ORIGINAL

 

Efficacy and safety of two dosing regimens with tadalafil in Spanish men with erectile dysfunction: results from the sure study in 14 European countries

 

Martín-Morales A¹, Moncada-Iribarren I², Cruz-Navarro N³, Sanz-Terrada B⁴, Cassinello-Hervás A⁴, Chan M⁵, Casariego-García-Lubén J⁴

 

¹Service of Urology. Carlos Haya Hospital. Málaga (Spain). ²Service of Urology. Gregorio Marañón Hospital. Madrid (Spain). ³Service of Urology. Virgen del Rocío Hospital. Seville (Spain). ⁴Lilly S.A. Alcobendas, Madrid (Spain). ⁵Eli Lilly Canada Inc, Toronto, Ontario (Canada).

 

Actas Urol Esp. 2006;30(8):791-800

 

 

Erectile dysfunction (ED), defined as the inability to obtain or maintain an erection sufficient to allow satisfactory sexual intercourse, affects 12.1% of the Spanish male population to one degree or other¹.

Most patients with ED present an initially organic origin of the disorder, followed by incorporation of a psychoaffective component and fear of failure that in turn reinforce and exacerbate the dysfunction². Phosphodiesterase-5 (PDE5) inhibitors are considered to be the first choice treatment for ED in most patients, due to their efficacy and safety³.

These drugs restore erectile function, almost completely inhibiting PDE5activity, though there are biochemical differences among them that give rise to differences in terms of the time to onset of action, the duration of action, interactions with other drug substances, and adverse effects.

Therefore, the present medical approach to ED must take into account the patient needs and preferences⁴, offering the available alternative that best adapts to each individual^5-6.

Tadalafil is marketed in over 100 countries throughout the world, including the United States and Europe. Most clinical studies conducted to date with tadalafil have evaluated its use when administered “on demand” (OD), i.e., as decided by the patient prior to sexual intercourse. A combined analysis of the data obtained by 11studies with tadalafil⁷ showed that 54% of the patients with ED who used the drug at a dose of 20 mg OD during 12 weeks recovered normal erectile function, as reflected by the scores obtained (≥26) with the International Index of Erectile Function (IIEF). In addition, recent studies indicate that tadalafil offers an erectile response time-window or duration extending from 16 minutes⁸ to 36 hours after administration^7-14. As a result, tadalafil could provide almost continuous coverage when administered on a regular basis, allowing patients and their couples to decide when they wish to have sexual intercourse - without concern about the time available for such intercourse.

This study presents the results obtained in a cohort of Spanish ED patients that participated in the SURE (Scheduled Use versus on demand Regimen Evaluation) study, carried out in 14 European countries. The SURE study was designed to evaluate patient preference for an alternative 3 times a week scheduled administration regimen (SCH) versus the traditional OD use of such drugs. The global results of this study have already been reported by Mirone et al¹⁴.

 

MATERIALS AND METHODS

Patients and study design

A total of 418 patients with ED from 33 Spanish centers were invited to participate in the SURE study. This was a multicenter, crossover open-label clinical trial with a duration of 12 weeks, conducted in 14 European countries (involving a total of 4262 patients) to determine ED patient preference for one of the following tadalafil treatment regimens: OD (20 mg) or SCH (3 times/week)¹⁵. “On demand” (OD) was defined as administration of the drug as decided by the patient prior to sexual intercourse, though without exceeding the maximum limit of one dose a day. In turn, “scheduled” dosing (SCH) was defined as the regular administration of tadalafil 3 times a week (Monday, Wednesday and Friday / Tuesday, Thursday and Saturday), regardless of spontaneous sexual activity.

The recruited participants were males over 18 years of age with a history of ED for at least 3 months. The included patients were required to have a stable relationship with the same female couple throughout the duration of the study. A broad range of patients with ED of different functional degrees (mild to severe) and origins (psychogenic, organic and mixed) were allowed to participate. In the initial selection period the patients were required to make at least 4 intercourse attempts with their couple. In addition, they agreed not to use any treatment for ED during the pretreatment and treatment phases of the study, as well as during the 96 hours after the last study visit.

Patients receiving treatment with nitrates, chemotherapeutic agents or antiandrogenic drugs, or with a history of symptomatic congestive heart failure, were not allowed to participate in the trial.

