Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial.

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.

Effects of expiratory muscle strength training on maximal respiratory pressure and swallow-related quality of life in individuals with multiple sclerosis.

BACKGROUND: Weakening and dyscoordination of expiratory muscles in multiple sclerosis (MS) can impair respiratory and swallow function. OBJECTIVE: The objective of this paper is to test a novel expiratory muscle strength training (EMST) device on expiratory pressure, swallow function, and swallow-related quality-of-life (SWAL-QOL) in individuals with MS. METHODS: Participants with MS were randomized to a five-week breathing practice of either positive pressure load (EMST) or near-zero pressure (sham). We compared baseline to post-treatment data according to maximum expiratory pressure (MEP), abnormal airway penetration and aspiration (PAS), and SWAL-QOL. RESULTS: Both groups improved in MEP (p < 0.001). Forty percent of the EMST group improved on PAS, and 15% worsened; conversely, 21.4% of the sham group worsened and 14.3% improved. There was no group difference in overall SWAL-QOL; but the EMST group had significantly greater gain versus sham on the Burden (p = 0.014) and Pharyngeal Swallow (p = 0.022) domains. Both groups improved in SWAL-QOL domains of Fear, Burden Mental Health, but only the EMST group improved in the SWAL-QOL and domains of Pharyngeal Swallow function, and Saliva management. CONCLUSION: Results suggest that strengthening of expiratory muscles can occur with repetition of focused breathing practice in the absence of high resistance. Conversely, results from the PAS and SWAL-QOL domains suggest that the high resistance of the EMST was required in order to improve the functional safety (reduced penetration/aspiration) and coordination of swallowing, specifically pharyngeal function and saliva management.

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation.

BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.

Measurement of Voluntary Cough Production and Airway Protection in Parkinson Disease.

OBJECTIVE: To examine relations between peak expiratory (cough) airflow rate and swallowing symptom severity in participants with Parkinson disease (PD). DESIGN: Cross-sectional study. SETTING: Outpatient radiology clinic at an acute care hospital. PARTICIPANTS: Men and women with PD (N=68). INTERVENTIONS: Participants were cued to cough into an analog peak flow meter then swallowed three 20-mL thin liquid barium boluses. Analyses were directed at detecting potential relations among disease severity, swallowing symptom severity, and peak expiratory (cough) airflow rate. MAIN OUTCOME MEASURES: Peak expiratory (cough) airflow rate and swallow symptom severity. RESULTS: Peak expiratory (cough) airflow rate varied significantly across swallowing severity classifications. Participants with more severe disease displayed a significant, linear decrease in peak expiratory (cough) airflow rate than those participants with earlier stage, less severe disease. Swallowing symptom severity varied significantly across groups when comparing participants with less severe PD with those with more severe PD. Participants with early stage PD demonstrated little to no swallowing symptoms and had the highest measures of peak expiratory (cough) airflow rate. In contrast, participants with the most severe swallowing symptoms also displayed the lowest measures of peak expiratory (cough) airflow rate. CONCLUSIONS: Relations existed among PD severity, swallowing symptom severity, and peak expiratory (cough) airflow rate in participants with PD. Peak expiratory (cough) airflow rate may eventually stand as a noninvasive predictor of aspiration risk in those with PD, particularly those with later stage disease. Inclusion of peak expiratory (cough) airflow rates into existing clinical swallowing assessments may increase the sensitivity and predictive validity of these assessments.

Long-term, multicenter study of the safety and efficacy of topical alprostadil cream in male patients with erectile dysfunction.

INTRODUCTION: Alprostadil is approved for treatment of male erectile dysfunction (ED) by injection or urethral insertion. Topical delivery of alprostadil offers an improved alternative. AIM: To evaluate the long-term safety and efficacy of topical alprostadil cream. METHODS: This was a multicenter, open-label, long-term study in 1,161 patients (998 double-blind rollover; 163 naïve) with ED. For the first 4 weeks, patients could administer eight doses of 200 mcg alprostadil to the penis meatus before intercourse (up to 2 per/week). Patients then self-selected to administer 300 or 100 mcg doses if hypo-responsive or hyper-responsive, respectively, or 200 mcg if no change, for up to 9 months (2 doses/week). MAIN OUTCOME MEASURES: Safety evaluated patient/partner adverse events (AEs), changes in vital signs, clinical laboratory tests, physical examinations, and electrocardiograms. Efficacy assessed International Index of Erectile Function, Sexual Encounter Profile, Patient Self Assessment of Erection, and Global Assessment Questionnaire. RESULTS: Approximately 12% of patients discontinued due to hypo-/hyper-responsiveness, 16% withdrew consent for a variety of reasons, and less than 5% discontinued because of AEs. The majority of patients (73%) selected 300 mcg alprostadil as the final dose. The most common AEs involved application site burning or erythema (12.2%), meatal or glans pain (4.4%), and prolonged or painful erection (1.3%). Only 5 (0.4%) patients reported a prolonged erection of >or=4 hours (priapism). Vaginal burning or itching (2.1%) was reported most frequently by partners. The majority of patients (74%) demonstrated an overall improvement in erectile function on most end-points, especially after adjusting dose strength to their individual responsiveness. CONCLUSIONS: Topical alprostadil cream was considered effective and safe by most patients and their partners, with most AEs limited to the application site. Dose adjustment to 300 mcg alprostadil facilitated the greatest improvement in erectile function in the majority of patients. A separate report will integrate patient data from the open-label extension and prior double-blind studies.

