Craig A. Peterson

Treatment of Men with Erectile Dysfunction with Transurethral Alprostadil

BACKGROUND Erectile dysfunction in men is common. We evaluated a system by which alprostadil (prostaglandin E1) is delivered transurethrally to treat this disorder. METHODS Alprostadil was delivered transurethrally in a double-blind, placebo-controlled study of 1511 men, 27 to 88 years of age, who had chronic erectile dysfunction from various organic causes. The men were first tested in the clinic with up to four doses of the drug (125, 250, 500, and 1000 microg); those who had sufficient responses were randomly assigned to treatment with either the effective dose of alprostadil or placebo for three months at home. RESULTS During in-clinic testing, 996 men (65.9 percent) had erections sufficient for intercourse. Of these men, 961 reported the results of at least one home treatment; 299 of the 461 treated with alprostadil (64.9 percent) had intercourse successfully at least once, as compared with 93 of the 500 who received placebo (18.6 percent, P<0.001). On average, 7 of 10 alprostadil administrations were followed by intercourse in men responsive to treatment. The efficacy of alprostadil was similar regardless of age or the cause of erectile dysfunction, including vascular disease, diabetes, surgery, and trauma (P<0.001 for all comparisons with placebo). The most common side effect was mild penile pain, which occurred after 10.8 percent of alprostadil treatments, but the pain rarely resulted in refusal to continue in the study. Hypotension occurred in the clinic in 3.3 percent of men receiving alprostadil. Hypotension-related symptoms were uncommon at home. No men had priapism or penile fibrosis. CONCLUSIONS In men with erectile dysfunction, transurethral alprostadil therapy resulted in erections in the clinic and in intercourse at home.

Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial

BACKGROUND Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. We therefore assessed the efficacy and safety of two doses of phentermine plus topiramate controlled-release combination as an adjunct to diet and lifestyle modification for weight loss and metabolic risk reduction in individuals who were overweight and obese, with two or more risk factors. METHODS In this 56-week phase 3 trial, we randomly assigned overweight or obese adults (aged 18-70 years), with a body-mass index of 27-45 kg/m(2) and two or more comorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity) to placebo, once-daily phentermine 7·5 mg plus topiramate 46·0 mg, or once-daily phentermine 15·0 mg plus topiramate 92·0 mg in a 2:1:2 ratio in 93 centres in the USA. Drugs were administered orally. Patients were randomly assigned by use of a computer-generated algorithm that was implemented through an interactive voice response system, and were stratified by sex and diabetic status. Investigators, patients, and study sponsors were masked to treatment. Primary endpoints were the percentage change in bodyweight and the proportion of patients achieving at least 5% weight loss. Analysis was by intention to treat. This study is registered with Clinical Trials.gov, number NCT00553787. FINDINGS Of 2487 patients, 994 were assigned to placebo, 498 to phentermine 7·5 mg plus topiramate 46·0 mg, and 995 to phentermine 15·0 mg plus topiramate 92·0 mg; 979, 488, and 981 patients, respectively, were analysed. At 56 weeks, change in bodyweight was -1·4 kg (least-squares mean -1·2%, 95% CI -1·8 to -0·7), -8·1 kg (-7·8%, -8·5 to -7·1; p<0·0001), and -10·2 kg (-9·8%, -10·4 to -9·3; p<0·0001) in the patients assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively. 204 (21%) patients achieved at least 5% weight loss with placebo, 303 (62%; odds ratio 6·3, 95% CI 4·9 to 8·0; p<0·0001) with phentermine 7·5 mg plus topiramate 46·0 mg, and 687 (70%; 9·0, 7·3 to 11·1; p<0·0001) with phentermine 15·0 mg plus topiramate 92·0 mg; for ≥10% weight loss, the corresponding numbers were 72 (7%), 182 (37%; 7·6, 5·6 to 10·2; p<0·0001), and 467 (48%; 11·7, 8·9 to 15·4; p<0·0001). The most common adverse events were dry mouth (24 [2%], 67 [13%], and 207 [21%] in the groups assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively), paraesthesia (20 [2%], 68 [14%], and 204 [21%], respectively), constipation (59 [6%], 75 [15%], and 173 [17%], respectively), insomnia (47 [5%], 29 [6%], and 102 [10%], respectively), dizziness (31 [3%], 36 [7%], 99 [10%], respectively), and dysgeusia (11 [1%], 37 [7%], and 103 [10%], respectively). 38 (4%) patients assigned to placebo, 19 (4%) to phentermine 7·5 mg plus topiramate 46·0 mg, and 73 (7%) to phentermine 15·0 mg plus topiramate 92·0 mg had depression-related adverse events; and 28 (3%), 24 (5%), and 77 (8%), respectively, had anxiety-related adverse events. INTERPRETATION The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors. FUNDING Vivus.

Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study

Background: Obesity is a serious chronic disease. Controlled-release phentermine/topiramate (PHEN/TPM CR), as an adjunct to lifestyle modification, has previously shown significant weight loss compared with placebo in a 56-wk study in overweight and obese subjects with ≥2 weight-related comorbidities. Objective: This study evaluated the long-term efficacy and safety of PHEN/TPM CR in overweight and obese subjects with cardiometabolic disease. Design: This was a placebo-controlled, double-blind, 52-wk extension study; volunteers at selected sites continued with original randomly assigned treatment [placebo, 7.5 mg phentermine/46 mg controlled-release topiramate (7.5/46), or 15 mg phentermine/92 mg controlled-release topiramate (15/92)] to complete a total of 108 wk. All subjects participated in a lifestyle-modification program. Results: Of 866 eligible subjects, 676 (78%) elected to continue in the extension. Overall, 84.0% of subjects completed the study, with similar completion rates between treatment groups. At week 108, PHEN/TPM CR was associated with significant, sustained weight loss (intent-to-treat with last observation carried forward; P < 0.0001 compared with placebo); least-squares mean percentage changes from baseline in body weight were –1.8%, –9.3%, and –10.5% for placebo, 7.5/46, and 15/92, respectively. Significantly more PHEN/TPM CR–treated subjects at each dose achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss compared with placebo (P < 0.001). PHEN/TPM CR improved cardiovascular and metabolic variables and decreased rates of incident diabetes in comparison with placebo. PHEN/TPM CR was well tolerated over 108 wk, with reduced rates of adverse events occurring between weeks 56 and 108 compared with rates between weeks 0 and 56. Conclusion: PHEN/TPM CR in conjunction with lifestyle modification may provide a well-tolerated and effective option for the sustained treatment of obesity complicated by cardiometabolic disease. This trial was registered at clinicaltrials.gov as NCT00796367.

Controlled‐Release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial (EQUIP)

A 56‐week randomized controlled trial was conducted to evaluate safety and efficacy of a controlled‐release combination of phentermine and topiramate (PHEN/TPM CR) for weight loss (WL) and metabolic improvements. Men and women with class II and III obesity (BMI ≥ 35 kg/m2) were randomized to placebo, PHEN/TPM CR 3.75/23 mg, or PHEN/TPM CR 15/92 mg, added to a reduced‐energy diet. Primary end points were percent WL and proportions of patients achieving 5% WL. Secondary end points included waist circumference (WC), systolic and diastolic blood pressure (BP), fasting glucose, and lipid measures. In the primary analysis (randomized patients with at least one postbaseline weight measurement who took at least one dose of assigned drug or placebo), patients in the placebo, 3.75/23, and 15/92 groups lost 1.6%, 5.1%, and 10.9% of baseline body weight (BW), respectively, at 56 weeks (P < 0.0001). In categorical analysis, 17.3% of placebo patients, 44.9% of 3.75/23 patients, and 66.7% of 15/92 patients, lost at least 5% of baseline BW at 56 weeks (P < 0.0001). The 15/92 group had significantly greater changes relative to placebo for WC, systolic and diastolic BP, fasting glucose, triglycerides, total cholesterol, low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL). The most common adverse events were paresthesia, dry mouth, constipation, dysgeusia, and insomnia. Dropout rate from the study was 47.1% for placebo patients, 39.0% for 3.75/23 patients, and 33.6% of 15/92 patients. PHEN/TPM CR demonstrated dose‐dependent effects on weight and metabolic variables in the direction expected to be beneficial with no evidence of serious adverse events induced by treatment.

Evaluation of phentermine and topiramate versus phentermine/topiramate extended‐release in obese adults

A 28‐week, randomized, controlled trial compared the combination of phentermine and topiramate extended‐release (PHEN/TPM ER) with its components as monotherapies and with placebo in obese adults.

