Sexual MedicineEvaluation of the Efficacy and Safety of Once-a-Day Dosing of Tadalafil 5 mg and 10 mg in the Treatment of Erectile Dysfunction: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Tadalafil 5 and 10mg taken once daily significantly improved EF as measured by all secondary efficacy variables. Based on “yes” responses to GAQ, 84.5% (tadalafil 5mg) and 84.6% (tadalafil 10mg) of men thought treatment improved their erections (28.3% of men who took placebo, p<0.001).

• Can be part of a treatment plan for psychological ED.
• Success with medication can help break the cycle of anxiety.
• May be used on an occasional basis for situational ED.
• Useful for men who desire spontaneity due to long duration.
• Not suitable for everyone; a thorough medical history is essential.
• Discuss all treatment options, benefits, and risks with your doctor.

Of the men who had an IIEF EF domain score <26 at baseline, 51.5% (tadalafil 5mg) and 50.5% (tadalafil 10mg) achieved an EF domain score 26–30 (“no ED”) at endpoint (8.3% of men who took placebo, p<0.001). The safety evaluation included all 268 enrolled subjects.

• For BPH, it relaxes smooth muscle in the prostate and bladder.
• Can be prescribed with other BPH medications like finasteride.
• May reduce the need for BPH-related surgery.
• Monitor for signs of allergic reaction: hives, swelling, difficulty breathing.
• In case of overdose, seek immediate medical attention.
• Overdose symptoms may include severe headache, vomiting.

The mean number of doses per week was calculated as the number of doses taken divided by the number of weeks on therapy until the last scheduled visit. Subjects on tadalafil took an average of 6.5 doses per week; subjects on placebo took an average of 6.6 doses per week. The majority (87.3%) of subjects completed the study. Nine (3.4%) discontinued because of adverse events (Fig. One patient in the tadalafil 5mg group with renal cell carcinoma died during the treatment period.

The study investigator determined that his death was unrelated to the drug. Treatment-emergent adverse events were generally mild to moderate in severity: 53.8% reported as mild and 32.8% reported as moderate. The most common treatment-emergent adverse events reported were dyspepsia, headache, back pain, upper abdominal pain, and myalgia (Table 3). One patient who took tadalafil 5mg reported an incident of “gritty feeling in the eyes.” There were no incidents of myocardial infarction (MI).

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The percentage of patients who attained an IIEF EF score of 26–30 at endpoint was analyzed with a logistic model that included terms of pooled site, treatment group, EF at baseline, and baseline-by-treatment interaction (if p<0.10). Data analyses were performed by the Eli Lilly Global Statistical Science Group. The first subject was randomized October 2001 and the last completed treatment in March 2002. Of 293 patients screened, 268 were enrolled and 234 completed the study (Fig. Treatment compliance was defined as taking at least 70% of doses between visits; 96.2% (placebo), 94.2% (tadalafil 5mg), and 93.0% (tadalafil 10mg) of patients were compliant.

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Treatment group demographics were similar at baseline (Table 1). Tadalafil 5 and 10mg taken daily significantly improved EF as measured by all primary efficacy variables (Table 2). As stipulated in the protocol, the primary analysis did not exclude patients with an IIEF EF domain score ≥26 at baseline. A post hoc analysis that excluded 14 patients with “no ED” at baseline resulted in slightly lower baseline and endpoint 20mg tadalafil price scores without change in statistical interpretation (Table 2). A post hoc analysis of efficacy by ED severity group (excluding the 14 patients with “no ED”) showed EF improvement regardless of baseline ED severity (Figs. ED is a chronic disease associated with underlying cardiovascular, neurological, endocrine, and psychological diseases and factors [17]. Historically, pharmacologic ED treatment has been linked to anticipated sexual activity.

This required men to inject vasoactive drugs into the penis or apply mechanical devices such as a vacuum device just before sexual activity. Oral PDE5 inhibitors alleviate many of these inconveniences and complications, but, treatment requires that dosing and sexual activity occur within a restricted time window.

Primary efficacy endpoints

The protocol stipulated that these men would be included in the mild category. Treatment lasted 12 to 15 weeks and consisted of three visits four to five weeks apart. Patients were instructed to take one dose of study drug around the same time each day. Three efficacy instruments were used: the IIEF EF domain, the Sexual Encounter Profile (SEP) diary, and a Global Assessment Question (GAQ): “Has the treatment you have been taking during this study improved your erections?”. The co-primary efficacy measures were change from baseline in IIEF EF domain score, and change from baseline in per-patient mean percentage of “yes” responses to SEP Question 2 (SEP2, “Were you able to insert your penis into your partner’s vagina?”) and SEP Question 3 (SEP3, “Did your erection last long enough for you to have successful intercourse?”).

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Secondary efficacy measures were percentage of “yes” responses to the GAQ; and percentage of men who achieved an EF domain score of at least 26 (“no ED”) at endpoint, who had a baseline EF domain score below 26. A post hoc analysis was also done to determine change from baseline in the EF domain score for each baseline ED severity subgroup. Safety was assessed by evaluating all reported treatment-emergent adverse events, vital signs measurements, electrocardiograms, and standard safety laboratory assessments for all randomized patients. Treatment-emergent adverse events were defined as any adverse event that first occurred or worsened after randomization, and were mapped with the Medical Dictionary for Regulatory Activities. Subjects voluntarily reported adverse events throughout the study. The current study suggests daily administration of tadalafil 5 and 10mg is efficacious and well tolerated in the treatment of ED.

