Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial

Vaart, Thijs van der; Plasschaert, Ellen; Rietman, André B.; Renard, Marleen; Oostenbrink, Rianne; Vogels, Annick; Wit, Marie‐Claire Y. de; Descheemaeker, Mie-Jef; Vergouwe, Yvonne; Catsman‐Berrevoets, Coriene E.; Legius, Eric; Elgersma, Ype; Moll, Henriëtte A.

doi:10.1016/s1474-4422(13)70227-8

Cited by 113 publications

(85 citation statements)

References 30 publications

(55 reference statements)

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“…4 Initial trials using statin medications in children with NF1 have been inconclusive. While 2 randomized controlled trials of simvastatin reported no treatment effect on cognitive outcomes, 5,6 studies evaluating lovastatin have been more promising. An initial open-label phase I trial of lovastatin demonstrated normalization of functional connectivity within the default mode network 7 with accompanying improvements in memory and attention.…”

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confidence: 99%

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

et al. 2016

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Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1).Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n 5 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n 5 74; 40 mg/d) or placebo (n 5 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population.Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population.

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confidence: 99%

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

et al. 2016

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“…Although the Riccardi scale for disease severity (Riccardi, 1992) has frequently been used to assess impairments (Upadhyaya & David, 2012; van der Vaart et al, 2013; Wolkenstein et al, 2001), many worries and health‐care needs of our respondents are not addressed by this scale, since it mainly focuses on disease characteristics at a somatic level. This suggests there is a need for assessing the full impact of NF1 on all ICF domains, including limitations in activities and participation.…”

Section: Discussionmentioning

confidence: 99%

Worries and needs of adults and parents of adults with neurofibromatosis type 1

Rietman

Helden²,

Both³

et al. 2018

American J of Med Genetics Pt A

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Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder associated with lifelong tumor growth propensity and neurocognitive impairments. Although follow‐up of adults with NF1 often focuses on tumor growth, follow‐up of cognitive or social problems and other NF1‐related comorbidity is often not a part of standardized care. In order to provide optimal care services for these patients, we explored the care needs of adults with NF1. A qualitative study was performed using semi‐structured group interviews, exploring worries and care needs in medical, psychological, and socioeconomic domains, also focusing on the transition from pediatric to adult care. Four focus groups were conducted, including young adult patients, patients over age 30, and parents of young adult patients. In total, 30 patients and 12 parents participated. Data were transcribed verbatim and analyzed by computerized thematic analysis. Themes were organized using the World Health Organization International classification of functioning, disability, and health (ICF). Results indicated many and diverse worries and care needs both during the transitional period and in adulthood in medical, mental health, and socioeconomic domains. Worries could be categorized into 13 themes. Parents reported high stress levels and difficulties with their parental role. Participants expressed the need for more information, access to NF1 experts, daily living support, care for mental health and socioeconomic participation, and closer communication between health‐care providers. In conclusion, worries and needs of patients and parents underline the importance of multidisciplinary follow‐up and continuity of care during and after the transitional period. Additionally, parental stress requires more attention from care providers.

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“…The first generation of drug development for the cognitive deficits directly targeted the RAS-MAPK pathway, mostly by reducing abnormally enhanced RAS activity, and was remarkably successful in animal studies Lee et al, 2014;Li et al, 2005). Moreover, in clinical trials, FDA-approved statins, which showed beneficial effects in mouse models, were tested on neurobehavioral phenotypes in NF1 patients (Bearden, Hellemann, Rosser, Montojo, Jonas, Enrique et al, 2016;Krab, de GoedeBolder, Aarsen, Pluijm, Bouman, van der Geest et al, 2008a;Mainberger, Jung, Zenker, Wahllander, Freudenberg, Langer et al, 2013;van der Vaart, Plasschaert, Rietman, Renard, Oostenbrink, Vogels et al, 2013). Although small trials with lovastatin suggested beneficial effects of statins on cognitive function in NF1 patients (Bearden et al, 2016;Mainberger et al, 2013), large scale randomized placebo-controlled trials with simvastatin were not successful in showing efficacy against cognitive impairments (Krab et al, 2008a;van der Vaart et al, 2013), which suggests the necessity of developing next generation treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

Ryu

Lee

2016

Neurobiology of Learning and Memory

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Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial

Cited by 113 publications

References 30 publications

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

Worries and needs of adults and parents of adults with neurofibromatosis type 1

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

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