An integrated analysis of alprostadil topical cream for the treatment of erectile dysfunction in 1732 patients.

OBJECTIVE: To assess the safety and efficacy of topical alprostadil cream for erectile dysfunction (ED). METHODS: Patients with an ED score of 25 or less on the erectile function domain of the International Index of Erectile Function (IIEF) were randomly assigned to placebo or topical alprostadil cream (100, 200, or 300 microg) for at-home use for 12 weeks in two multicenter, double-blind, parallel-group studies. Patients receiving organic nitrates and patients with diabetes were included. Primary end points included the change in score for the erectile function domain of the IIEF and the change from baseline for the Sexual Encounter Profile (SEP) questions 2 (vaginal penetration success) and 3 (maintenance of erection to ejaculation). Safety was based on observed and reported adverse events and clinical laboratory results. Data from each study were pooled into a single integrated analysis. RESULTS: A total of 1732 patients received placebo (n = 434) or topical alprostadil cream at 100 microg (n = 434), 200 microg (n = 430), or 300 microg (n = 434). The mean changes from baseline to end point in IIEF erectile function (EF) domain scores were -0.7, 1.6, 2.5, and 2.4 points for each group, respectively (P <0.001). Scores on SEP questions 2 and 3 improved slightly but significantly for all drug treatment groups compared with placebo (P <0.001). Most adverse events were localized to the application site and resolved within 2 hours. CONCLUSIONS: Topical alprostadil cream significantly improves ED in a broad range of patients. Most adverse events were limited to the application site and were generally well tolerated.

Efficacy and safety of topical alprostadil cream for the treatment of female sexual arousal disorder (FSAD): a double-blind, multicenter, randomized, and placebo-controlled clinical trial.

We evaluated the efficacy and safety of three doses of a novel alprostadil cream in a randomized, double-blind, placebo-controlled study in 94 women presenting with female sexual arousal disorder of at least 6 month s duration. We sent the subjects home with 10 premeasured doses of 500 g, 1000 g, or 1500 g alprostadil or a placebo cream to be applied to the vulvar area prior to vaginal intercourse over a period of 6 weeks. The primary efficacy parameter, the arousal success rate (as measured by diary responses to the Female Sexual Encounter Profile [FSEP]), was highest in the alprostadil 1000 g group and lowest in the 500 g group, but the responses were not different from that of the placebo cream, at the p = 0.05 level, for any of the three alprostadil doses. However, the change from baseline for Item 6 of the Female Sexual Function Index (FSFI; Rosen et al., 2000; satisfaction with arousal during sexual activity) suggested an important dose-related trend (p = 0.173; 1500 g versus placebo). The mean percent responder rate (responder = > 50% arousal success rate with > 3 sexual attempts) suggested a dose-response effect (p = 0.157; 1500 g versus placebo). Adverse events were generally mild or moderate in intensity and mainly involved localized reactions in the genital area.

Topical alprostadil cream for the treatment of erectile dysfunction: a combined analysis of the phase II program.

OBJECTIVES: To present a meta-analysis of the efficacy and safety data of two recently completed Phase II studies examining a novel alprostadil topical cream for the treatment of erectile dysfunction (ED). METHODS: Patients (n = 303) with ED of at least 3 months' duration were randomized to receive placebo or 50, 100, 200, or 300 microg alprostadil in two nearly identical 11-dose, multicenter, at-home studies of a novel topical cream containing alprostadil and a proprietary skin permeation enhancer. The primary efficacy endpoint was the change in erectile function domain score from baseline to the final visit. Secondary endpoints included changes in scores for questions 3 and 4 of the International Index of Erectile Function and standard diary analyses. Safety was assessed by analysis of adverse events, changes in laboratory test results, and physical examination findings. RESULTS: The mean baseline parameters for the erectile function score, ED history, and secondary diagnoses suggested no significant differences among the treatment groups. The changes from baseline to the final visit erectile function scores were 0.98 +/- 0.84, 3.4 +/- 1.3, 3.4 +/- 0.88 (P <0.05), 5.3 +/- 0.92 (P <0.001), and 9.4 +/- 1.43 (P <0.001) for the ascending dose groups. Most secondary efficacy endpoints were significant for the 200 and 300-microg dose groups. Dose-related trends in efficacy were observed. Adverse events were localized to the application site, were of mild or moderate intensity, and were of short duration. CONCLUSIONS: These results suggest topical alprostadil cream, when combined with a novel dermal permeation-enhancer, to be a potentially useful agent for the treatment of ED.