Efficacy and Safety of Snafi Following Spinal Cord Injury

Summary

The goal is to determine the efficacy and safety of tadalafil in men requiring erectile dysfunction (ED) in men with traumatic spinal cord injury (LIC).

Design and implementation in clinical practice in Europe in parallel, randomized, double-blind, placebo-controlled, flexible dose titration, parallel group.

Patients enrolled in the study had a secret EDI (all levels of spinal cord injury) and lasted 6 months or more before 1 visit.

After the 4-week interruption of the intervention, patients were randomly assigned to the 10-week treatment period with 10-week snafi 20 mg tadalafil, 10 mg, (n = 142) or placebo (n = 44) assessments, at 4 weeks. intervals. The dose of talalafil is maintained or titrated (10 or 20 mg) for 4 to 8 weeks.

The main outcome measures were measured using the International Erectile Function Index (IIEF), Sexual Encounter Profile (SEP), and the Global Assessment Question (GAQ). Treatments included adverse events and vital signs at each visit.

Results The mean age was 38 years. The mean score for the IIEF erectile function domain was 13.4, followed by 12-week treatment with 22.6 for tadalafil and 13.6 for placebo (P <.001). After treatment, the tadalafil group was significantly higher compared to the placebo group (P <.001) in the percentage of successful patients per patient (SEP question 2; 75.4% vs. 41.1%) and sexual attempts (SEP question 3; 47.6% vs. 16.8%); Percentage of improved buildings (GAQ Question 1; 84.6% vs. 19.5%); and ejaculation frequency (IIEF Question 9; P = .03). The 2 most common treatment-related events compared to placebo were headache (8.5% vs. 4.5%) and urinary tract injury (7.7% vs. 6.8%).


Consequences Tadalafil (10 mg and 20 mg) improved erectile function and ED was well tolerated in men with LH with trauma.


Test record clintrials.gov ID: NCT00421083. Published online September 10, 2007 (doi: 10.1001 / archneur.64.11.nct70001).


Worldwide, spinal cord injury (CRI) occurs most often in young men, resulting in negative physical, social, and psychological consequences.1-3 Field dysfunction (ED), inability to fit and maintain the penis. sexual performance is a common 4 difficulty in men with CPI. The degree of sexual impairment may vary with the extent and extent of the neurological injury. Only 25% of men with CPI interact well.5. The current treatment option for patients with ED and SCI is an oral phosphodiesterase 5 (PDE5) inhibitor, which is a first-line treatment for most men with ED.

Following sexual stimulation, a PDE5 inhibitor facilitates erection by a second messenger cyclic guanoinophosphate (cGMP) (Figure 1) .6 snafi price in pakistan is a potent inhibitor of PDE5, which has been shown to be effective and highly tolerated in men. ED.7 Additional studies with Talafil indicate that TI may be an important treatment option in men with SCI.8,9 This study may determine the efficacy and safety of tadalafil in post-traumatic STI in ED.

Methods
Study design
Free round flexible titration, this parallel placebo-controlled group, flexible dose titration, was conducted in France, Germany, Italy, and Spain to determine the efficacy and safety of tadalafil (up to a dose per day prior to sexual activity) in men with ED. after a traumatic event.

This study consisted of 2 periods: no treatment duration at 4 weeks and then a 12-week treatment period (Figure 2). Patients who signed informed consent at visit 1 (V1) underwent at least 4 attempts at sex without medication. After the (V2) period, select patients were randomly assigned (3: 1) to receive tadalafil, 10 mg, or placebo for a 12-week treatment period after each 4-week interval to begin with the assessments. After the first treatment interval (V3), tadalafil 10 mg titalafil 20 mg (compressed 2 mg 10-tachophil) was titrated or unchanged. After the second treatment interval (V4), the dose of tadalafil was dosed with tadalafil 20 mg, tadalafil 10 mg or unchanged. The researcher determined whether the patient's response to the medication was based on the previous treatment interval. Subjects were instructed to take a dose of the study drug prior to the potential for sexual activity with water, whatever the food. Patients can begin sexual activity at various times after dosing to determine their optimal window of opportunity. They were instructed to take more than one dose per day.


The treatment group was randomly assigned to patients (3: 1) according to residual upright function (REF); Severity of SCI as defined by the American Spinal Injury Association (ASIA) severity scale; and country.