Why is this medication prescribed?

Written informed consent was obtained in conformity with the Declaration of Helsinki (revised 1989) and applicable local laws. The ethics committees of all participating institutions approved the final protocol. Subjects were excluded from enrollment for any of the following: ED caused by other sexual or endocrine disorders such as premature ejaculation or hypogonadism, history of radical prostatectomy (except bilateral nerve-sparing prostatectomy) or other pelvic surgery with subsequent ED, clinically significant hepatobiliary or renal disease, hemoglobin A1c >13%, unstable cardiovascular disease [14], current nitrate use, congestive heart failure, or recent significant central nervous system injuries. Patients who had previously enrolled in any tadalafil study, and those with prior ineffective treatment with sildenafil were ineligible. This multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluated the efficacy and safety of once-a-day dosing of placebo, tadalafil 5mg, and tadalafil 10mg, administered for 12 weeks to men with ED from 20 centers from Argentina, Brazil, France, Germany, and the United Kingdom.

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This study (Lilly ICOS LLC study identifier H6-MC-LVCV) began with a screening period that lasted four to five weeks. Eligible subjects were randomly assigned via central telephone to treatment groups 1:2:2 (placebo:5mg, tadalafil:10mg, tadalafil). Randomization was stratified by ED severity as measured by the International Index of Erectile Function Erectile Function domain (IIEF EF) [15]. Three stratifications of severity were used: severe (EF domain score 1–10), moderate (11–16), and mild (17–30). Because patients were enrolled based on a history of ED, some men scored 26–30 (“no ED”) [15] at baseline. Patients who took tadalafil 5 and 10mg daily had significant EF improvement compared with placebo as assessed by IIEF, SEP, and GAQ.

6. Response and effectiveness

A sample size of 250 patients would give approximately 90% power to detect a significant treatment effect between placebo and the least-effective tadalafil dosing group. All analyses were conducted on an intent-to-treat basis. Efficacy analyses included all randomized patients who had a baseline measurement and at least one post-baseline measurement. The last observation carried forward imputation methodology was used to replace missing IIEF EF domain scores. For each SEP question, baseline and post-baseline scores were the number of “yes” responses relative to the number of sexual encounters during the run-in and treatment periods, respectively.

Timing and duration for tadalafil

Proportions of “yes” responses to SEP diary questions were treated as continuous variables. IIEF EF domain, SEP2, and SEP3 were analyzed with an Analysis of Covariance model that included terms of treatment group, pooled site, baseline value for each primary efficacy variable, and baseline-by-treatment interaction (if p<0.10). To protect against type 1 error caused by comparing two tadalafil doses with placebo, the pairwise p-values that compared treatment groups were adjusted by the method of Dunnett [16]. A logistic regression model that included terms of pooled site, treatment group, EF at baseline, and baseline-by-treatment interaction was used to perform secondary analysis to evaluate GAQ at endpoint by treatment group. Only patients who responded to GAQ were included in the analysis. Although this study did not compare daily to on-demand dosing efficacy results are comparable to those seen in on-demand dosing studies.

In the current study, the mean IIEF EF domain score increased by 9.7 (tadalafil 5mg) and 9.4 points (tadalafil 10mg). In an analysis of 11 pooled, placebo-controlled studies of tadalafil [9], the mean IIEF EF domain score increased by 6.5 (10mg) and 8.6 points (20mg). The magnitude of change in the mild subgroup in the current study was comparatively small, and frequently did not reach statistical significance.

• May cause dizziness; avoid driving until you know its effects.
• Can cause nasal congestion, flushing, or muscle aches.
• Serious cardiovascular events are possible during sexual activity.
• Men with pre-existing heart conditions should use with caution.
• Seek emergency help for chest pain, dizziness, or nausea during sex.
• Inform all healthcare providers you are taking tadalafil.

This is expected, since the baseline for mild patients is higher (less “room to improve”). However, the change was 4.5 (5mg) and 4.8 points (10mg), which is clinically significant (Raymond C. Rosen, Ph.D., personal communication). Also, the sample size in this study limited the power of the analysis. When subgroups are larger, as in the 11 pooled studies (mild patients, n=112) a 3.7-point change (10mg on demand) reached statistical significance [9]. Because daily dosing with tadalafil was efficacious, this regimen may provide a novel approach to ED therapy in which sexual activity need not be tied to drug administration. As reported by Hanson-Divers et al., the five measures considered most important to patients in defining success were cure, pleasure, partner satisfaction, reproduction, and naturalness [8].

• For daily use, take at approximately the same time each day.
• If you miss a daily dose, take it when remembered unless near next.
• For on-demand, plan ahead as it needs time to become effective.
• Do not crush, chew, or split the tablet unless instructed.
• 10 mg is a common starting dose for on-demand therapy.
• Your doctor may adjust dose based on tolerance and efficacy.

Thus, taking a long-acting drug once a day may be the best way for some patients to forget their ED and be ready for spontaneous sexual activity.