child development update - Amazon Web...
Transcript of child development update - Amazon Web...
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autism RESEARCHCENTRE
ASD clinical trials: what we know and where research is going
Evdokia Anagnostou, MDAssociate Professor, Department of Pediatrics, University of TorontoSenior Clinician Scientist, Bloorview Research InstituteCanada Research Chair, Translational Therapeutics in ASD
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Disclosures• Consulting:Roche,Takeda• Funding:
– BrainCanada,OntarioBrainInstitute,CIHR,DoD,HRSA,NCE-NeuroDevNet,AutismSpeaks,PSI,ALVAfoundation
– Unrestrictedgrant:Sanofi-Aventis– Grantsupport:SynapDx
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Jason LerchStephen SchererRosanna WeksbergJames EllisKarun SinghSuma JacobRob NicolsonTerry Bennett
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AUTISMSPECTRUMDISORDERS
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CurrentApproachesPONDnetwork:HB,UofToronto;McMaster;Lawson,WesternU,QueensU
ATN:HB,UofToronto;OSU;Pittsburgh;Vanderbilt;ColumbiaOther:UIC,Minnesota,RushU,MountSinaiNY
• Targetemerginggenomicvariation
• Riluzole• Memantine• Tideglusib
• Targetneuropathologytargets
• Omega3fattyacids
• Pioglitazone
• Targetneurocircuitryofinterest
•Oxytocin
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RiluzolevsplaceboinASD(co-Pis:RobNicolson,TerryBennet)
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• 60childrenandyouthwithASD– 7-17years– Stablemedsandtherapies
• Randomized1:1• 12weeksexposure• F/u1monthpastlastdose(week16)
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Riluzole Placebo p
Age 11.6±3.6* 11.5±2.4 ns
M:F 23:6 24:5 ns
%Caucasian 79% 55% ns
IQ 80.2±28.4 70.1±18.6 ns
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Riluzole Placebo p
Baseline Week12 Baseline Week12
ABC-L* 12.1±6.9** 8.6±6.6 12.8±7.8 10.4±8.1 0.3
ABC-I* 11.9±7.7** 7.6±7.8 14.3±9.2 14.0±11.2 0.03
ABC-H 18.9±10.2 13.9±9.7 21.9±11.6 21.2±13.2 0.03
SCAS 18.1±12.1 13.3±11.5 15.0±11.5 14.9±12.1 0.09
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Socialabilities:ABCSocialwithdrawal
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Externalizingbehaviors
p= 0.02; d= 0.45, coeff estimate for riluzole: -4.56
P=0.02; d=0.4Coeff estimate for riluzole: -5.24
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Targeting networks of relevance: the example of oxytocin
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RCTofINoxytocininyouthwithASDMethods
• 60youthrandomized,1:1• HollandBloorview,UniversityofToronto• UniversityofMinnesota– DrJacob
– Earlytermination:6:5active,1placebo
• 12weeksexposure• Follow-upat24weeks
• Dose:0.4IU/kg/dose,2dosesaday,8+/- 2hoursapart
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RCTofINoxytocininyouthwithASDMethods:Inclusion/Exclusion
• Ages10-17years• VIQandPIQ>70• Stableconcomitantmedications• Stablemedicalhistory• Notonhormonalbirthcontrol
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RCTofINoxytocininyouthwithASDBaselineCharacteristics
Oxytocinn=30
Placebon=30
Age 12.5(1.7) 12.4(1.9)
sex 28:2 26:4
FullscaleIQ 106.1(17) 98.9(16.5)
VerbalIQ 101.3(16.6) 98.1(15.9)
Non-verbalIQ 110(20.2) 99.9(16.7)
RaceCaucasianBlackAsianAmIndian/InuitOther
241113
270112
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RCTofINoxytocininyouthwithASDLetsFaceIt– facesvshouses– sameordifferent
0 4 8 12 16 20 2480
85
90
95
100Let's Face It: Faces
Week
PlaceboOxytocin
0 4 8 12 16 20 24
70
75
80
85
90
95Let's Face It: Houses
Week
PlaceboOxytocin
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RCTofINoxytocininyouthwithASDPedsQL
