Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Design of Two Phase III Studies (SIGN Trials).
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ABSTRACT:
SUBMITTER: Crutel V
PROVIDER: S-EPMC8254707 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC8496673 | biostudies-literature
Project description:In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl-)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3-11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2-18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily.
| S-EPMC5416661 | biostudies-literature
Project description:Bumetanide has been reported to alter synaptic excitation-inhibition (E-I) balance by potentiating the action of ?-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5?mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (?-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score???3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.
| S-EPMC7026137 | biostudies-literature
Project description:Bumetanide, a drug being studied in autism spectrum disorder (ASD) may act to restore gamma-aminobutyric acid (GABA) function, which may be modulated by the immune system. However, the interaction between bumetanide and the immune system remains unclear. Seventy-nine children with ASD were analysed from a longitudinal sample for a 3-month treatment of bumetanide. The covariation between symptom improvements and cytokine changes was calculated and validated by sparse canonical correlation analysis. Response patterns to bumetanide were revealed by clustering analysis. Five classifiers were used to test whether including the baseline information of cytokines could improve the prediction of the response patterns using an independent test sample. An immuno-behavioural covariation was identified between symptom improvements in the Childhood Autism Rating Scale (CARS) and the cytokine changes among interferon (IFN)-γ, monokine induced by gamma interferon and IFN-α2. Using this covariation, three groups with distinct response patterns to bumetanide were detected, including the best (21.5%, n = 17; Hedge's g of improvement in CARS = 2.16), the least (22.8%, n = 18; g = 1.02) and the medium (55.7%, n = 44; g = 1.42) responding groups. Including the cytokine levels significantly improved the prediction of the best responding group before treatment (the best area under the curve, AUC = 0.832) compared with the model without the cytokine levels (95% confidence interval of the improvement in AUC was [0.287, 0.319]). Cytokine measurements can help in identifying possible responders to bumetanide in ASD children, suggesting that immune responses may interact with the mechanism of action of bumetanide to enhance the GABA function in ASD.
| S-EPMC9166783 | biostudies-literature
Project description:This study evaluated the parental perception of the oral health-related quality of life (OHRQoL) of children and adolescents with autism spectrum disorder (ASD) and their family functioning. Moreover, sociodemographic factors associated with parental ratings of OHRQoL were assessed. A hundred parents/guardians of children and adolescents aged 6 to 14 years with ASD (ASD group) and 101 unaffected children and adolescents (UCA group) participated. Data collection was carried out using a Google form, containing three sections: (1st) Socioeconomic data and health history; (2nd) Oral health assessment by parental report; (3rd) The short forms of the Parental-Caregiver Perceptions Questionnaire (16-P-CPQ) and the Family Impact Scale (4-FIS). The scores of 16-P-CPQ total and subscales and 4-FIS were significantly higher for the ASD group (p < 0.02), except for the oral symptoms subscale (p > 0.05). Older ages (OR = 1.24), brushing 0/1x day (OR = 2.21), teeth grinding (OR = 2.20), gingival bleeding (OR = 3.34), parents with an elementary school degree (OR = 0.314) and family incomes less or equal to the minimum wage (OR = 3.049) were associated with a worse OHRQoL. Parents in the ASD group had a worse perception of QHRQoL when compared to the UCA group. 'Frequency of tooth brushing', 'gingival bleeding', and 'teeth grinding' were predictors of the worst parental perception of their children's OHRQoL. Families with low socioeconomic conditions were more strongly affected by the oral conditions of their children.
| S-EPMC9859466 | biostudies-literature
Project description:We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli. In keeping with clinical trials, our data support the Excitatory/Inhibitory dysfunction hypothesis in autism, and indicate that bumetanide may improve specific aspects of social processing in autism. Future double-blind placebo controlled studies with larger cohorts of participants will help clarify the mechanisms of bumetanide action in autism.
