Jed Kaminetsky

OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and Urinary Incontinence: Results of a Phase 3, Randomized, Placebo Controlled Trial

Purpose: Overactive bladder affects 12% to 17% of the general population and almost a third experience urinary incontinence, which may severely impact health related quality of life. Oral anticholinergics are the mainstay of pharmacological treatment but they are limited by inadequate efficacy or side effects, leading to a high discontinuation rate. We report the results of the first large (557 patients), phase 3, placebo controlled trial of onabotulinumtoxinA in patients with overactive bladder and urinary incontinence inadequately managed with anticholinergics. Materials and Methods: Eligible patients with overactive bladder, 3 or more urgency urinary incontinence episodes in 3 days and 8 or more micturitions per day were randomized 1:1 to receive intradetrusor injection of onabotulinumtoxinA 100 U or placebo. Co‐primary end points were the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a positive response on the treatment benefit scale at posttreatment week 12. Secondary end points included other overactive bladder symptoms and health related quality of life. Adverse events were assessed. Results: OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (−2.65 vs −0.87, p <0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo treated patients reported a positive response on the treatment benefit scale (60.8% vs 29.2%, p <0.001). All other overactive bladder symptoms improved vs placebo (p ≤0.05). OnabotulinumtoxinA improved patient health related quality of life across multiple measures (p <0.001). Uncomplicated urinary tract infection was the most common adverse event. A 5.4% rate of urinary retention was observed. Conclusions: OnabotulinumtoxinA 100 U showed significant, clinically relevant improvement in all overactive bladder symptoms and health related quality of life in patients inadequately treated with anticholinergics and was well tolerated.

Diagnostic performance of PCA3 to detect prostate cancer in men with increased prostate specific antigen: a prospective study of 1,962 cases.

PURPOSE The detection of prostate cancer relies primarily on abnormal digital rectal examination or increased serum prostate specific antigen concentration. However, low positive predictive values result in many men with increased prostate specific antigen and/or suspicious digital rectal examination having a negative biopsy. We investigated the value of the PCA3 (prostate cancer gene 3) urine test in predicting the likelihood of diagnosis of cancer before biopsy. MATERIALS AND METHODS We performed a prospective, community based clinical trial to evaluate PCA3 score before any biopsy. This trial was conducted at 50 urology practices in the United States. Samples were obtained from 1,962 men with increased serum prostate specific antigen (greater than 2.5 ng/ml) and/or abnormal digital rectal examination before transrectal prostate needle biopsy. Study samples (urinary PCA3 and biopsies) were processed and analyzed by a central laboratory. Sensitivity-specificity analyses were conducted. RESULTS A total of 1,913 urine samples (97.5%) were adequate for PCA3 testing. Of 802 cases diagnosed with prostate cancer 222 had high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation and were suspicious for cancer, whereas 889 cases were benign. The traditional PCA3 cutoff of 35 reduced the number of false-positives from 1,089 to 249, a 77.1% reduction. However, false-negatives (missed cancers) increased significantly from 17 to 413, an increase of more than 2,300%. Lowering the PCA3 cutoff to 10 reduced the number of false-positives 35.4% and false-negatives only increased 5.6%. CONCLUSIONS Urinary PCA3 testing in conjunction with prostate specific antigen has the potential to significantly decrease the number of unnecessary prostate biopsies.

Urodynamic Effects of Once Daily Tadalafil in Men With Lower Urinary Tract Symptoms Secondary to Clinical Benign Prostatic Hyperplasia: A Randomized, Placebo Controlled 12-Week Clinical Trial

PURPOSE We explored the impact of once daily tadalafil on urodynamic measures in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia via invasive and noninvasive urodynamic studies. MATERIALS AND METHODS We conducted a multicenter, randomized, double blind, placebo controlled clinical trial comparing once daily tadalafil 20 mg vs placebo during 12 weeks in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia with or without bladder outlet obstruction. Invasive and noninvasive urodynamics, International Prostate Symptom Score and general safety were assessed. The primary study end point was change in detrusor pressure at maximum urinary flow rate. RESULTS Urodynamic measures remained largely unchanged during the study with no statistically significant or clinically adverse difference between tadalafil and placebo in change in detrusor pressure at maximum urinary flow rate (mean difference between treatments -2.2 cm H(2)O, p = 0.33) or any other urodynamic parameter assessed including maximum urinary flow rate, maximum detrusor pressure, bladder outlet obstruction index or bladder capacity (all measures p > or = 0.13). Treatment with tadalafil resulted in significant improvements in International Prostate Symptom Score (mean difference between treatments -4.2, p < 0.001). Tadalafil was generally well tolerated with the majority of adverse events being mild to moderate in severity and few patients discontinuing due to adverse events (tadalafil 2.0%, placebo 1.0%). CONCLUSIONS Treatment with tadalafil once daily for lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia showed no negative impact on bladder function as measured by detrusor pressure at maximum urinary flow rate or on any other urodynamic parameter assessed. Nonetheless men receiving tadalafil reported significant improvements in International Prostate Symptom Score with an adverse events profile similar to other recent studies of tadalafil for lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia.

Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment

Study Type – Therapy (RCT)
Level of Evidence 1b

Oral Enclomiphene Citrate Stimulates the Endogenous Production of Testosterone and Sperm Counts in Men with Low Testosterone: Comparison with Testosterone Gel

INTRODUCTION Clomiphene citrate is employed off-label in men who have low testosterone and for the restoration of sperm counts in men who have used exogenous testosterone. Clomiphene is a mixture of two diastereoisomers: zuclomiphene and enclomiphene. We evaluated enclomiphene citrate in men with secondary hypogonadism. AIM Our aim was to compare oral enclomiphene citrate as an alternative to topical testosterone. MAIN OUTCOME MEASURES Blood levels of total testosterone (TT), estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin, thyroid stimulation hormone, prolactin, and insulin-like growth factor 1 IGF-1 were measured at certain times after treatment with each agent. Sperm parameters were determined at the same visits. Free testosterone (FT) was calculated. METHODS This was a proof-of-principle, randomized, open-label, fixed dose, active-control, two-center phase IIB study in 12 men with secondary hypogonadism treated previously with topical testosterone. RESULTS After discontinuation of topical testosterone, morning TT values averaged 165 ± 66 pg/dL. After 3 months, there was a significant rise in men receiving enclomiphene citrate and gel that was sustained for 3 months. At 6 months, TT levels were 545 ± 268 and 525 ± 256 pg/dL for groups receiving the gel and enclomiphene citrate, respectively. Only men in the enclomiphene citrate group demonstrated increased LH and FSH. TT decreased one month posttreatment to pretreatment values. Enclomiphene citrate elevated sperm counts in seven out of seven men at 3 months and six out of six men at 6 months with sperm concentrations in the 75-334 × 10(6) /mL range. The gel was ineffective in raising sperm counts above 20 × 10(6) /mL for all five men at 3 months and raised counts in only two or five men at 6 months. At follow-up, only enclomiphene citrate treatment was associated with elevated sperm counts. CONCLUSIONS Enclomiphene citrate increased testosterone and sperm counts. Concomitant changes in LH and FSH suggest normalization of endogenous testosterone production and restoration of sperm counts through the hypothalamic-pituitary-testicular axis.

Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement

To determine the effects of daily oral doses of enclomiphene citrate compared with topical testosterone gel treatment on serum total testosterone (TT), luteinising hormone (LH), follicle‐stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism.

Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial

Aim: Evaluate efficacy/safety of bremelanotide (BMT), a melanocortin-receptor-4 agonist, to treat female sexual dysfunctions in premenopausal women. Methods: Patients randomized to receive placebo or BMT 0.75, 1.25 or 1.75 mg self-administered subcutaneously, as desired, over 12 weeks. Primary end point was change in satisfying sexual events/month. Secondary end points included total score changes on female sexual function index and female sexual distress scale-desire/arousal/orgasm. Results: Efficacy data, n = 327. For 1.25/1.75-mg pooled versus placebo, mean changes from baseline to study end were +0.7 versus +0.2 satisfying sexual events/month (p = 0.0180), +3.6 versus +1.9 female sexual function index total score (p = 0.0017), −11.1 versus −6.8 female sexual distress scale-desire/arousal/orgasm total score (p = 0.0014). Adverse events: nausea, flushing, headache. Conclusion: In premenopausal women with female sexual dysfunctions, self-administered, as desired, subcutaneous BMT was safe, effective, and well tolerated (NCT01382719).

