autism RESEARCH CENTRE Methodological challenges in Designing - - PowerPoint PPT Presentation

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RESEARCH CENTRE Methodological challenges in Designing Clinical Trials in ASD

Evdokia Anagnostou, MD

Professor, Department of Pediatrics, University of Toronto Senior Clinician Scientist, Bloorview Research Institute Canada Research Chair, Translational Therapeutics in ASD

• D. Sims Chair in Autism

Disclosures

• Consulting: Roche, Quadrant
• Collaborations: SIEMENS
• Funding:

– Ontario Brain Institute, CIHR, NIH, DoD, HRSA, NCE-NeuroDevNet, Autism Speaks, Brain Canada, Azrieli Foundation – Pharma grant support: ROCHE – In kind support: AMO pharma. Simons foundation -CRA

Knowledg dge Transla lation ion Biosta tatis istic tics

Challenges in clinical trials in ASD

• Construct confusion:

– What to target (heterogeneity of phenotypes and biologies)

– Phenotype

– Construct confusion (e.g. actual diagnostic constructs: vague behavioral constructs: anxiety, social function vs withdrawal vs cognition, repetitive behaviors)

– Biology: genomic heterogeneity, influence of common variants, gene X environment interactions

– Biomarkers for: Diagnosis ? Early reads? Stratification?

Pinto et al 2014

Challenges in clinical trials in ASD

• Poor m easurem ent

– Construct confusion – Poor Sensitivity to change – Developed for diagnosis; sample characteristics – High placebo response

• Seaside Therapeutics trial of Arbaclofen

Unpublished data , Paul Wang

Working group with academia, self advocacy organizations and industry Process and results presented to regulators Met monthly over 14 months, with 2 face to face meetings Systematic search of the literature covering publications to 2012 Measures evaluated for: Clinical domain coverage Psychometric properties (content and construct validity, internal consistency, inter-rater and test-retest reliability) Sensitivity to change Other considerations: Burden, availability in languages

Updates since 2015 publication: ABC-SW

Updates since 2015 publication: ABC-SW

POND Network Riluzole vs placebo in ASD (co-Pis: Rob Nicolson, Terry Bennet) n=60 POND Network Tideglusib vs placebo in ASD (co-Pis: Rob Nicolson, Terry Bennet) n=90

• 60
• 50
• 40
• 30
• 20
• 10

Placebo AMO-02 % Change ABC Social Wihdrawal Score

Cohen’s D effect size = 0.44 p = 0.055

Updates since 2015 publication: SRS

Updates since 2015 publication: Vineland

Measure Placebo N=58 (54 completers) Arbaclofen N=57 (44 completers) Baseline Week 12 Change Baseline Week 12 Change p-value Secondary Efficacy Measure Vineland-II Socialization 61.1 (12.9) 63.1 (13.4) 1.8 (7.5) 58.5 (12.1) 66.0 (18.5) 7.1 (10.7) 0.006

POND Network Tideglusib vs placebo in ASD n=90

Placebo response

• High expectations

– Subjects / families – Investigators

• Non specific therapeutic

effects

– Symptom variation

• Biology

– Imaging (reward system;

systems expected to respond to intervention)

– Genomics (e.g. serotonin related

gene polymorphisms in anxiety, Furmark etal 2008, monoaminergic tone in depression, Leuchter AF et al 2009)

– Patient factors:

– Severity: interaction with primary measure – Age, sex, early in the course of disorder

– Study factors:

– Informant – Measure – number of sites – length of trial – year of trial – # of visits

Caveats

• But

– Vineland Social positive predictor of treatment vs placebo response – ??capacity

Intranasal oxytocin vs placebo in adolescents with ASD

Holland Bloorview, U Toronto: Anagnostou University of Minesotta: Jacob

Emotional Functioning Social Functioning School Functioning Psychosocial Health Physical Health Total Score

• 5

5 10 15 20 25

Change from baseline Oxytocin Placebo Week 12 Week 24

Challenges in Clinical Trials in ASD

• SAMPLE SIZES

– Scarce phase 3 studies – Some studies have unacceptably low sample sizes even for phase 2 designs – Characteristics of populations – Standard of care in ASD

ARBA Study

A Randomized Placebo-controlled Trial of ARBaclofen vs. Placebo in the Treatment of Children and Adolescents with ASD

Collaborations

• AIMS-2 network
• Co-designed and harmonized protocols
• Pooled secondary analysis
• ~200 participants

I m prove sam ple sizes

Study Overview

• Random ized, placebo-controlled, double-blind, parallel

design

• 1 6 w eeks of random ization
• 1 6 w eeks open label
• Outcom e m easures: Primary: Vineland –Social; Secondary:

ABC-SW

• Biom arkers: Sensory processing, EEG, epigenetics
• Lim it variability: verbal children

Construct and outcom e m easure change Hetereogeneity

Exploratory Measures - aims

• BOSCC – social abilities ; Autism Impact measure – AIM – core symptoms; PedsQL – quality of

life

• adaptive and global function (daily living skills and motor skills as measured by the Vineland-

3, and Clinical global Impression- Severity)

• Electrophysiology (EEG) and sensory discrimination

As this is also an embedded trial in a biomarker core [Province of Ontario Neurodevelopmental Disorders Network (POND)], we will explore whether cognitive/adaptive/global functioning, genomics and/or imaging characteristics are associated with treatment response or safety (post hoc approach to stratification) New m easures Heterogeneity, early reads

In s sum ummary

• Challenges: construct confusion, heterogeneity of unclear structure,

measurement issues, placebo response

• We continue to learn lessons about placebo response and refine

measurement

• Despite construct confusion, biomarker and other marker discovery

crucial to allow for both early reads and stratification

• Successes will apply to multiple neurodevelopmental conditions, given
• verlapping biological constructs
• Collaboration critical to adequate sample sizes