Males previously treated with some PDE5 inhibitor were allowed to participate.

Following a pretreatment period of 3-4 weeks during which the patients were selected, randomized assignation to one of the following treatment regimens was carried out: OD (20 mg) before sexual intercourse and involving a maximum of one dose a day, or SCH (3 times/week) during 5-6 weeks. After a one-week washout period, the patients were crossed over to the alternate regimen for another 5-6weeks. The 3 times a week regimen was in turn divided into two subgroups: subgroup A (Monday, Wednesday and Friday) and subgroup B (Tuesday, Thursday and Saturday). At the end of the treatment period, the patients were allowed to choose their preferred treatment (OD or SCH), to continue for a minimum of two further weeks in an extension of the trial (Fig. 1).

 

FIGURE 1. SURE study design.

 

Study variables

Preference: The principal study variable was patient preference for one treatment regimen or other, based on the answers obtained at the end of the 5-6 weeks treatment crossover period in response to the “Preferred Treatment Question” (PTQ): “Which treatment option do you prefer?” (OD or 3 times/week).

Efficacy: As secondary variables, evaluations were made of efficacy and patient satisfaction with tadalafil, and their relation to the preferred treatment regimen, based on the International Index of Erectile Function (IIEF) and the Sexual Encounter Profile (SEP) questionnaires.

To evaluate the effects of tadalafil upon erectile function, use was made of the IIEF and SEP. The former is a validated multidimensional, self-administered questionnaire comprising 15 questions that explore 5 domains of male sexual function: erectile function, orgasmic function, sexual desire, satisfaction during intercourse, and global satisfaction during the previous 4weeks¹⁵. The SEP in turn is a diary comprising 5questions that evaluate the results of each attempted intercourse, and which the patient answers after each such attempt.

The efficacy of treatment in relation to erection was evaluated by means of the changes experienced from the start to the end of the study in the erectile function (EF) domain of the IIEF, and the percentage of affirmative answers to questions 2 (capacity to introduce the penis in the vagina) and 3(capacity to maintain an erection long enough to ensure successful intercourse) of the SEP.

On the other hand, patient satisfaction with sexual intercourse was evaluated in terms of the changes in score obtained in the satisfaction domain of the IIEF from the start to the end of the study, and the percentage of affirmative answers to questions 4 (satisfaction with firmness of the erection) and 5 (global satisfaction with the sexual experience) of the SEP.

Safety: The safety analysis comprised all patients randomized to treatment. The treatment-emergent adverse events (TEAEs), defined as those appearing for the first time or that worsened after the baseline evaluation, were classified using the terms of the Medical Dictionary for Regulatory Activities (MedDRA version 5.0).

Statistical analysis: The study analysis was based on the intent-to-treat (ITT) criterion. The principal study variable was the PTQ, and the analysis included all patients that completed the questionnaire. The null hypothesis was that the proportion of patients preferring the OD regimen was the same as that preferring the SCH regimen. The single sample z-test with a two-sided significance of 0.05, was used to analyze the null hypothesis. For all the other efficacy variables, the IIEF domain scores and questions 1-5 of the SEP, the analyses included all those patients for which one baseline observation and at least one post-baseline observation were available. The change in efficacy variables versus baseline was subjected to analysis of variance (ANOVA) for crossed data. This model included fixed terms for the treatment regimen (OD or SCH), the baseline value of the efficacy variable, center, period and baseline situation with treatment, and a randomized term for the patient. In all of the models, the observation of nonsignificant interaction (p>0.1) led to withdrawal from the model. No drag effect was included, since the one-week pharmacological washout period between the treatment periods was considered sufficient to eliminate all pharmacodynamic effects of tadalafil corresponding to the previous treatment period. In the treatment phase of this study, co-morbidity was evaluated as registered on the first visit, along with the possible adverse events (AEs) recorded prior to randomization, to establish the baseline AEs in both treatment periods. Use was made of all the AEs persisting at the end of the second treatment period to establish the baseline AEs for the extension phase.

