Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)Citation formats

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Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA). / Stivaros, Stavros; Garg, Shruti; Tziraki, Maria; Cai, Ying; Thomas, Owen; Mellor, Joseph; Morris, Andrew A; Jim, Carly; Szumanska-Ryt, Karolina; Parkes, Laura M; Haroon, Hamied A; Montaldi, Daniela; Webb, Nicholas; Keane, John; Castellanos, Francisco X; Silva, Alcino J; Huson, Sue; Williams, Stephen; Gareth Evans, D; Emsley, Richard; Green, Jonathan; SANTA Consortium.

In: Molecular Autism, Vol. 9, 2018, p. 12.

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Stivaros, S, Garg, S, Tziraki, M, Cai, Y, Thomas, O, Mellor, J, Morris, AA, Jim, C, Szumanska-Ryt, K, Parkes, LM, Haroon, HA, Montaldi, D, Webb, N, Keane, J, Castellanos, FX, Silva, AJ, Huson, S, Williams, S, Gareth Evans, D, Emsley, R, Green, J & SANTA Consortium 2018, 'Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)', Molecular Autism, vol. 9, pp. 12. https://doi.org/10.1186/s13229-018-0190-z

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Stivaros, Stavros ; Garg, Shruti ; Tziraki, Maria ; Cai, Ying ; Thomas, Owen ; Mellor, Joseph ; Morris, Andrew A ; Jim, Carly ; Szumanska-Ryt, Karolina ; Parkes, Laura M ; Haroon, Hamied A ; Montaldi, Daniela ; Webb, Nicholas ; Keane, John ; Castellanos, Francisco X ; Silva, Alcino J ; Huson, Sue ; Williams, Stephen ; Gareth Evans, D ; Emsley, Richard ; Green, Jonathan ; SANTA Consortium. / Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA). In: Molecular Autism. 2018 ; Vol. 9. pp. 12.

Bibtex

@article{2493ef422655428583a14055fd38818c,
title = "Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)",
abstract = "Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes.Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression).Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12,p = .055), GABA/Glx ratio (t(12) = - 2.78,p = .016), and reduced grey nuclei Glx (ANCOVAp< 0.05, Mann-Whitneyp< 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitneyp < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitneyp < 0.01). Machine-learning classification of imaging outcomes achieved 79{\%} (p < .05) accuracy differentiating groups at endpoint against chance level (64{\%},p = 0.25) at baseline. Three of 12 (25{\%}) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome.Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network.Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu).",
author = "Stavros Stivaros and Shruti Garg and Maria Tziraki and Ying Cai and Owen Thomas and Joseph Mellor and Morris, {Andrew A} and Carly Jim and Karolina Szumanska-Ryt and Parkes, {Laura M} and Haroon, {Hamied A} and Daniela Montaldi and Nicholas Webb and John Keane and Castellanos, {Francisco X} and Silva, {Alcino J} and Sue Huson and Stephen Williams and {Gareth Evans}, D and Richard Emsley and Jonathan Green and {SANTA Consortium}",
year = "2018",
doi = "10.1186/s13229-018-0190-z",
language = "English",
volume = "9",
pages = "12",
journal = "Molecular Autism",
issn = "2040-2392",
publisher = "Springer Nature",

}

RIS

TY - JOUR

T1 - Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)

AU - Stivaros, Stavros

AU - Garg, Shruti

AU - Tziraki, Maria

AU - Cai, Ying

AU - Thomas, Owen

AU - Mellor, Joseph

AU - Morris, Andrew A

AU - Jim, Carly

AU - Szumanska-Ryt, Karolina

AU - Parkes, Laura M

AU - Haroon, Hamied A

AU - Montaldi, Daniela

AU - Webb, Nicholas

AU - Keane, John

AU - Castellanos, Francisco X

AU - Silva, Alcino J

AU - Huson, Sue

AU - Williams, Stephen

AU - Gareth Evans, D

AU - Emsley, Richard

AU - Green, Jonathan

AU - SANTA Consortium

PY - 2018

Y1 - 2018

N2 - Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes.Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression).Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12,p = .055), GABA/Glx ratio (t(12) = - 2.78,p = .016), and reduced grey nuclei Glx (ANCOVAp< 0.05, Mann-Whitneyp< 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitneyp < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitneyp < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%,p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome.Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network.Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu).

AB - Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes.Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression).Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12,p = .055), GABA/Glx ratio (t(12) = - 2.78,p = .016), and reduced grey nuclei Glx (ANCOVAp< 0.05, Mann-Whitneyp< 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitneyp < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitneyp < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%,p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome.Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network.Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu).

U2 - 10.1186/s13229-018-0190-z

DO - 10.1186/s13229-018-0190-z

M3 - Article

VL - 9

SP - 12

JO - Molecular Autism

JF - Molecular Autism

SN - 2040-2392

ER -