| S-EPMC5827728 | biostudies-literature
Project description:We present the secondary-analysis of neurocognitive tests in the 'Bumetanide in Autism Medication and Biomarker' (BAMBI;EUDRA-CT-2014-001560-35) study, a randomized double-blind placebo-controlled (1:1) trial testing 3-months bumetanide treatment (≤ 1 mg twice-daily) in unmedicated children 7-15 years with ASD. Children with IQ ≥ 70 were analyzed for baseline deficits and treatment-effects on the intention-to-treat-population with generalized-linear-models, principal component analysis and network analysis. Ninety-two children were allocated to treatment and 83 eligible for analyses. Heterogeneous neurocognitive impairments were found that were unaffected by bumetanide treatment. Network analysis showed higher modularity after treatment (mean difference:-0.165, 95%CI:-0.317 to - 0.013,p = .034) and changes in the relative importance of response inhibition in the neurocognitive network (mean difference:-0.037, 95%CI:-0.073 to - 0.001,p = .042). This study offers perspectives to include neurocognitive tests in ASD trials.
| S-EPMC10907457 | biostudies-literature
Project description:BackgroundExperimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder.MethodsWe conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ.ResultsOf the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups.ConclusionsThis placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).
| S-EPMC9701092 | biostudies-literature
Project description:ObjectiveThis study examined how state and trait anxiety of adolescents with autism spectrum disorders (ASD) are associated with their demographic characteristics, repetitive and restricted behaviors (RRBs), and internalizing and externalizing problem behaviors.MethodsA total of 96 participants with ASD (mean age=14.30 years; 91 males) completed a battery of tests including the State/Trait Anxiety Inventory (STAI), the Autism Diagnostic Interview-Revised, the Social Responsiveness Scale (SRS), and a cognitive test measuring intelligence quotient (IQ). Participants' parents completed the Child Behavior Checklist (CBCL). Pearson's correlations among age, IQ, two subscales of the STAI (i.e., STAIS and STAIT, measuring self-reported state and trait anxiety, respectively), and the Anxiety subscale of CBCL (i.e., CBCL-Anxiety, measuring parent-reported trait anxiety) were computed. Subsequently, Pearson's correlations were computed among the three anxiety measures, RRBs, and problem behaviors, while controlling for participants' age and IQ.ResultsThe STAIS and CBCL-Anxiety were both significantly correlated with higher age, sensory sensitivity, depressive symptoms, somatic complaints, and aggressive behaviors. All three anxiety variables were significantly and positively correlated with total SRS RRB scores. Additionally, the STAIS and STAIT were significantly associated with more severe Compulsion/Adherence behaviors, and the CBCL-Anxiety was also significantly associated with more severe Rule-breaking Behaviors.ConclusionSelf-reported state anxiety showed association patterns similar to those of parent-reported trait anxiety. Future studies investigating the precise operationalization of different anxiety instruments are needed to accurately measure the anxiety of adolescents with ASD.
| S-EPMC8016686 | biostudies-literature
Project description:Objectives:To assess and compare the oral health status of children with and without autism spectrum disorders (ASD) in China. Methods:This study recruited 144 children with ASD and 228 unrelated children with typical development (TD) aged 3-16 years from China. Data were collected using parent-reported questionnaires. Oral problems (oral symptoms and habits), oral health measures (oral hygiene practice and dental care experience), and the impact on the child's quality of life (based on a modified version of the Parental-Caregiver Perception Questionnaire) were assessed and compared between the two groups. Results:Children with ASD had worse oral health status than children with TD. Oral symptoms were more prevalent in the ASD group, especially halitosis (p < 0.001), food impaction (p < 0.001), and oral lesions (p < 0.001), than the TD group. The rate of damaging oral habits, including mouth breathing (p < 0.001) and object biting (p < 0.05), was also high in the ASD group. Compared with the TD group, more children with ASD did not brush their teeth independently and frequently (p < 0.001), had difficulty accessing dental care (p < 0.01), and reported unpleasant dental experiences (p < 0.001). The presence of ASD was associated with decreased oral health-related quality of life (p < 0.001) in these children and their families. Conclusion:Oral problems such as halitosis and bad oral habits are more prevalent among children with ASD. These children also lack oral hygiene practice and dental visits. This situation negatively impacts their quality of life, and must be brought to the attention of their treating dentists.
| S-EPMC7232536 | biostudies-literature