Effects of phentermine / topiramate extended-release, phentermine, and placebo on ambulatory blood pressure monitoring in adults with overweight or obesity: A randomized, multicenter, double-blind study.

Background: A fixed-dose combination of phentermine and extended-release topiramate (PHEN/TPM - approved for weight management) has demonstrated in-clinic reduction of blood pressure (BP). Ambulatory BP monitoring (ABPM) may be a better predictor of cardiovascular disease risk than in-clinic BP. Methods: This randomized, multicenter, double-blind study enrolled 565 adults with overweight/obesity. Inclusion criteria included participants willing to wear ABPM device for 24 h. Exclusion criteria included screening blood pressure >140/90 mmHg and antihypertensive medications not stable for 3 months prior to randomization. Participants received placebo (n = 184), phentermine 30 mg; (n = 191), or PHEN 15 mg/TPM 92 mg; (n = 190). 24-hour ABPM was performed at baseline and at week 8. The primary endpoint was mean 24-h systolic BP (SBP) as measured by ABPM, in the per protocol population. Results: Participants were mostly female (73.5 â€‹%) and White (81.6 â€‹%), with a mean age of 53.4 years; 32.4 â€‹% had no hypertension diagnosis or treatment, 62.5 â€‹% had hypertension using 0 to 2 antihypertensive medications, and 5.1 â€‹% had hypertension using ≥ 3 antihypertensive medications. Baseline mean SBP/diastolic BP (DBP) was 123.9/77.6 â€‹mmHg. At week 8, mean SBP change was -0.1 â€‹mmHg (placebo), +1.4 â€‹mmHg (phentermine 30 â€‹mg), and -3.3 â€‹mmHg (PHEN/TPM). Between-group difference for PHEN/TPM versus placebo was -3.2 â€‹mmHg (95 â€‹% CI: -5.48, -0.93 â€‹mmHg; p â€‹= â€‹0.0059). The between-group difference for PHEN/TPM versus phentermine 30 â€‹mg was -4.7 â€‹mmHg (95 â€‹% CI: -6.96, -2.45 â€‹mmHg; p â€‹< â€‹0.0001). Common (>2 â€‹% in any treatment group) adverse events (i.e., dry mouth, constipation, nausea, dizziness, paresthesia, dysgeusia, headache, COVID-19, urinary tract infection, insomnia, and anxiety) were mostly mild or moderate. Conclusions: In this randomized, multicenter, double-blind ABPM study, PHEN/ TPM reduced SBP compared to either placebo or phentermine 30 mg (Funding: Vivus LLC; ClinicalTrials.gov: NCT05215418).

Health-related quality of life in two randomized controlled trials of phentermine/topiramate for obesity: What mediates improvement?

PURPOSE: Phentermine/topiramate combination therapy resulted in significant weight loss and improvements in cardiometabolic risk factors in patients with obesity/overweight in two published 56-week randomized, placebo-controlled trials (EQUIP and CONQUER). The purpose of the current study was to examine whether phentermine/topiramate is also associated with greater improvements in health-related quality of life (HRQOL) and whether HRQOL improvements are solely attributable to weight reduction. METHODS: Patients in EQUIP (n = 751) had a body mass index (BMI) ≥ 35 with no obesity-related comorbidity. Patients in CONQUER (n = 1623) had a BMI ≥ 27 and ≤ 45 and at least two obesity-related comorbid conditions. HRQOL was assessed with Impact of Weight on Quality of Life-Lite (IWQOL-Lite) and Medical Outcomes Study Short Form (SF-36) (CONQUER only). RESULTS: Significant improvements in both obesity-specific and physical HRQOL were observed at 56 weeks in both trials (p < .0001). In EQUIP, BMI reduction fully mediated improvements in IWQOL-Lite total score (p < .0001). In CONQUER, both BMI reduction (all p values < .0001) and change in depressive symptoms (all p values < .025) were significant mediators of improved IWQOL-Lite total score and SF-36 Physical Component Summary score. Gender, psychiatric history, and baseline triglycerides moderated these relationships. CONCLUSIONS: Both trials demonstrated that treatment with phentermine/topiramate improved HRQOL compared with placebo. Although reduction in BMI accounted for the majority of improvements in obesity-specific and physical HRQOL, decrease in depressive symptoms was also a significant mediator. Results highlight the predominance of weight reduction as a key factor in improving HRQOL in obesity.

