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1.
J Neurodev Disord ; 16(1): 22, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38671361

ABSTRACT

BACKGROUND: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602. METHODS: To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0-36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP). RESULTS: Relative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants. CONCLUSION: Long-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families. TRIAL REGISTRATION: Clinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).


Subject(s)
Delayed-Action Preparations , Diazoxide , Hyperphagia , Prader-Willi Syndrome , Humans , Prader-Willi Syndrome/complications , Prader-Willi Syndrome/drug therapy , Female , Male , Hyperphagia/drug therapy , Hyperphagia/etiology , Child , Adult , Adolescent , Diazoxide/administration & dosage , Diazoxide/pharmacology , Young Adult , Child, Preschool , Cohort Studies
2.
Obesity (Silver Spring) ; 32(2): 252-261, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37919617

ABSTRACT

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.


Subject(s)
Prader-Willi Syndrome , Humans , Child, Preschool , Prader-Willi Syndrome/drug therapy , Prader-Willi Syndrome/complications , Diazoxide/pharmacology , Diazoxide/therapeutic use , Hyperphagia/complications , Body Composition , Insulin/therapeutic use
3.
Ann Allergy Asthma Immunol ; 107(4): 364-70, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21962098

ABSTRACT

BACKGROUND: Brief nasal carbon dioxide insufflation has previously been shown to provide rapid relief of the symptoms of allergic rhinitis. OBJECTIVE: To examine the safety and efficacy of nasal carbon dioxide on the symptoms of perennial allergic rhinitis. METHODS: This was a randomized, double-blind, placebo-controlled, multicenter, in-clinic study that evaluated 2 flow rates (5 or 10 mL/s) and 2 administration durations (10 or 30 seconds per nostril) for nasal carbon dioxide vs placebo. Study participants rated their symptoms in clinic for 4 hours after administration and then through 24 hours outside the clinic. A total of 348 symptomatic patients with a minimum 2-year history of perennial allergic rhinitis requiring pharmacotherapy were randomized and treated. RESULTS: The mean change in total nasal symptom score from baseline at 30 minutes (the primary end point) showed greater improvement in the nasal carbon dioxide-treated groups compared with placebo. This change was statistically significant in the group treated with 10 mL/s for 10 seconds per nostril: -4.69 carbon dioxide vs -2.00 placebo (P = .03). The effect of a single dose lasted approximately 4 to 6 hours. The mean change from baseline at 30 minutes in total nonnasal symptom score was also statistically significant (-4.06 carbon dioxide vs -2.25 placebo, P = .029) for this group. The most common adverse events were nasal discomfort, lacrimation, and headache. CONCLUSION: The study provides further evidence that nasal carbon dioxide is a potentially efficacious treatment for the symptoms of allergic rhinitis.


Subject(s)
Carbon Dioxide/administration & dosage , Rhinitis, Allergic, Perennial/drug therapy , Administration, Inhalation , Adolescent , Adult , Aged , Double-Blind Method , Female , Humans , Male , Middle Aged , Young Adult
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