EmotionalFunctioning
SocialFunctioning
SchoolFunctioning
PsychosocialHealth
PhysicalHealth
TotalScore
-5
0
5
10
15
20
25
Changefrom
baseline
OxytocinPlaceboWeek12Week24
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• OxyBloodlevels– Changecomparedtoplacebo
• Otherpredictorsoftreatmentresponse:– PedsQL:Est=0-0.6,F:27.8,p=0.000
– Snps• Deltalog(pOT):p=0.006(drugcond*rs4686302)
• DeltaPQL-soc:p=0.029(drugcond*rs6791619)
• DeltaPQL-psyc:p=0.040(drugcond*rs6791619)
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Pioglitazone• PPRgammainhibitor• 5-12years• 16-weeks,singleblind,2-weekplaceborun-in,MTD
• 0.25mg/Kg,0.5mg/Kgand0.75mg/Kg
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Pioglitazone
• Maximumtolerateddose0.75mg/kg
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Estimate(95%CL) Estimate(95%CL)
t-testp-value
Baseline Week8 Week16 Week16-Baseline
n 27 25 25
ABCSocialWithdrawal10.1
(6.6;13.7)7.5
(4.8;10.3)6.7
(3.8;9.6)3.4
(1.6;5.3) 0.0005
SRSTotal188.4
(73.6;103.2)88.2
(78.9;97.5)85.8
(75.2;96.4)2.6
(-12.0;17.2) 0.7
ABCIrritability13.8
(10.2;17.4)11.2
(8.3;14.0)10.0
(6.9;13.0)3.8
(1.3;6.3)0.004
ABCHyperactivity21.7
(17.6;25.7)18.7
(14.9;22.4)16.5
(13.2;19.7)5.2
(2.6;7.8)0.0003
BASC-2Anxiety28.9
(5.5;12.2)8.1
(5.3;10.8)8.2
(5.2;11.3)0.6
(-1.5;2.8) 0.6
RBSRTotal33.0
(25.7;40.3)27.5
(20.6;34.3)24.5
(17.4;31.5)8.5
(3.7;13.3)0.0009
CY-BOCS112.6
(11.1;14.2)10.7
(9.4;12.1)9.4
(8.0;10.9)3.2
(2.0;4.4) <.0001
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• Design– 16weeksRCT
• 16weeksblindeddiscontinuation
• Outcomemeasures:– Primary:BMIzscore– Secondary:BMI,weight– Exploratory:Metabolicparameters;ABCirritability;memory
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AdverseEvents
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Metformin (n = 28) Placebo (n = 32) Treatment Difference
16-week Change
95% CI p16-week Change
95% CI p16-week change
95% CIEffect Size
p
Total cholesterol (mmol/L) -0.027
(-0.227,0.173) 0.79 -0.085
(-0.268,0.097) 0.35 0.058
(-0.212,0.328) 0.123 0.67
LDL (mmol/L) -0.114(-
0.271,0.043) 0.15 -0.011(-
0.158,0.137) 0.89 -0.104(-
0.318,0.111) 0.278 0.34
HDL (mmol/L) 0.085(-
0.037,0.206) 0.17 -0.025(-
0.136,0.085) 0.65 0.110(-
0.053,0.273) 0.357 0.18
Triglycerides (mmol/L) 0.065(-
0.252,0.382) 0.68 0.070(-
0.222,0.361) 0.63 -0.005(-
0.418,0.408) 0.006 0.98Glucose, fasting (mmol/L) -0.170
(-0.371,0.031) 0.10 -0.134
(-0.320,0.052) 0.16 -0.036
(-0.287,0.215) 0.064 0.78
Insulin, fasting (pmol/L) 13.7 (-72.5,99.9) 0.75 20.5 (-58.6,99.7) 0.61 -6.8
(-123.7,110.1) 0.030 0.91
HOMA-IR 0.53 (-2.39,3.44) 0.72 0.59 (-2.07,3.26) 0.66 -0.07 (-3.99,3.86) 0.009 0.97Hgb A1C (mmol/mol) -0.59 (-1.56,0.39) 0.23 0.37 (-0.51,1.25) 0.41 -0.95 (-2.26,0.35) 0.403 0.15
ABC Lethargy -2.08 (-4.80,0.63) 0.13 -1.06 (-3.64,1.52) 0.41 -1.02 (-4.54,2.50) 0.146 0.56ABC Stereotypy -0.34 (-1.54,0.85) 0.57 -1.16 (-2.30,-0.03) 0.044 0.82 (-0.72,2.36) 0.239 0.29ABC Hyperactivity -1.14 (-3.79,1.50) 0.39 -1.60 (-4.10,0.89) 0.20 0.46 (-3.09,4.00) 0.069 0.80ABC Inappropriate Speech -0.67 (-1.37,0.03) 0.060 -0.11 (-0.77,0.55) 0.74 -0.56 (-1.50,0.38) 0.305 0.24
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Effects of Metformin on Spatial and Verbal Memory in Children with ASD and Overweight
Associated with Atypical Antipsychotic Use
Authorship List
Michael G. Aman, Ph.D., Jill A. Hollway, Ph.D., J. Veenstra-VanderWeele, M.D., Benjamin L. Handen, Ph.D., Kevin B. Sanders, M.D., James Chan, M.S., Eric Macklin, Ph.D., L. Eugene Arnold, M.D., M.Ed.,
Taylor Wong, B.S., Cassandra Newsom, M.D., Rianne Hastie Adams, M.S.W., Sarah Marler, M.A., Naomi Peleg, M.Sc., and Evdokia A. Anagnostou, M.D.