Efficacy of Avanafil 15 Minutes after Dosing in Men with Erectile Dysfunction: A Randomized, Double-Blind, Placebo Controlled Study.

PURPOSE: We examined the therapeutic effects of avanafil 15 minutes after dosing in men with mild to severe erectile dysfunction. MATERIALS AND METHODS: This randomized, double-blind, placebo controlled, 12-week study (4-week run-in and 8-week treatment) randomized 145 men to placebo, 147 to avanafil 100 mg and 148 to avanafil 200 mg on demand. The primary efficacy variable was the per subject proportion of sexual attempts during the treatment period in which subjects achieved erection sufficient for vaginal penetration within approximately 15 minutes after dosing as measured by a stopwatch. The attempt had to enable successful completion of sexual intercourse according to SEP question 3. RESULTS: Significantly greater mean per subject percentages of successful intercourse attempts within approximately 15 minutes after dosing were observed for avanafil 100 mg (mean 25.9%, LS mean ± SE 24.7% ± 2.9%) and 200 mg (mean 29.1%, LS mean 28.2% ± 2.9%) vs placebo (mean 14.9%, LS mean 13.8% ± 2.9%, p = 0.001 and <0.001, respectively). After treatment we noted a statistically significant difference between avanafil and placebo in the average per subject proportion of successful intercourse attempts according to SEP question 3 as early as 10 minutes in the 200 mg group and 12 minutes in the 100 mg group. Treatment emergent adverse events included headache, upper respiratory tract infection and nasal congestion, and most such events were mild or moderate in severity. CONCLUSIONS: Avanafil was efficacious within approximately 15 minutes of dosing compared to placebo. A statistically significant treatment difference in the percentage of successful sexual attempts was demonstrated as early as 10 minutes after treatment.

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.

OBJECTIVE: To evaluate the safety, efficacy and time course of three doses of avanafil (50 mg, 100 mg and 200 mg) compared with sildenafil 50 mg or placebo, given in conjunction with visual sexual stimulation (VSS) videos in men with mild to moderate erectile dysfunction (ED). PATIENTS AND METHODS: Male patients, 35-70 years of age, with mild to moderate ED of ≥6 months duration, were included in the study. During the course of the study, each patient received placebo, active control (sildenafil 50 mg), and one dose of avanafil (50 mg, 100 mg or 200 mg), all administered in random order at least 72 h apart. RigiScan® (Dacomed Corp., Minneapolis, MN, USA) monitoring was used in conjunction with 20-min VSS videos (20, 60, and 100 min after dosing) to determine the duration of and time to ≥60% penile rigidity, maximum rigidity, tumescent activity units (TAUs), rigidity activity units (RAUs), and responses to the five-point Erection Assessment Scale. Safety assessments included adverse events (AEs), vital sign changes in response to dosing, laboratory results (complete blood counts, chemistry panel, prostate-specific antigen, serum testosterone, prothrombin time and urine analysis) and physical examination findings. RESULTS: Eighty-three patients were randomized and received at least one dose of study medication; 82 patients completed the study. Peak response to avanafil occurred in the early interval (20-40 min after dosing), while peak response to sildenafil occurred either in the middle (60-80 min) or late (100-120 min) intervals after dosing. Results were qualitatively similar for all other efficacy endpoints. During the 20-40-min interval, the majority of values for TAUs and RAUs with the avanafil 50-mg, 100-mg and 200-mg treatments were significantly superior to placebo (P < 0.05). Avanafil treatment was generally well tolerated; facial flushing (7-15%) was the most commonly observed AE, and no visual disturbances were reported. CONCLUSION: A favourable safety profile and improvement in sexual function, coupled with rapid onset of action and durability of effect, make avanafil an attractive option for males with ED, especially in the setting of on-demand treatment.

Hemodynamic effect of avanafil and glyceryl trinitrate coadministration.

