Tadalafil clinical trials

During sexual stimulation, tadalafil will inhibit phosphodiesterase type 5 PDE5, which increases the amount of cGMP in smooth muscles cells thus enhancing erectile function. J Urol , Overview of the cardiovascular effects of tadalafil. Eur Heart J ; 4:H Gresser U, Gleiter CH.

Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil. Review of literature. Eur J Med ; The international index of erectile function IIEF Rosen et al , that includes the domains of EF, intercourse satisfaction, orgasmic function, sexual desire and overall satisfaction, was used to globally evaluate EF. Compared with placebo, tadalafil significantly enhanced, in a dose-dependent manner, in patients of different ages, all efficacy outcomes across disease etiologies and severities.

The primary efficacy outcome measure was the EF domain that consists of 6 questions with possible score range from 1 worse function to 30 normal function. The change of positive response to the questions 1 and 2 significantly increased from 2. Based on the cause of ED, there was a similar trend in the IIEF—EF domain score improvements, with the 20 mg group that had numerically greater mean changes across all severity groups than the 10 mg group.

The greatest percentage of tadalafil treated patients having normal EF at end-point were those with mild baseline ED, followed by those with moderate and severe ED. In particular, etiology, severity, duration, presence of comorbid conditions such as obesity, diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, depression, benign prostatic hyperplasia BPH , or concomitant treatment with antihypertensive or antidepressant drugs have been considered.

Overall, tadalafil proved to be effective in improving erectile function across a variety of patient demographics and illness characteristics including ED etiology, duration, severity, comorbidity, and concomitant treatments. Obesity is generally associated with increased risk of medical conditions such as diabetes mellitus, hypertension, depression or cardiovascular diseases, and BPH.

The obese subgroup had a statistically nonsignificant lower score on each of the efficacy measures with respect to the rest of the sample. As already expected Emmick et al ; Saenz De Tejada et al , whether affected from diabetes or hypertension, these subgroups had lower baseline and end-point scores. Both tadalafil doses showed statistically greater improvement than placebo for each ED severity level, with more pronounced amelioration in the moderate and severe ED patients because of the lower baseline scores.

The subgroups of patients with comorbid conditions taking tadalafil 20 mg showed significant improvements from baseline to end-point. Early treatment success may be important in enhancing self-confidence to continue successful treatment. The SEP diary questions assessed these three perspectives.

Note the high proportion of patients attaining initially a successful erection while on placebo. This success was not maintained under the measures of successful penetration, intercourse, and satisfaction. In a large population of men from Central and Eastern Europe and Eastern Mediterranean mean age 52 years; range 21—82 years , after 12 weeks of on demand treatment, tadalafil 20 mg versus placebo has confirmed its superior efficacy, also after stratification of IIEF—EF severity class from mild and moderate to severe Skoumal et al The same conclusions on tadalafil 20 mg were yielded in similar trials with populations of different ethnicity Allen et al ; Carson et al Regardless of the degree of ED, tadalafil 20 mg every other day for one month has been shown to improve endothelial function in patients with increased cardiovascular risk Rosano et al , since endothelial damage is a common marker of diseases of the cardiovascular system.

Age itself is an important risk factor for vascular disease and ED, and thereby endothelial dysfunction. In elderly patients 60—70 years affected by ED, with slight or no signs of carotid disease, resumption of spontaneous erections was obtained with chronic tadalafil 20 mg administered for three months on alternate days.

Nocturnal penile tumescence rigidity monitoring and PDU parameters were inversely related to different degrees of carotid wall alteration and showed a significant improvement in those patients with atherosclerotic plaques, probably due to the amelioration of endothelial function during treatment.

A retrospective analysis of pooled data from 12 placebo-controlled trials was conducted to characterize the efficacy and safety of tadalafil in men with diabetes mellitus Fonseca et al These scores correlated inversely with glycosylated hemoglobin HbA1c levels. Regardless of glycemic control and diabetic therapy, tadalafil 10 mg and 20 mg, compared with placebo, improved all primary efficacy outcomes in all patients.

