Safety and efficacy of rivastigmine in children with Down syndrome: A double blind placebo controlled trial

Abstract

Individuals with Down syndrome (DS) have decreased cholinergic function and an uneven profile of cognitive abilities, with more pronounced deficits in learning, memory, and expressive language. Cholinesterase inhibitors may improve cognitive function in adults and adolescents with DS, but studies in children with DS have been limited. This study aimed to: (i) investigate the safety and efficacy of rivastigmine treatment; (ii) build upon our open-label studies in children with DS in a double-blind, placebo-controlled clinical trial; and (iii) investigate specific cognitive domains that may respond to rivastigmine treatment. We conducted a 20-week double-blind, placebo-controlled trial to investigate the safety and efficacy of rivastigmine in 22 children and adolescents with DS aged 10-17 years. Safety measures included reports of adverse events, laboratory parameters, and electrocardiograms. Efficacy measures included parental assessments of adaptive behavior and executive function, and direct measures of language and memory. No group differences were found on safety measures and 22 of 24 participants that passed study screening completed the study. The results did not demonstrate evidence for significant improvement in aspects of cognition, language, or overall function in the children receiving rivastigmine. Our results suggest that rivastigmine is safe and well-tolerated for children and adolescents with DS, but may not be effective for improving performance on the selected measures in this study. However, larger samples and/or alternate measures could possibly reveal improvements in cognitive function with rivastigmine treatment. Further research is needed to define a battery of cognitive measures that is sensitive to treatment effects in DS. © 2016 Wiley Periodicals, Inc.

Challenges in measuring the effects of pharmacological interventions on cognitive and adaptive functioning in individuals with Down syndrome: A systematic review

“…Subtests from several editions of the Clinical Evaluation of Language Fundamentals (CELF) assessment have been more sensitive to change in trials than other standardized language measures reported, such as the Test of Problem Solving (TOPS) (Zachman, Jorgensen, Huisingh, & Barrett, ), Differential Abilities Scale‐II (DAS‐II) (Elliott, ), Peabody Picture Vocabulary Test‐Third Edition (PPVT‐III) (Dunn & Dunn, ), and the Test of Reception of Grammar, Version 2 (TROG‐II) (Bishop, ) with some notable caveats. The Clinical Evaluation of Language Fundamentals‐Preschool (CELP‐P) Expressive Language Score and Total Language Score (Wiig, Secord, & Semel, ) detected treatment effects among adolescents in an open trial (Heller, Spiridigliozzi, Crissman, Sullivan, et al, ), with some evidence of ceiling effects, but was not sensitive to performance changes in a longer‐term follow‐up study (Heller et al, ), or when treatment group improvements were compared to placebo or comparison group changes (Kishnani et al, ; Spiridigliozzi et al, ). The Clinical Evaluation of Language Fundamentals‐Third Edition (CELF‐3) (Semel, Wiig, & Secord, ) Receptive and Expressive Language Scores and Total Score demonstrated utility in detecting treatment effects in an open‐label trial among children (Heller et al, ), but not in a large randomized controlled trial (RTC) with adults (Kishnani et al, ), which found a substantial number of participants at the floor.…”

“…The CELF‐Revised (CELF‐R) (Semel, Wiig, & Secord, ) was not useful in detecting changes in an open‐label trial in adults (Heller et al, ). One noteworthy non‐standardized measure, the Test of Verbal Expression and Reasoning (TOVER) (Heller, Spiridigliozzi, & Kishnani, ), was used in four trials to assess expressive language (Heller, Spiridigliozzi, Crissman, Sullivan, et al, ; Heller et al, ; Kishnani et al, ; Spiridigliozzi et al, ). Although it only detected treatment effects in one open‐label trial among adolescents (Heller, Spiridigliozzi, Crissman, Sullivan, et al, ), it is mentioned here as a potentially useful non‐standardized measure for future development and research in DS and other neurodevelopmental disorders.…”

“…Since this investigation, a number of other clinical trials have explored the use of ChEIs, NMDA antagonists (Boada et al, ) and inverse GABA agonists (e.g., https://ClinicalTrials.gov identifiers: NCT02484703 and NCT02024789) with children, adolescents, and adults with DS without dementia (see Figure ). Early open‐label trials provided preliminary data in support of the cognitive benefits from ChEI intervention (Heller et al, ; Heller et al, ; Heller, Spiridigliozzi, Crissman, Sullivan et al, ; Kishnani, Sullivan et al, ; Spiridigliozzi et al, ), leading to double‐blind, placebo‐controlled efficacy trials (Boada et al, ; Johnson, Fahey, Chicoine, Chong, & Gitelman, ; Kishnani et al, ; Kishnani et al, ; Spiridigliozzi et al, ). Data from this body of research have yielded mixed results in terms of the treatment effects of pharmacological agents in individuals with DS.…”

Pharmacotherapeutic Considerations for Individuals with Down Syndrome

“…Rivastigmine, a cholinergic agent used for the treatment of mild to moderate dementia, has also been studied in subjects with DSAD. In one double‐blind placebo‐controlled trial in 22 children and adolescents with DS, rivastigmine treatment did not improve cognition, language, or overall function . It was noted that subjects with DSAD tolerated rivastigmine therapy well.…”

“…In one double-blind placebo-controlled trial in 22 children and adolescents with DS, rivastigmine treatment did not improve cognition, language, or overall function. 26 It was noted that subjects with DSAD tolerated rivastigmine therapy well.…”