Patient population
Among the enrolled patients, men were at least 18 years of age after spinal ED and traumatic neurological impairment with SCI (all severity levels were specified on the ASIA scale) and V1 occurred 6 months earlier. Patients agreed with the treatment phase and other treatment phase and did not use the final treatment for 96 hours. Exclusion criteria were men who had the following conditions: (1) untreated ED due to endocrine disease or premature ejaculation; (2) radical prostatectomy who have not obtained an erection or have had clinically significant penile implants or penile deformities; (3) uncontrolled diabetes mellitus (hemoglobin A1c level greater than 13.0%); (4) clinically relevant renal or hepatobiliary disorders; (5) severe or unstable coronary artery disease, cardiac dysfunction, coronary intervention, or any uncontrolled supraventricular arrhythmia; (6) hypertension (> 170 mm systolic Hg or> 100 mm diastolic Hg) or hypotension (<90 mm systolic Hg or <50 mg diastolic Hg); (7) injury of the central nervous system; (8) with nitrates, cancer chemotherapy, antiandrogen or α-blockers; (9) prior use of tadalafil; (10) in the opinion of the investigator prior to effective treatment with PDE5 inhibitors; and (11) any situation that would interfere with the subject's ability to provide informed consent or study instruction may increase the risk or distort the interpretation of the study results. Patients with autonomic dyslexia in the past did not exclude participation in this study. However, if the researcher is not desirable for a patient because dyslexia is at greater risk for severe autonomy, that patient may be suspended based on the final exclusion criteria mentioned here. Patients agreed not to use any other treatment for at least 4 weeks prior to receiving the initial dose of the study medication (i.e., the duration of the study), during the treatment phase of the study and 96 hours after the last study visit. it was completed. Patients began to study drug treatment in randomized V2.

Efficacy measures
The primary measures of efficacy were the domain of erectile function (EF) of the International Index of Erectile Function (IIEF) and questions 2 (SEP2) and 3 (SEP3) of the Sexual Encounter Profile.

The IIEF is a validated, multidimensional and self-administered questionnaire that is used to evaluate the effectiveness of therapy for ED11. The IIEF consists of 15 questions that are grouped into 5 domains. The IIEF questionnaire was administered at the end of the initial period (baseline) and at each visit during the 12 weeks of treatment. The EF domain consists of 6 questions with a possible score of 1 to 30. The EF domain is a validated diagnostic tool to classify the severity of ED12. The severity of the ED was defined using the IIEF-EF domain score: 5 or less, without attempts of intercourse; 6 to 10, severe DE; 11 to 16, moderate DE; 17 to 21, mild to moderate SD; 22 to 25, mild erectile dysfunction; and 26 or more, "normal" erectile function. A 4 to 5 increase in the IIEF-EF score is considered clinically significant.

The daily SEP is another common measure of the effectiveness of therapy for erectile dysfunction and consists of 5 questions. The questions address the sexual events the patient experienced while trying to have sex. SEP2 asked: "Could you insert your penis into your partner's vagina?", And SEP3 asked: "Did your erection last long enough to have a successful sexual relationship?" In this study, the questionnaire was administered at each visit of the treatment phase and the response of the patients after each attempt at sexual intercourse during a treatment interval.


Secondary measures of efficacy in this study included the Global Assessment Question 1 (GAQ1) and GAQ2. These questions were presented to the patients at the last study visit and they were asked if the treatment improved their erections (GAQ1) and, if so, if the treatment improved their ability to participate in sexual activities (GAQ2). Additional secondary measures of efficacy were the other 4 domains IIEF (sexual satisfaction, orgasmic function, sexual desire, general satisfaction), IIEF question 9 (ejaculation frequency) and IIEF question 10 (orgasm frequency). Another point of interest in this study, although not a measure of efficacy, was the percentage of patients with normal IIEF-EF domain scores (≥26) at the end of the study.

Security analysis

Safety was assessed by evaluating all emerging adverse treatment events (ASD), serious adverse events (SAE) and vital signs (blood pressure and heart rate) at each visit of the 12-week treatment phase. Vital signs were also collected before the start of the filming phase. All events were coded in the Medical Dictionary for Regulatory Activities (MedDRA) version 8.0 (www.meddramsso.com/MSSOWeb/index.htm).

Statistic Analysis

A sample size of 180 was used to provide at least 90% potency to detect significant treatment effects for the 10 mg dose of snafi tablets tadalafil in each of the 3 endpoints at an α level of .05. There was no α adjustment for the 3 primary efficacy measures (domain IIEF-EF, subject SEP2 and subject SEP3) because the 3 variables were required to reach statistical significance for the null hypothesis to be rejected. The sample size was driven by the SEP2 analysis in the entire population of subjects because this test required that most subjects detect a significant difference.

Primary and secondary efficacy assessed were performed by intention to treat. The primary efficacy assessed were performed on the original scale data using the change from the beginning. No data transformations were performed. The 2 treatment groups, tadalafil and placebo, were compared throughout the study. For each efficacy variable, the population of analysis included all patients with an initial measurement and at least 1 subsequent measurement.

We analyzed the IIEF-EF domain scores using a convention of last observation transmitted. For each SEP question, the baseline and subsequent scores were percentage of affirmative answers in relation to the number of sexual encounters during the preinclusion period and the treatment period, respectively. Post-start SEP questions included the percentage of affirmative answers in relation to the number of sexual attempts in the treatment period. The proportions of affirmative answers to the questions of the SEP newspaper were treated as continuous variables. We analyzed the IIEF-EF, SEP2 and SEP3 domain using a covariance analysis model (ANCOVA) that included terms of treatment group, clustered site, reference value for each primary efficacy variable, severity of SCI and degree of REF at baseline. . A term for the treatment interaction with the baseline value was included if the interaction was significant at P <.10. Sexual satisfaction during IIEF, orgasmic function, sexual desire and domains of general satisfaction and individual questions of IIEF were analyzed using similar ANCOVA models.