The subgroup receiving tadalafil 20 mg experienced a mean improvement of 7. Tadalafil 20 mg was effectively administered in the treatment of men suffering from ED following bilateral nerve sparing radical retropubic prostatectomy Montorsi, Padma-Nathan, et al Compared with placebo, a greater improvement on all the evaluated end-points was reported. A subgroup of patients with at least a post-operative tumescence, meaning a post-surgical minimal cavernous innervation damage, reported an increase of 5.

In a randomized blind cross-over trial for the treatment of ED in 30 male spinal cord-injured patients mean age In these patients, either psychogenic erections or reflexive spinally elicited erections or both are necessary for PDE5 inhibitor response. Tadalafil and sildenafil allowed patients to achieve erections whit a mean total score on IIEF of Most of the side effects reported in the clinical trials are dose-dependent and consistent with the vasodilatatory effect of PDE-5 inhibition.

When tadalafil was administered on an on-demand basis headache and dyspepsia were the most frequent symptoms, followed by back pain, nasal congestion, myalgia, and flushing.

Subgroup analyses have revealed no differences between incidences of adverse events in tadalafil-treated men over 65 years compared with the younger group. No relevant differences in the frequency and pattern of side-effects have been reported when tadalafil was schedully administered eg, three times per week, or daily. The daily administration of tadalafil was well tolerated with headache, dyspepsia, facial flushing, nasal congestion, and backache as the most frequently reported adverse events McMahon Side-effects were generally mild to moderate and decreased in frequency during continued treatment.

In a comprehensive review on the cardiovascular effects of tadalafil, a safety assessment of more than subjects who received the drug during clinical studies was performed Kloner et al When tadalafil 10 mg and 20 mg was administered to healthy subjects, minimal, but statistically significant differences over placebo in standing systolic SBP and diastolic blood pressure DBP were observed.

An update on thirty-five placebo-controlled and eight open clinical trials of tadalafil demonstrated no increased risk of cardiovascular adverse events such as myocardial infarction, cerebrovascular events or cardiac mortality Jackson et al The evidence that duration of action for tadalafil is well beyond the elimination half-life, advises for a careful monitoring of its long-term effect.

However, the duration of side-effects has not been measured in the majority of the studies. Due to the potential for a clinically significant decrease in blood pressure, the major contraindications of the PDE5 inhibitors are concomitant use with nitrates or molsidomine-containing medications, because of the increased sensitivity to nitroglycerin Dishy et al Interaction between grapefruit juice and sildenafil, tadalafil, or vardenafil may cause serious systemic vasodilatation Bailey and Dresser , and we do suggest such a possibility with alcohol as well Frajese and Pozzi Since men with ED have high incidence of cardiovascular disease, diabetes mellitus and BPH, they are likely to be taking medications that affect blood pressure like the alpha-blockers terazosin and doxazosin Simonsen Tadalafil augmented the hypotensive effects of doxazosin, but had little hemodynamic interaction with tamsulosin, a drug prescribed for BPH Kloner et al The long-term safety and tolerability of tadalafil 10—20 mg in the treatment of erectile dysfunction has been assessed, evaluating in a 18—24 month open extension trial in subjects mean age 57, range 23—83 years Montorsi, Verheyden, et al The total tadalafil exposure was patient-years.

Headache Consistent with the low affinity of tadalafil for PDE6, only 1 patient complained of cyanopsia blue vision. The rate of discontinuation due to adverse events was 6. No clinically significant laboratory, or electrocardiographic findings, or changes in vital signs, or serious adverse events 8.

Back pain or myalgia or both appearing as a consequence of PDE5 inhibition was experienced by 8. The potential mechanism of this side effect remains unknown.

The underlying symptoms include diffuse bilateral lower lumbar gluteal, thigh, or thoracolumbar muscular discomfort, exacerbated by recumbency. The integrated analysis of ten placebo-controlled tadalafil studies, including patients Seftel et al , showed that laboratory markers of inflammation or muscle damage and renal plasma flow were unchanged with respect to baseline, and no lumbar or gluteal myositis was evidenced by positron emission tomography scan or magnetic resonance imaging.

