Maladaptive behaviors in individuals with Angelman syndrome.

Maladaptive behaviors are challenging and a source of stress for caregivers of individuals with Angelman Syndrome (AS). There is limited information on how these maladaptive behaviors vary over time among individuals with AS due to different genetic etiologies. In this study, caregivers of 301 individuals with AS were asked questions about their child's behavior and completed the Aberrant Behavior Checklist-Community version (ABC-C). Developmental functioning was evaluated with either the Bayley Scales of Infant Development, Third Edition (Bayley-III) or the Mullen Scales of Early Learning (MSEL). Family functioning was assessed using the parent-completed Parenting Stress Index (PSI) and the Family Quality of Life questionnaire (FQoL). Approximately 70% of participants had AS due to a deletion on the maternally-inherited copy of chromosome 15q11q13. Results revealed that at baseline, individuals with AS had low scores in the domains of lethargy (mean: 2.6-4.2 depending on genotype) and stereotypy (mean: 2.3-4.2 depending on genotype). Higher cognitive functioning was associated with increased irritability (r = 0.32, p < .01). Hyperactivity (p < .05) and irritability (p < .05) increased with age across all genotypes and should be ongoing targets for both behavioral and pharmacological treatment. Concerns for short attention span were endorsed by more than 70% of caregivers at baseline. Maladaptive behaviors, particularly hyperactivity, irritability and aggression, adversely affected parental stress, and family quality of life.

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS.

BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

Neuropsychological endpoints for clinical trials in methylmalonic acidemia and propionic acidemia: A pilot study.

Introduction: This pilot study assessed instruments measuring relatively discrete neuropsychological domains to inform the selection of clinical outcome assessments that may be considered for interventional trials in methylmalonic acidemia (MMA) and propionic acidemia (PA). Methods: Tests and questionnaires were selected for their possible relevance to MMA and PA and potential sensitivity to modest changes in functioning and behavior. Results: Twenty-one patients (<18 years, n = 10;>18 years, n = 11) and/or their caregivers responded to video interviews and paper tests. Language deficits and significant motor deficits in some participants impacted scoring, especially in the verbal and processing speed sections of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) and the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV). However, all participants ≥12 years of age were able to complete the Cookie Theft Picture Task. Thus, verbal discourse remains a potentially useful endpoint for participants in this age group. The Vineland Adaptive Behavior Scales (VABS-3) Adaptive Behavior Composite and Communication Scores confirmed delayed or immature functioning in day-to-day activities in these participants. Significant motor deficits prevented completion of some tests. Computerized processing speed tasks, which require pressing a button or tapping a computer screen, may be easier than writing or checking off boxes on paper in this cohort. Sleep characteristics among MMA participants were within normative ranges of the Child and Adolescent Sleep Checklist (CASC), indicating that this measurement would not provide valuable data in a clinical trial. Despite their challenges, responses to the Metabolic Quality of Life Questionnaire indicated these patients and their caregivers perceive an overall high quality of life. Conclusion: Overall, test and questionnaire results were notably different between participants with MMA and participants with PA. The study demonstrates that pilot studies can detect instruments that may not be appropriate for individuals with language or motor deficits and that may not provide a broad range of scores reflecting disease severity. It also provides a rationale for focusing on discrete neuropsychological domains since some aspects of functioning were less affected than others and some were more closely related to disease severity. When global measures are used, overall scores may mask specific deficits. A pilot study like this one cannot ensure that scores will change over time in response to a specific treatment in a clinical trial. However, it can avert the selection of instruments that do not show associations with severity or biomedical parameters likely to be the target of a clinical trial. A pilot study can also identify when differences in diagnoses and baseline functioning need to be addressed prior to developing the analytical plan for the trial.

Predictors of Treatment Response to Tesamorelin, a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat.

BACKGROUND: Tesamorelin, a synthetic analog of human growth hormone-releasing factor, decreases visceral adipose tissue (VAT) in human immunodeficiency virus (HIV)-infected patients with lipodystrophy. OBJECTIVES: 1) To evaluate the utility of patient characteristics and validated disease-risk scores, namely indicator variables for the metabolic syndrome defined by the International Diabetes Federation (MetS-IDF) or the National Cholesterol Education Program (MetS-NCEP) and the Framingham Risk Score (FRS), as predictors of VAT reduction during tesamorelin therapy at 3 and 6 months, and 2) To explore the characteristics of patients who reached a threshold of VAT <140 cm2, a level associated with lower risk of adverse health outcomes, after 6 months of treatment with tesamorelin. METHODS: Data were analyzed from two Phase 3 studies in which HIV-infected patients with excess abdominal fat were randomized in a 2:1 ratio to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) subcutaneously daily for 6 months, using ANOVA and ANCOVA models. RESULTS: Metabolic syndrome (MetS-IDF or MetS-NCEP) and FRS were significantly associated with VAT at baseline. Presence of metabolic syndrome ([MetS-NCEP), triglyceride levels >1.7 mmol/L, and white race had a significant impact on likelihood of response to tesamorelin after 6 months of therapy (interaction p-values 0.054, 0.063, and 0.025, respectively). No predictive factors were identified at 3 months. The odds of a VAT reduction to <140 cm2 for subjects treated with tesamorelin was 3.9 times greater than that of subjects randomized to placebo after controlling for study, gender, baseline body mass index (BMI) and baseline VAT (95% confidence interval [CI] 2.03; 7.44). CONCLUSIONS: Individuals with baseline MetS-NCEP, elevated triglyceride levels, or white race were most likely to experience reductions in VAT after 6 months of tesamorelin treatment. The odds of response of VAT <140 cm2 was 3.9 times greater for tesamorelin-treated patients than that of patients receiving placebo.

Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3-month randomized controlled study.

BACKGROUND: A controlled-release (CR) formulation of zileuton was developed to simplify administration from 600 mg 4 times daily (Zyflo) to 1,200 mg twice daily. OBJECTIVE: To evaluate the efficacy of zileuton CR, two 600-mg tablets twice daily, compared with placebo. METHODS: Patients with moderate asthma treated with short-acting beta-agonists only were randomized to receive zileuton CR, 1,200 mg twice daily (n = 206); placebo CR, twice daily (n = 203); zileuton immediate-release (IR), 600 mg 4 times daily (n = 101); or placebo IR, 4 times daily (n = 103), for 12 weeks. The primary efficacy variable was change from baseline in morning trough forced expiratory volume in 1 second (FEV1). RESULTS: Improvement in trough FEV1 was observed after 2 weeks of treatment (P = .001) and was maintained throughout the study. After 12 weeks of dosing, FEV1 improved by a mean of 0.39 L (20.8%) in the zileuton CR group vs 0.27 L (12.7%) in the placebo CR group (P = .02). A significant decline in beta-agonist use and a smaller proportion of patients reporting asthma exacerbations were observed in the zileuton CR group vs the placebo CR group. Adverse event profiles were similar across treatment groups. Elevations in alanine aminotransferase levels at least 3 times the upper limit of normal that reversed after drug withdrawal were seen in 5 zileuton CR-treated patients (2.5%) vs 1 placebo CR-treated patient (0.5%). CONCLUSIONS: Treatment with zileuton CR, 1,200 mg twice daily, resulted in a significant improvement in asthma control, and the safety and efficacy profile was similar to that observed with zileuton IR, 600 mg 4 times daily (Zyflo).