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Background: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABA A -α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance., Methods: Basmisanil, a selective GABA A -α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents., Results: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life., Conclusions: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome., Trial Registration: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789., (© 2022. The Author(s).)

Measures of adaptive behavior are important in the assessment and treatment of individuals with intellectual disabilities (ID). The purpose of the current study was to evaluate the stability of an established and a novel measure of adaptive behavior over time, and their suitability as outcome measures in clinical trials targeting individuals with Down syndrome (DS). This 6-month, longitudinal, noninterventional, multinational study included adolescents (12-17 years) and adults (18-30 years) with DS. Participants were from seven countries (11 different sites) with English, Spanish and French as their native language. The Vineland Adaptive Behavior Scales-II (VABS-II) and a newly developed Clinician Global Impression (CGI) scale were administered at baseline, 1 and 6 months. Adults had lower composite standard scores on all domains of the VABS-II compared with adolescents. The communication domain was a weakness relative to the socialization and daily living skills domains on the VABS-II and the CGI-Severity scale. These findings were stable over 6 months, as exhibited by high intraclass correlations (>0.75). These results provide valuable baseline data for use in trial design and endpoint selection for studies including individuals with DS. ClinicalTrials.gov identifier: NCT01580384., (© 2018 Wiley Periodicals, Inc.)

Introduction: To date, there is little research on health-related quality of life (HRQoL) in Down syndrome (DS), and existing research is variable with regard to reported HRQoL in DS. There are also no HRQoL measures developed specifically to be used with individuals with Down syndrome., Methods: A multi-national, longitudinal, 24-week non-interventional study was conducted in adolescents and adults with DS. HRQoL was assessed (n = 90) using the parent-report KIDSCREEN-27 questionnaire., Results: HRQoL domain scores were found to be similar to those in the KIDSCREEN-27 European normative group data set on the Physical Well-being, Psychological Well-being, Autonomy and Parent Relations domains. Compared with the normative data set, the adolescent participants with DS in the current study were found to have lower scores on the Social Support and Peers domain and higher scores than the normative group on the School Environment domain. The test-retest reliability of the KIDSCREEN-27 was also examined using the intraclass correlation coefficient (ICC) in a subgroup of stable participants. The KIDSCREEN-27 demonstrated poor-to-moderate test-retest reliability; however, test-retest reliability was assessed using a long time interval between assessment time points., Conclusion: The findings of this study underline that further research is needed to better understand the nature of HRQoL in DS. Further research using a shorter time interval between assessment time points to examine test-retest reliability is also required., Funding: F. Hoffmann-La Roche Ltd.

Aim: The aim of this study was to describe the incidence of morbidities and the prevalence of medical prescriptions in a large Down syndrome population., Method: A retrospective cohort study was carried out using the UK Clinical Practice Research Datalink from 1 January 2004 to 31 December 2013. We matched individuals with Down syndrome to randomly selected control participants by practice site, sex, birth year, and recording period., Results: A total of 6430 individuals with Down syndrome (3009 females, 3421 males) and 19 176 controls (8966 females, 10,210 males) were included in the study. The incidence of cardiovascular disorders, gastrointestinal diseases (incidence rate ratio [IRR] 7.9 at 3 to <6y: yearly prevalence ratio [YPR] for laxatives 4.7), and sleeping disorders (IRR 4.8 in 3 to <6y) was increased in children with Down syndrome versus control participants. New onset of congenital heart malformation, ear diseases, eye disorders, autism, hypothyroidism, diabetes, and obesity were more frequent in childhood and remained elevated in adulthood (overall IRR 35.5, 1.7, 3.1, 4.4, 13.1, 1.3, and 2.6 respectively), whereas the gap widened in adulthood for epilepsy and intellectual disability (IRR 15.2 and 158 respectively, in participants older than 30y). At ≥ 30 years, the incidence of hypotension and dementia was raised (IRR 3.0 and 92.1 respectively; YPR for dementia drugs: 76.3); and that of hypertension, depression and anxiety was lowered (IRR 0.2, 0.5, and 0.4 respectively)., Interpretation: The profile of newly occurring morbidities in Down syndrome varies across the developmental lifespan., (© 2015 Roche Products Limited. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Trisomy 21 is the most common viable trisomy. Although it is invariably associated with mild to severe developmental delay and intellectual disability, no gross central nervous system malformation has been consistently identified in individuals with trisomy 21. We present the case of a monozygotic twin pregnancy in which both fetuses were identified as having trisomy 21 and partial agenesis of the corpus callosum. We discuss this rare association in the context of an emerging understanding of the neurobiology of trisomy 21., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. Methods: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12–13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. Results: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. Conclusions: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. Trial registration: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is the most commonly identifiable genetic form of intellectual disability. Individuals with DS have considerable deficits in intellectual functioning (i.e., low intellectual quotient, delayed learning and/or impaired language development) and adaptive behavior. Previous pharmacological studies in this population have been limited by a lack of appropriate endpoints that accurately measured change in cognitive and functional abilities. Therefore, the current longitudinal observational study assessed the suitability and reliability of existing cognitive scales to determine which tools would be the most effective in future interventional clinical studies. Subtests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Clinical Evaluation of Language Fundamentals-Preschool-2 (CELF-P-2), and the Observer Memory Questionnaire-Parent Form (OMQ-PF), Behavior Rating Inventory of Executive Function®-Preschool Version (BRIEF-P) and Leiter International Performance Scale-Revised were assessed. The results reported here have contributed to the optimization of trial design and endpoint selection for the Phase 2 study of a new selective negative allosteric modulator of the GABAA receptor a5-subtype (Basmisanil), and can be applied to other studies in the DS population. [ABSTRACT FROM AUTHOR]