 

RESULTS

Patient characteristics

A total of 418 recruited Spanish patients were randomized to receive one or the other crossover treatment sequence (Fig. 2). Of these patients, 366 ompleted the study (87.6%). Of the 52 patients (12.4%) that abandoned the study, 5% did so because of AEs, 3.1% because of personal problems or decision, 2.4% due to a lack of efficacy, 1.5% because of failure to meet the protocol inclusion criteria or as a result of breaches in protocol, and the remaining 0.5% as a consequence of loss to follow-up. The demographic characteristics of the patients in the two treatment sequences are reported in Table 1.

 

FIGURE 2. Patient distribution.

 

 

Table 1

Demographic characteristics of the patients and causes of erectile dysfunction (ED)

 

The mean age of the patients was 54.9 years. The majority (89.5%) had a history of more than one year of ED, the etiology of which was largely organic (47.4%) or mixed (38%). The severity of ED at the start of the study was mild in 42.6% of the patients, moderate in 25.6%, and severe in 31.8%.

 

Principle study variable: Patient preference (PTQ)

At the end of the treatment period, a total of 374 patients answered the question: "Which treatment option do you prefer? (OD / SCH)". Based on the percentage distribution of answers, a significantly larger number of patients were seen to prefer tadalafil OD (55.9%; n=209) versus SCH (44.1%; n=165); p<0.05) in the study extension phase.

 

Secondary variables: IIEF and SEP

Both dosing regimens proved effective. In both regimens, tadalafil treatment led to similar improvement in the EF domain of the IIEF versus the baseline period. Thus, the patients administered the OD regimen showed improvement in the mean scores from 15.1at baseline to 24.7 at the end of treatment, while those administered the SCH regimen improved from 15.0at baseline to 25.1 after the treatment phase (p>0.05). This improvement was more manifest in those patients with severe ED (score in the EF domain of the IIEF ≤10) at the start of the study, as can be seen from the mean change in EF domain score reflected in Figure 3.

 

FIGURE 3. Mean change versus baseline in the EF domain of the IIEF, stratified according to the severity of ED at baseline.

 

Specifically, a significantly greater percentage of patients normalized their EF (score in the EF domain of the IIEF ≥26) after receiving tadalafil SCH versus tadalafil OD (69.3% vs. 64.3%, respectively) (Fig. 4), including those in whom the dysfunction was most severe (score in the EF domain of the IIEF <10) in the baseline period (57.9% with tadalafil SCH vs. 49.6% with tadalafil OD)(p<0.05). Likewise, in the domain of sexual desire, treatment with tadalafil SCH led to improvement in the mean baseline score from 6.4 to 7.3, which was significantly greater (p<0.05) than the improvement observed for tadalafil OD (from 6.4 to 7.1) (Fig. 5).

 

FIGURE 4. Percentage of patients reaching an EF domain score in the IIEF within the normal limits for EF.

 

 

FIGURE 5. Mean change in IIEF domain scores versus the start of the study with both treatment regimens (OD/SCH).

 

Likewise, at the end of treatment, the sexual intercourse success rate (SEP3) was 75.6% and 72.2% with the SCH and OD regimens, respectively (p<0.05)(Fig. 5). In the same way, for the rest of individual questions of the SEP questionnaire, the differences were significantly in favor of the scheduled regimen (Fig. 6).

 

FIGURE 6. Mean change versus baseline in the Sexual Encounters Profile (SEP).

 

The patients showed greater satisfaction with the SCH regimen according to their answers to questions 4 (Are you satisfied with the firmness of your erections?) and 5 (Are you generally satisfied with your sexual relations?) of the SEP diary (p=0.001). The mean change from the start of the study to the end of treatment in the general satisfaction domain of the IIEF questionnaire was 3.0and 2.9for the SCH and OD regimens, respectively (p<0.05)(Fig. 5).

 

Safety

Tadalafil was well tolerated in both treatment regimens. The most common adverse events (incidence ≥5%) were dyspepsia, headache and back pain. Table 2 shows the AEs with an incidence of ≥2%.

 

Table 2

Treatment-emergent adverse events reported during the randomized treatment phase and study extension, with an incidence of ≥2%.****

 

The patients receiving the SCH regimen used a larger number of doses per week than during the OD treatment period (mean 2.3 vs. 1.7), as can be seen in Table 3. No clinically significant differences were observed in the incidence of AEs between the two dosing regimens. Likewise, no alteration was recorded in heart rate or blood pressure in any of the treatment groups. In 5% of the patients the AEs led to withdrawal from the study.