Selectivity of Avanafil, a PDE5 Inhibitor for the Treatment of Erectile Dysfunction: Implications for Clinical Safety and Improved Tolerability

INTRODUCTION Phosphodiesterase type 5 (PDE5) inhibitors are indicated for the treatment of erectile dysfunction (ED); however, they can also inhibit other PDE isozymes, affecting their target tissues (e.g., PDE1: heart; PDE6: retina; and PDE11: skeletal muscle), which in some cases can cause unwanted side effects and therapy discontinuation. Data from in vitro studies showed that avanafil, a PDE5 inhibitor for the treatment of ED, exhibited strong selectivity toward PDE5 and against all other PDE isozymes. AIM To review the inhibitory effects of avanafil for PDE isozymes compared with those of sildenafil, tadalafil, and vardenafil and to discuss these results within the context of clinical trial safety observations. METHODS Review of in vitro selectivity data for avanafil (published primary data from a peer-reviewed journal and scientific congress abstracts); PubMed search for pertinent publications on PDE5 inhibitor safety data; and review of published articles and abstracts from avanafil phase 1, 2, and 3 clinical trials. MAIN OUTCOME MEASURES A low incidence of some PDE-related adverse events may be reflected by the high selectivity of avanafil against non-PDE5 isozymes. RESULTS Avanafil is highly selective toward PDE5 and against all other PDE isozymes tested. Lower selectivity against PDE1, PDE6, and PDE11 is consistent with results from randomized, placebo-controlled, phase 3 trials in which musculoskeletal and hemodynamic adverse events were reported in <2% of patients and no color vision-related abnormalities were reported with avanafil doses up to 200 mg once daily. CONCLUSIONS Data suggest that avanafil may confer a safety benefit, in terms of a lower incidence of specific adverse events, by virtue of its high specificity to PDE5 and its overall selectivity against other PDE isozymes.

Avanafil for the Treatment of Erectile Dysfunction: A Multicenter, Randomized, Double-Blind Study in Men With Diabetes Mellitus

OBJECTIVE To prospectively assess the safety and effectiveness of the investigational phosphodiesterase 5 inhibitor avanafil to treat erectile dysfunction in men with diabetes mellitus. PATIENTS AND METHODS This 12-week, multicenter, double-blind, placebo-controlled study conducted between December 15, 2008, and February 11, 2010, randomized 390 men with diabetes and erectile dysfunction 1:1:1 to receive avanafil, 100 mg (n=129), avanafil, 200 mg (n=131), or placebo (n=130). Coprimary end points assessed changes in the percentage of sexual attempts in which men were able to maintain an erection of sufficient duration to have successful intercourse (Sexual Encounter Profile [SEP] 3), percentage of sexual attempts in which men were able to insert the penis into the partners vagina (SEP 2), and International Index of Erectile Function erectile function domain score. RESULTS Compared with placebo, least-squares mean change from baseline to study end in SEP 3, SEP 2, and International Index of Erectile Function erectile function domain score were significantly improved with both avanafil, 100 mg (P≤.002), and avanafil, 200 mg (P<.001). Additional analyses indicated that successful intercourse could be initiated in 15 minutes or less through more than 6 hours after avanafil dosing. Adverse events most commonly reported with avanafil treatment were headache, nasopharyngitis, flushing, and sinus congestion. CONCLUSION Avanafil was safe and effective for treating erectile dysfunction in men with diabetes and was effective as early as 15 minutes and more than 6 hours after dosing. The adverse events seen with avanafil were similar to those seen with other phosphodiesterase 5 inhibitors. TRIAL REGISTRATION clinicaltrials.gov Identifier NCT00809471.