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Table2.EffectsofMetforminvs.Placebo(Panel2)andeffectofTimeandMetformin(Panel3)onMemoryPerformance
PBOPhase1vs.MetPhase1 BaselinetoWeek32
Variable n PBO-Ph1 MetPh1 Estim. p E.S. PBO-Met Met-Met Estim. pNEPSYMemoryforDesigns
MDContentScore(0-60)a 45 2.126 2.718 0.593 0.732 0.084 3.447 6.100 2.653 0.206
MDSpatialScore(0-30)b 45 1.210 -0.769 -1.979 0.042 0.464 0.589 2.017 1.428 0.228
MDTotalScore(0-150)c 45 12.727 5.370 -7.357 0.208 0.357 15.269 20.280 5.011 0.491
MDDContentScore(0-20)d 37 1.108 1.378 0.270 0.718 0.129 1.159 0.361 -0.799 0.494
MDDSpatialScores(0-10)e 37 0.988 0.405 -0.583 0.107 0.451 0.380 0.395 0.015 0.976
MDDTotalScore(0-50)f 37 6.089 2.593 -3.497 0.182 0.514 3.622 1.761 -1.861 0.592
Mod.CaliforniaVerbalLearningTest-C
ShortDelayRecallScore(0-50) 48 1.344 0.084 -1.261 0.530 0.184 4.672 3.270 -1.403 0.421
LongDelayRecallScore(0-10) 48 -0.067 0.303 0.370 0.555 0.183 0.492 1.360 0.868 0.098
Recognitions&RejectionsScore(0-20) 440.161 4.430 4.268 0.127 0.340 4.020 4.791 0.771 0.795
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Knowledge TranslationBiostatistics
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co-clinical trials in neurodevelopmental disorders
Jason Lerch and Evdokia Anagnostou
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Co-Clinical Trials for Lung Cancer
MEK inhibitor (selumetinib)
100%
Kras Kras + p53 Kras + Lkb1
100% 0% 10%Chen, Zhao, Katherine Cheng, Zandra Walton, Yuchuan Wang, Hiromichi Ebi, Takeshi Shimamura, Yan Liu, and others. "A Murine Lung Cancer Co-clinical Trial Identifies
Genetic Modifiers of Therapeutic Response." Nature 483, no. 7391 (2012): doi:10.1038/nature10937.
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Co-Clinical Trials for Lung Cancer
MEK inhibitor (selumetinib)
100%
Kras Kras + p53 Kras + Lkb1
100% 0% 10%Chen, Zhao, Katherine Cheng, Zandra Walton, Yuchuan Wang, Hiromichi Ebi, Takeshi Shimamura, Yan Liu, and others. "A Murine Lung Cancer Co-clinical Trial Identifies
Genetic Modifiers of Therapeutic Response." Nature 483, no. 7391 (2012): doi:10.1038/nature10937.
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GSK3 PATHWAYS
TIdeglusib
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Figure 2: The effect of tideglusib on cognitive deficits and hyperactivity in the open field in the FMR1 knockout transgenic mouse model of Fragile X Syndrome. The figure shows Vehicle (V) and tideglusib (T) in wild type (WT) and FMR1 knockout mice (FXS). Panel A shows the performance on a test of context-dependent fear conditioning. Panel B shows activity in the open field. Note that p <0.05 compared with untreated wild type mice (Franklin et al 2013)
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TIDE: RCT of tideglusib vs placebo in ASD
• 90 youths 12-17
• What we do different:• 1. Embeded in POND• 2. Additional biomarkers • 3. added social adaptive function to battery
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Next study:Arbacofen vs placebo
• What we do different:• co clinical trial• Embeded in POND• Electrophysiology as an exploratory marker• Collaboration with EU-AIMS to double the sample size
• Change of primary to social adaptive function• Extend exposure to 16 weeks• Limit to verbal children
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From disability to possibility
Thank you to families and individuals who have participated in our studies
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TIDEGLUSIB (GSK3 inhibitor)● Regulates circadian clock
● Regulates inflammatory response (reduces pro-inflammatory cytokines, increases anti-inflammatory cytokines)
● Regulates neurogenesis/cell differentiation
● Phosphorylates histone deacetylase 3
● Key role in synaptic plasticity (via NMDA mediated LTD).