 

Table 3

Drug exposure

 

Discussion

The phosphodiesterase-5 (PDE5) inhibitors, traditionally administered on demand (OD) according to the patient needs, have shown similar efficacy in improving erectile function (EF). However, efficacy and safety are not always tied to satisfaction with the treatment if other patient expectations are not met, such as “naturalness”, discretion and acceptance of the treatment on the part of the couple¹⁶.

Tadalafil, a selective PDE5 inhibitor with a half-life of 17.5 hours, has demonstrated efficacy for up to 36 hours after administration (7-14), thus affording patients a large time window in which to decide when to start sexual intercourse. These properties of tadalafil moreover would allow patients to make use of a fixed-dose treatment regimen as an alternative to conventional on demand treatment for erectile dysfunction (ED). A dosing regimen comprising tadalafil 3 times a week offers almost continuous coverage, thus securing increased flexibility for ED patients and their couples in deciding when to have sexual intercourse, and avoiding the need to coordinate the sexual encounter with administration of the drug. In the present randomized, crossover and open-label study with parallel treatment regimens, the patients were instructed to take tadalafil according to the conventional on demand regimen, and with the new 3times a week scheme, in order to determine which treatment modality is preferred, and to assess the efficacy and safety of the drug.

As can be seen from the results of this study, a larger proportion of patients preferred the on demand regimen (55.9%) versus dosing 3 times a week (44.1%). These observations coincide with the findings of the SURE study, where 57.8% of the patients preferred the on demand regimen, while 42.2% favored dosing 3 times a week¹⁵. The number of patients that preferred this latter dosing scheme versus the classical OD protocol is quite considerable, particularly on taking into account that this is a new treatment scheme, and that the tendency is usually in favor of the classical regimen. This result suggests that if patients were allowed to choose, a significant percentage would consider the SCH regimen desirable and effective.

The two dosing regimens - scheduled and on demand - improved EF versus baseline, with similar results in both cases. However, the scheduled 3 times/week regimen generally yielded better scores in the IIEF domains - reaching statistical significance in the case of the domain corresponding to sexual desire (p=0.021). Likewise, the sexual intercourse success rate (SEP3) and percentage of patients that normalized EF were significantly greater (IIEF EF domain ≥26)(p=0.025). In turn, the patients showed increased satisfaction with the SCH regimen as reflected by questions 4 and 5of the SEP diary and the scores corresponding to the general satisfaction domain of the IIEF questionnaire.

Although this was an open-label study, the findings coincide with those of earlier studies, as can be seen in the global study of randomized, double blind and controlled trials conducted with tadalafil⁷, where 68% of intercourse attempts proved successful among the patients using 20 mg of the drug on demand, and 54% achieved normal EF at the end of treatment. Both treatment regimens were well tolerated, and no clinically significant differences in tolerability were observed between them.

These results show that the patients and their couples can have intercourse in a broad interval of time after administration of a dose of tadalafil, regardless of the treatment regimen prescribed (on demand or 3 times a week). Anticipated anxiety about failure in these patients, with adoption of the so-called spectator role, can be reduced by the scheduled tadalafil dosing regimen, since the patients are able to forget about limited drug action intervals. With such a broad response period, the physician is able to recommend different dosing regimens, based on the unique characteristics of tadalafil.

 

CONCLUSIONS

A larger proportion of patients preferred tadalafil 20 mg on demand to a maximum of one dose per day versus the 3times/week regimen, though an important percentage of subjects (41%) favored the latter form of treatment. Both tadalafil dosing schemes proved effective and were well tolerated, allowing the patients to choose the option best suited to restore normal function and spontaneity in their sexual activity.