ERECTILE RESPONSE TO TRANSURETHRAL ALPROSTADIL, PRAZOSIN AND ALPROSTADIL-PRAZOSIN COMBINATIONS

PURPOSE Transurethral alprostadil has been shown to be efficacious in many men with erectile dysfunction. We compared transurethral alprostadil and prazosin alone, and in combination to treat this disorder. MATERIALS AND METHODS In this double-blind, placebo controlled study the erectile responses to transurethral alprostadil, prazosin and alprostadil-prazosin combinations were assessed in 234 men 26.8 to 81.5 years old with complete organic erectile dysfunction. Patients self-administered a random sequence of 7 doses in the clinic in 4 weeks. The erectile response was assessed using categorical and visual analog scales. RESULTS Full penile enlargement or rigidity was achieved by 165 of the 234 men (70.5%) after at least 1 active dose of medication. The most effective alprostadil dose (500 microg.) resulted in full penile enlargement or rigidity in 51.8% of administrations, whereas the most effective prazosin dose (2,000 microg.) and placebo resulted in a similar response in 12.7 and 2.7%, respectively (p <0.001). The 500/2,000 microg. alprostadil/prazosin combination, which resulted in full enlargement or rigidity in 58.9% of doses, was only slightly better than the most effective dose of alprostadil alone (500 microg.). However, combinations of 125/500 and 250/500 microg. alprostadil/prazosin were more effective (p <0.01) than 125 and 250 microg. alprostadil given alone, respectively. The most common side effect of therapy was penile pain, which rarely led to study discontinuation. Hypotension most commonly developed at the higher alprostadil-prazosin combination. CONCLUSIONS Transurethral alprostadil and alprostadil-prazosin combinations produced erections in men with complete organic erectile dysfunction. This combination therapy may be an option in patients who do not respond to transurethral alprostadil alone.

Low-dose estradiol spray to treat vasomotor symptoms: a randomized controlled trial.

OBJECTIVE: To investigate the safety and efficacy of a transdermal estradiol (E2) spray in women with postmenopausal vasomotor symptoms. METHOD: A randomized, double-blind, placebo-controlled, multicenter, parallel-group clinical trial was conducted. Postmenopausal women (N=454) with at least eight moderate-to-severe hot flushes per day applied daily, one, two, or three E2 (90 microliter spray contains 1.53 mg E2) or matching placebo sprays. The primary efficacy endpoints were mean change from baseline in frequency and severity of moderate-to-severe hot flushes at weeks 4 and 12. RESULTS: All three E2 groups showed a significant decrease in hot flushes at weeks 4 and 12 compared with their placebo groups (P<.010). The mean change in frequency at week 12 was eight fewer flushes per day for women in the E2 groups and between four and six fewer flushes for women in the placebo groups. Women in the three- and two-E2 spray groups demonstrated significant (P<.050) reductions in severity score at weeks 4 and 12; women in the one-spray group showed significant reductions at week 5. At week 12, the majority (74–85%) of women on E2 showed at least a 50% hot flush frequency reduction as compared with 46% in the placebo group. The systemic E2 delivery rates at week 12 were approximately 0.021 mg/d, 0.029 mg/d, and 0.040 mg/d for the one-, two-, and three-spray doses, respectively. Common adverse events were similar to those previously reported with other transdermal products. Treatment-related application site reaction rate was similar to placebo (1.3% compared with 1.8%). CONCLUSION: The three dose levels of E2 spray achieved efficacy at 0.021–0.040 mg/d delivery rates. The spray is a well-tolerated, new, convenient method of delivering low-dose E2 transdermally. Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00122200 LEVEL OF EVIDENCE: I

A phase II, single-blind, randomized, crossover evaluation of the safety and efficacy of avanafil using visual sexual stimulation in patients with mild to moderate erectile dysfunction.

Phosphoesterase type 5 inhibitors (PDE5is) are considered standard‐of‐care for the treatment of men with erectile dysfunction. Recommended administration of currently used PDE5is are between 60‐ to 120‐minutes before sexual activity. RigiScan® monitoring has been validated in previous clinical studies of PDE5 inhibitors. Using a highly objective measure of sexual function (RigiScan monitoring), data show that the onset of action of avanafil was rapid. Response to treatment with avanafil was associated most frequently with the earliest time interval tested (20–40 minutes after dosing), compared with sildenafil 50 mg (100 to 120 minutes after dosing). However, avanafil treatments showed some degree of efficacy across all time intervals tested (including 60–80 minutes and 100–120 minutes post‐dosing). These results were consistent with data from phase 3 trials which showed a rapid onset of action with avanafil (as early as 15 minutes) and a long duration of effect (up to 6 hours in some patients). Safety results were consistent with those reported in phase 3 trials, and showed that avanafil was well tolerated and adverse events were generally low and mild in severity.