A Phase I, double-blind, randomized, crossover study in healthy males (N=106) was conducted between March 21, 2004, and May 17, 2004, to determine the magnitude and duration of the hemodynamic interaction of avanafil (a phosphodiesterase type-5 inhibitor for treating males with erectile dysfunction) when coadministered with glyceryl trinitrate (NTG) compared with sildenafil and placebo. Subjects received avanafil (200 mg), sildenafil (100 mg), and placebo (on separate days) via the oral route followed by NTG (0.4 mg) 12, 8, 4, 1, or 0.5 hours post-dose via the sublingual route. Blood pressure (BP) and heart rate (HR) were assessed at defined intervals. Throughout the study (after administration of the study drug, and including the period after NTG administration), the effects of avanafil and sildenafil on BP and HR were significantly greatest overall, at the shortest (0.5-hour) time interval compared with placebo. By the 8- and 12-hour time intervals, no significant difference in BP or HR was observed for avanafil (8 and 12 hours) or sildenafil (12 hours) (p>0.05, compared with placebo). Compared with avanafil, sildenafil had a significantly greater effect when dosed 0.5 hours before NTG on standing HR (p=0.05); 1 hour before NTG on standing systolic blood pressure (SBP) (p<0.05), sitting SBP (p=0.01) and standing HR (p<0.01); and 12 hours before NTG on standing SBP (p=0.05). Throughout the study, symptomatic hypotension adverse events occurred in 27%, 29%, and 12%, and clinically significant reductions in standing SBP (≥30 mmHg) occurred in 15%, 29%, and 12% of subjects dosed with avanafil, sildenafil, and placebo, respectively (overall treatment differences: p<0.01 and p<0.05, respectively). These data show that avanafil and sildenafil have no significant effect on BP and HR if administered to healthy males ≥8 hours (avanafil) or ≥12 hours (sildenafil) before a sublingual dose of NTG. However, results may differ in populations with known vascular disease, especially those using other concurrent pharmacotherapy. These findings may be of interest to clinicians who treat patients with erectile dysfunction and who also have a cardiovascular condition. Of note, the applicability of these results in such patients may be limited because the enrollment comprised healthy, normal subjects.

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 partner's 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.

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.

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/m(2)) 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.

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.

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.

The effects of skin-to-skin contact, application site washing, and sunscreen use on the pharmacokinetics of estradiol from a metered-dose transdermal spray.

OBJECTIVE: This study evaluated the transfer of estradiol by skin-to-skin contact and the influence of washing and sunscreen use on the absorption of estradiol from a transdermal spray. DESIGN: Studies were conducted in the same group of 20 healthy postmenopausal women over a period of 18 days. The women were dosed with three sprays of study medication once daily (a total daily dose of 4.59 mg). To evaluate skin-to-skin transfer, estradiol levels in 20 untreated men were evaluated before and after direct skin-to-skin contact with the application sites of 20 treated women after application of study medication on study days 1 to 3. To examine the effect of washing the application site, estradiol absorption was evaluated when the application site was washed 1 hour after application compared with the unwashed site on study days 10 to 12. To examine the effects of sunscreen use, estradiol pharmacokinetic profiles were evaluated when sunscreen was applied before and after study drug application on study days 14 to 17. RESULTS: The 90% CI of the ratios of the areas under the serum estradiol-time curves (AUC0-24) in untreated men before and after contact with treated women was 1.00 to 1.07, which was within the prespecified equivalence range (0.8-1.25). The 90% CI of the AUC0-24 ratios with and without application site washing was 0.92 to 1.15. Application of sunscreen 1 hour after study drug resulted in a 90% CI of AUC0-24 ratios of 0.76 to 1.08. Application of sunscreen 1 hour before study drug resulted in a 90% CI of AUC0-24 ratios of 0.86 to 1.23. CONCLUSIONS: The use of a transdermal estradiol spray did not result in a significant transfer of estradiol by skin-to-skin contact. Washing the application site did not significantly affect absorption of estradiol. Estradiol absorption was slightly decreased due to the application of sunscreen after study drug application, but was unaffected when sunscreen was applied before study drug.