 

Acknowledgements

This clinical study was carried out under the sponsorship of Laboratorios Lilly, S.A., Avda. de la Industria, 30. 28108- Alcobendas (Madrid) - Spain. The authors thank the contributions to this study made by doctors Adrián de la Fuente, Ana Loizaga, Ana Segura-Paños, Ander Astobieta, Carlos Pertusa-Peña, Emilio Julve, Enrique Cuñat-Albert, Esteban Blanco, Fernando Meijide, Francisco Chicote, Francisco Javier Gallo, Francisco Ramada, Jesús García-Alonso, Cristóbal López, Jordi Cortada, José Antonio Portillo, José Luis Martín-Benito, José M. Martínez Sagarra, José Manuel Barros, José Martínez-Jabaloyas, José Ramón Cortiñas, Luis Martínez-Piñeiro, Luis Resel-Estévez, Luis Rodríguez-Vela, Manuel Rivas del Fresno, Manuel Ruiz-Ramo, Manuel Varela-Salgado, Marceliano García-Pérez, Mariano Roselló, Mario Brassesco, Pedro Gutiérrez, Rafael Gutiérrez del Pozo, Rafael Prieto, Ramón Telleria-Elorz, Venancio Chantada, and by Elena Bolaños, Paz Sánchez, Elvira Ancillo, María Costi and Inés Lorenzo.

 

REFERENCES

1. Martin-Morales A, Sanchez-Cruz JJ, Saenz de Tejada I, Rodriguez-Vela L, Jimenez-Cruz JF, Burgos-Rodriguez R. Prevalence and independent risk factors for erectile dysfunction in Spain: results of the “Epidemiología de la Disfunción Eréctil Masculina” Study. J Urol. 2001;166(2):569-574; discussion 574-575.[PubMed]

2. Guirao Sanchez L, García-Giralda Ruiz L, Sandoval Martínez C, et al. Erectile dysfunction in primary care as possible marker of health status: associated factors and response to sildenafil. Atención Primaria 2002;30(5):290-296. [PubMed]

3. Wespes E, Amar E, Hatzichristou D, Montorsi F, Pryor J, Vardi Y, European Association of Urology. Guidelines on erectile dysfunction. Eur Urol. 2002;41(1):1-5. [PubMed]

4. Heaton JPW, Hackett G, Savage D, Padley RJ. Patient choice is critical in managing erectile dysfunction. Eur Urol Suppl. 2002;(3):33-37.

5. Chen J, et al. Sildenafil versus the vacuum erection device. Patient preference. J Urol 2000;166:1779-1781. [PubMed]

6. Hackett GI. What do patients expect from erectile dysfunction therapy?. European Urology Supplements 2002;1(8):4-11.

7. Carson CC, et al. The efficacy and safety of tadalafil: an update. BJU Int. 2004;93(9):1276-1281. [PubMed]

8. Rosen RC, Padma-Nathan H, Shabsigh R, Khalil Saikali, Watkins V, Pullman W. Determining the earliest time within 30 minutes to erectogenic effect after tadalafil 10 and 20 mg: A multicenter, randomized, double-blind, placebo-controlled, at-home study. J Sex Med 2004;1(2):193-200. [PubMed]

9. Brock GB, McMahon CG, Chen KK, Costigan T, Shen W; Watkins V et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002;168 (4 Pt 1):1332-1336. [PubMed]

10. Padma-Nathan H, Rosen RC, Shabsigh R. Cialis (tadalafil) provides prompt response and extended period of responsiveness for the treatment of men with erectile dysfunction (ED). J Urol 2001 May;165 suppl: 224.

11. Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 2003;62(1):121-125; discussion 125-126. [PubMed]

12. Young JM, et al. Tadalafil Improved Erectile Function at Twenty-Four and Thirty-Six Hours After Dosing in Men With Erectile Dysfunction: US Trial. J Androl. 2005;26(3):310-318. [PubMed]

13. Ficha técnica Tadalafilo.

14. Mirone V, et al. An Evaluation of an Alternative Dosing Regimen with Tadalafil 3 Times/week, for Men with Erectile Dysfunction: SURE Study in 14 European Countries. Eur Urol. 2005;47(6):846-854; discussion 854. Epub 2005 Mar 9. [PubMed]

15. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The International Index of Erectile Function (IIEF): a multidimensional scale for the assessment of erectile dysfunction. Urology 1997;49(6):822-830. [PubMed]

16. Hanson-Divers C, Jackon SE, Lue TF et al. Health outcomes variables important in the treatment of erectile dysfunction. J Urol.  1998;159(5):1541-1547. [PubMed]

 

Dr. A. Cassinello

E-mail: cassinello_alejo@lilly.com

(Manuscript received on May 3, 2006)