The secondary analysis to assess GAQ at the end point by treatment group was performed using a logistic regression model that includes the terms of the clustered site, the treatment group, the erectile function at the start of the study and the severity of the SCI. Only patients who responded to GAQ were included in the analysis. The percentage of patients who achieved a IIEF-EF domain score of 26 to 30 at the end point was analyzed using a logistic model that included terms of clustered site, treatment group, degree of REF at baseline, initial domain IIEF-EF and start × treatment interaction (if P <.10).

Results

This multicenter study included 197 patients who signed informed consent forms (Figure 3). Of these patients, 186 were randomly assigned in a 3: 1 ratio to tadalafil (n = 142) or placebo (n = 44). In the tadalafil treatment group, 129 patients (91%) completed the study. The treatment was interrupted by 4 patients (2.8%) due to adverse events and by 2 patients (1.4%) due to lack of efficacy. In the placebo group, 34 patients (77%) completed the study. Eight patients (18.2%) discontinued treatment due to lack of efficacy and 1 (2.3%) due to adverse events.

The demographic characteristics of the patients at the beginning of the study were comparable between the treatment groups (Table 1). The average age was 38 years (range, 18-66 years). Almost 70% of the patients in each group had deterioration of ASIA grade A (complete lesion), and at least 60% in each treatment group had SCI in T11 or higher. The mean baseline IIEF-EF domain score was 13.4, and more than 60% of patients had moderate to severe ED at baseline based on their IIEF-EF domain score (moderate, 11-16; severe, 1 -10). The highest percentage of patients in each treatment group had grade 2 REF (normal tumescence, weakened stiffness) (27.4%) or grade 3 (normal tumescence, slightly weakened stiffness) (42.5%).

Before entering the study, 96 patients (51.6%) took sildenafil citrate and 20 patients (10.8%) took vardenafil hydrochloride. 31 patients (16.7%) used treatments for erectile dysfunction that were not a PDE5 inhibitor, and 39 patients (21.0%) were not receiving treatment.

Primary Efficacy

Tadalafil significantly improved erectile function compared to placebo (P <.001) as measured by the improvement in the IIEF-EF domain score and in the SEP2 and SEP3 responses (Figure 4). At the start of the study, the mean IIEF-EF domain score was 13.5 for snafi tablet and 13.0 for placebo compared with 22.6 for the tadalafil group and 13.6 for placebo after 12 weeks of treatment (P <.001). In response to SEP2, the average percentage of attempts per patient with successful penetration was 75.4% for tadalafil and 41.1% for placebo (P <.001). In response to SEP3, the average percentage per patient of successful sexual intercourse attempts was 47.6% for tadalafil and 16.8% for placebo (p <0.001).

Secondary Efficiency

In addition to the EF domain of IIEF, the other 4 domains (sexual satisfaction, orgasmic function, sexual desire and general satisfaction) were evaluated. Compared to placebo, the change from the beginning to the end point in the tadalafil group was statistically significant (P <.01) in all IIEF domains except the desire domain (P = .97). There was also a significant improvement in the ejaculation frequency (IIEF question 9) (P = .03) and the frequency of orgasm (IIEF question 10) (P = .01).

A IIEF-EF domain score of less than 26, which indicates ED, was evaluated at the start of the study for 137 of 142 patients in the snafi treatment group (96.5%) and for 43 of 44 patients in the placebo group (97.7% ). Seventy-four patients (54.0%) with scores below 26 in the tadalafil group and 5 patients (11.6%) in the placebo group achieved a normal score (≥26) after 12 weeks of treatment on demand (Figure 5). This difference between the tadalafil and placebo groups was statistically significant (P <.001). An additional analysis of the IIEF-EF domain scores showed that for a subgroup of patients who had severe ED at the start of the study (IIEF-EF domain score ≤10), a higher percentage in the tadalafil group (40%) achieved an IIEF-EF domain score of 26 or more after treatment compared to placebo (0%) (P <.001).

In the tadalafil group, the IIEF-EF domain score improved from the reference point to the end point for all severity categories of baseline ED with the greatest changes in the moderate and severe categories. Compared to placebo, these changes were statistically significant (Figure 6).

The percentage of affirmative responses to GAQ1 ("Did the treatment improve your erections?") Was 84.6% for the tadalafil group compared to 19.5% for the placebo (P <.001). For GAQ2 ("Did the treatment improve your ability to participate in sexual activities?"), 78.5% of patients in the tadalafil group said yes compared to 14.6% for placebo (P <.001) (Figure 7).

The 3 main efficacy variables, the IIEF-EF domain score, SEP2 and SEP3, were further analyzed based on the degree of REF (grade 1 and grades 2-4), ASIA score (grade A and BD grades) and level of neurological lesion (C1-T11 and T12-S5) (Table 2 and Table 3). In general, statistical improvement