Across tadalafil clinical trials no impairment of blue-green color discrimination was detected, and color vision alterations were rare 0. Chronic tadalafil administration has no detrimental effect on human spermatogenesis or reproductive hormones Ellstrom et al Although efficacy and safety are two important characteristics when choosing a pharmacological treatment for ED, the ideal therapy should be reliable during maintenance.

Furthermore, beyond erection and penetration, intercourse success and overall satisfaction needs have to be considered. The primary goal in the treatment of ED should be the restoration of sexual life rather than merely the achievement of a penile erection. An important characteristic of tadalafil is its prolonged period of responsiveness.

In prescribing a therapy for ED, the long lasting effect of the drug may not be the most important issue. Tadalafil is unique to the PDE5 inhibitors available because of its efficacy up to 36 h after dosing. If a qualifying participant has more than one female partner during the study, the participant will not be excluded from the trial.

However, the participant will be required to respond to the questionnaires based on his sexual interactions with only one of these partners. Make at least 4 sexual intercourse attempts, with the female sexual study partner, during the 4-week run-in period and during the final 4 weeks of each 8-week treatment period. Not use any ED treatment including the use of herbal therapy and traditional Chinese medicine TCM for the treatment of ED other than study medication at any time during the study and for 96 hours after study completion.

Partners Are female, at least 18 years of age at screening and will have the same male study subject as her sexual partner during the study. Are able to read, understand and provide signed informed consent.

Agree to make at least 4 sexual intercourse attempts with the male sexual study partner during the 4-week run-in phase and during the final 4 weeks of each 8-week treatment period. Willing to participate in recording responses to efficacy questionnaires, sexual quality of life questionnaires and other instruments used in this study. Exclusion Criteria: Present with ED caused by other primary sexual disorders including premature ejaculation or ED caused by untreated endocrine disease.

Have a history of radical prostatectomy, or other pelvic surgery with subsequent failure to achieve erection. Have a history of penile implant. Have a clinically significant penile deformity in the opinion of the investigator. Exhibit evidence of active symptomatic hepatobiliary disease at Visit 1. Present with chronic stable angina treated with long-acting nitrates, or with chronic stable angina requiring short-acting nitrates in the last 90 days, or with angina occurring during sexual intercourse in the last 6 months.

Have met the criteria for unstable angina within 6 months before screening, or have a history of myocardial infarction or coronary artery bypass graft surgery within 90 days before screening, or percutaneous coronary intervention within 90 days before screening. Have a history of sudden cardiac arrest despite medical or device therapy. Exhibit any evidence of congestive heart failure within 6 months before screening.

Have had a new or significant cardiac conduction defect within 90 days before screening. Have retinitis pigmentosa. Have a history of significant central nervous system injuries including stroke and spinal cord injury within the last 6 months.

Have a history of human immunodeficiency virus HIV infection. Have a condition that in the opinion of the investigator would interfere with the patient's ability to provide informed consent or comply with study instructions, would place the patient at increased risk, or might confound the interpretation of study results. Have a history of drug, alcohol, or substance abuse within the past 6 months, as assessed by the investigator. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.

Patients who are currently taking TCM for ED treatment within the last 30 days prior to study entry or planned concomitant administration of TCM for ED treatment during study enrolment. Are currently enrolled in, or discontinued with the last 30 days from a clinical trial involving an investigational product or unapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

Have a history of loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy NAION , regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. Have rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption lactose intolerance. Are currently in a sexual relationship with a female of child-bearing potential where no form of birth control is being used.

Maternal adverse events in all doses were recorded as least one grade 1 adverse events, as tadalafil was considered acceptable from the viewpoint of the mothers. The only fetal adverse event was a case of intrauterine fetal death related to the velamentous insertion of the umbilical cord. Neonatal adverse events showed no correlation to tadalafil dose, but were found more frequently in preterm births and, therefore, were correlated to infant prematurity.