out of the 44 patients enrolled by three during the study. centers in Mexico received all four treatments in The highest incidence of treatment-related AE their randomly assigned sequence. The differences was reported in the Tricombo group (7=40, 17.5%), between all four treatments were not large numeri- followed by Ph40 þ Pap150 (7=42, 16.7%), 100 mg cally and did not reach statistical significance for SC (6=40, 15%), and the Ph40 þ Apo6 group (4=41, any of the primary or secondary response variables, 9.8%; Table 3). except for the global assessment question.
International Journal of Impotence Research Combination therapy for ED PI Lammers et al 58
Figure 1 Rate of successful vaginal penetration, penetration leading to orgasm and overall treatment preference.
Table 3 Adverse events during treatment with different oral combinations for erectile dysfunction
Treatment group
SC100 PM40 þ Apo6 PM40 þ Pap150 PM40 þ Apo6 þ Pap150
Safety population (n)40414240 Adverse events (n,%) (a) Overall 6 (15.0) 7 (17.1) 8 (19.1) 10 (25.0) (b) Treatment-related 6 (15.0) 4 (9.8) 7 (16.7) 7 (17.5) Severity of AEs (n,%) (a) Overall: Mild 3 (7.5) 7 (17.1) 7 (16.7) 9 (22.5) Moderate 3 (7.5) 0 1 (2.4) 0 Severe 0 0 0 1 (2.5)a (b) Treatment-related: Mild 4 (10.0) 4 (9.8) 6 (14.3) 7 (17.5) Moderate 2 (5.0) 0 1 (2.4) 0 Severe 0 0 0 0 Serious AEs (n, %) 0 0 0 1 (2.5)a Cardiovascular AEs (n,%) (a) Overall 2 (5.0) 0 0 2 (5.0) (b) Treatment-related 1 (2.5) 0 0 2 (5.0) Most frequently reported AEs ( 4%; n,%): (a) Rhinitisb 3 (7.5)c3 4 (9.8)4 2 (4.8)2 6 (15.0)6 (b) Headache 3 (7.5)3 1 (2.4)1 1 (2.4)1 2 (5.0)1 (c) Dyspepsia 0 0 0 2 (5.0)2 (d) Nausea 0 0 2 (4.8)2 0
aRight nephrectomy, not related to treatment; bAll were mild in severity and treatment-related; cSuperindice indicates number of treatment-related adverse events.
The fact that the sildenafil medication was not However, previous sildenafil use only had a small blinded most likely introduced a recognition bias in but not significant effect on the primary efficacy the study in favor of Viagra1 especially because the outcome (Table 1). Previous users had a lower majority of study subjects were familiar with it and baseline SEP score, and a numerically weaker had used this medication before study participation. response to any of the four treatments, perhaps an
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Editorial Comment
DOI: 10.1038=sj=ijir=3900818
Apomorphine acts on central dopamine receptors subnormal erectile response. In the management and enhances signals in supraspinal neuronal path- of erectile dysfunction, apomorphine is approved ways, which are involved in the regulation of penile and clinically used by sublingual administration. erection, and can hereby improve an otherwise In the recommended dose-range, this route of
International Journal of Impotence Research