A Phase IV Prospective Evaluation of the Safety and Efficacy of Extended Release Testosterone Pellets for the Treatment of Male Hypogonadism

INTRODUCTION Men with hypogonadism exhibit decreased serum testosterone levels and may experience a constellation of clinical symptoms, including decrease in muscle mass, loss of sexual desire, impotence, and infertility. While previous studies have shown that implantation of extended release testosterone pellets can provide therapeutic levels of testosterone over several months, additional data are needed to establish this approach as the standard of care for male hypogonadism. AIM To evaluate the safety and efficacy of testosterone pellets over 6 months as a treatment for male hypogonadism in a clinical practice setting. METHODS A phase IV, single center, open-label study designed to assess the safety and efficacy of subcutaneous insertion of 8 to 12 testosterone 75 mg pellets (450 mg to 900 mg), during a single implantation procedure in hypogonadal men. Subjects who successfully completed the protocol were allowed to enroll in an extension study that included another implantation and 6 months of follow-up. MAIN OUTCOME MEASURES Safety was determined by investigator-reported adverse events, changes in vital signs, physical exam findings, and laboratory tests. Efficacy was based on serum laboratory tests, physical exams, implantation site evaluations, and vital signs. Secondary objectives were to assess patient preference for testosterone pellets and to maintain optimal total testosterone. RESULTS Mean testosterone significantly increased and luteinizing hormone (LH) levels significantly decreased from pre-implantation values at weeks 1, 4, and 12, and had returned to pre-implantation levels by week 24. Prostate-specific antigen levels remained unchanged for the duration of the study. Improvements in several symptoms of hypogonadism were determined with multiple questionnaires. Implanted testosterone pellets were generally well tolerated. CONCLUSION Implanted testosterone pellets can normalize testosterone and LH levels and improve symptoms for at least 3 months and up to 6 months in men with hypogonadism, and should be considered as a therapeutic option for hypogonadal men.

Clomiphene citrate and enclomiphene for the treatment of hypogonadal androgen deficiency

Hypogonadism has a number of important clinical consequences related to androgen deficiency and impaired spermatogenesis. The cause of this condition is multifactorial and can result from hypothalamic, pituitary or gonadal dysfunction as well as factors that affect hormonal signaling along the hypothalamic-pituitary-gonadal axis. While testosterone replacement is the most common treatment, it can paradoxically lead to infertility, and may be a less physiologic therapy for patients with secondary hypogonadism due to pituitary dysfunction. Clomiphene citrate, and its derivatives, may allow for restoration of gonadal function by restoring physiologic pituitary function in a subset of patients with hypogonadism.

In Men with Erectile Dysfunction, Satisfaction with Quality of Erections Correlates with Erection Hardness, Treatment Satisfaction, and Emotional Well-Being

INTRODUCTION The validated Quality of Erection Questionnaire (QEQ) evaluates satisfaction with erection quality. AIM To collate QEQ data, including correlations between QEQ outcomes and outcomes assessing emotional well-being, treatment satisfaction, and erection hardness after sildenafil citrate treatment. METHODS In four trials, men older than 18 years and with erectile dysfunction, a stable sexual partner, and no recent phosphodiesterase type 5 inhibitor use were randomized to double-blind flexible-dose sildenafil or placebo (1:1 ratio) for 6 or 10 weeks (two trials), fixed-dose 50 mg, 100 mg, and placebo (1:1:1 ratio) for 8 weeks (one trial), and 50 mg and 100 mg (1:1 ratio) for 4 weeks after 4 weeks of single-blind sildenafil 50 mg. Exclusion criteria included recent significant cardiovascular disease, use of nitrates, nitric oxide donors, cytochrome P450 3A4 inhibitors, or other erectile dysfunction treatment, and sildenafil hypersensitivity or previous severe or serious treatment-related adverse event. MAIN OUTCOMES MEASURES Scores on the QEQ, QEQ Question 5 (satisfaction with erection hardness), the Self-Esteem and Relationship Questionnaire, and the Erectile Dysfunction Inventory of Treatment Satisfaction; the percentage of occasions with Erection Hardness Score 3 (EHS 3, hard enough for penetration but not completely hard) and/or EHS 4 (completely hard and fully rigid); and Pearson correlation coefficients. RESULTS 1,296 men (18-80 years) were randomized. Except for the percentage of occasions with EHS 3, all outcomes improved in men treated with sildenafil and correlated positively with the change in QEQ scores in all trials. CONCLUSIONS Satisfaction with the quality of erections, which is easily monitored with the QEQ, correlated positively with measures of emotional well-being and treatment satisfaction and with the change in percentage of erections that were completely hard and fully rigid, but not with the change in percentage of erections that were hard enough for penetration but not completely hard.