Abstracts
P.0349
Sensitivity to detect a change in patients with clinical
global improvement using the childhood autism rating
scale (CARS)
V. Crutel 1, E. Lambert 2, R. Schmid 3, O. Ethgen 4, D. Ravel 5,
E. Lemonnier 6
1
Institut de Recherches Internationales Servier, Neuro
Immuno-Inflammation Therapeutic Area, Suresnes, France;
2
Institut de Recherches Internationales Servier, Clinical
development and R&D, Suresnes, France; 3 Les Labora-
toires Servier, Internal Medicines Franchise- Global Value
and Access, Suresnes, France; 4 University of Liège, Pub-
lic Health- Epidemiology and Health Economics, Liège,
Belgium; 5 Neurochlore, Research Department, Marseille,
France; 6 University Hospital Center- Limoges, Autism Ex-
pert Center and Autism Resource Center of Limousin, Limo-
ges, France
Introduction and aims: Autism spectrum disorder (ASD) is
a neurodevelopmental disorder, defined by impairments in
social communication and presence of restricted or repeti-
tive behaviors. The Childhood Autism Rating Scale (CARS),
a 15-item rating scale revised in 2010 (CARS-2), is a tool
developed for the screening and diagnosis of ASD in chil-
dren over two years of age. It has been recommended as
a primary efficacy measure in the 2017 EMA guideline for
the clinical development of medicinal products in ASD. The
scale is to be completed by healthcare providers and is often
used in research clinical studies [1]. CARS-2 is being used
as primary endpoint in several large on-going phase 3 trials
aiming to assess the effects of bumetanide, a drug hypoth-
esized to reinstate GABAergic inhibition in paediatric ASD
subjects. The psychometric properties of the CARS are well
described, however, only few data are available for its sen-
sitivity to detect changes.
The present study aims to investigate the ability of CARS
to detect changes by comparing its changes with those of
the Clinical Global Impression Scale-Improvement (CGI-I), a
well-established research rating tool reflecting the changes
in subjects symptoms and functioning.
Methods: Data from a phase 2 dose-ranging study of
bumetanide in an ASD paediatric population were used. The
primary endpoint was the change in CARS total score at the
end of follow-up (day 90 (D90)) compared to baseline. CGI-I
value at D90 was a secondary endpoint. CARS was assessed
by independent raters masked from subjects data and CGI-I
was assessed by main study investigators. Results are re-
ported elsewhere [2]. Briefly, 88 subjects (78 males and 10
females) were randomised to bumetanide oral liquid formu-
lation bid 0.5mg (n=20), 1.0mg (n=23), 2.0mg (n=22), or
placebo (n=23). Mean (± SD) age was 8.3±4.5 years (range:
from 2 to 17). All subjects had an initial CARS score >34 cor-
responding to moderate to severe autism. 73 subjects with
an available CARS value at D90 were included in the present
analysis. Sensitivity to change was assessed by comparing
mean CARS change from inclusion to D90 between the group
of subjects who improved (CGI-I+, defined as CGI-I scores
“minimally improved”, “much improved” or “very much im-
proved”) versus those who did not (CGI-I-, defined as CGI-
S254
I scores “no change”, “minimally worse, “much worse” or
“very much worse”), using an analysis of covariance ad-
justed on baseline CARS score.
Results: The decrease in CARS from inclusion to D90 was
markedly higher in CGI-I+ subjects (mean change: [95%CI]:-
4.78 [-5.65;-3.92] points) than in CGI-I- subjects (mean
change: [95%CI]: -0.76 [-2.19;0.68] points). The difference
between the two CGI-I categories in mean CARS changes
was statistically significant (-4.03 points, p-value<0.001),
suggesting that CARS was sensitive to subjects improvement
assessed by CGI-I.
Conclusions: This report suggests that the CARS scale is a
sensitive tool to detect changes over time in ASD symptoma-
tology. Although further investigation and validation are re-
quired, the approach allows to consider the scale as an ap-
propriate tool for clinical practice, clinical research and for
clinical development of medicinal products in ASD.
Conflict of interest
Disclosure statement:
Servier employee
References
[1] Randall, M., Egberts, K.J., Samtani, A., Scholten, R.J.,
Hooft, L., Livingstone, N., Sterling-Levis, K., Woolfenden, S.,
Williams, K., 2018. Diagnostic tests for autism spectrum disor-
der (ASD) in preschool children. Cochrane Database Syst Rev Jul
24, 7.
[2] Lemonnier, E., Villeneuve, N., Sonie, S., Serret, S., Rosier, A.,
Roue, M., Brosset, P., Viellard, M., Bernoux, D., Rondeau, S.,
Thummler, S., Ravel, D., Ben-Ari, Y., 2017. Effects of
bumetanide on neurobehavioral function in children and adoles-
cents with autism spectrum disorders. Transl.Psychiatry. Mar; 7
(3), e1056.
doi: 10.1016/j.euroneuro.2021.10.331
P.0350
Preference study in childhood autism spectrum
disorder (asd) using childhood autism rating scale
(CARS2): qualitative research and informal pilot study
K. Hartl 1, N. Durno 2, R. Schmid 3, M. Heisen 4, O. Ethgen 5,6,
Z. Szilvasy 7, E. Friedel 8, O. Wong 9, T. Charman 10,
A. San José Cáceres 11, A. Mühlbacher 12, B. Van Hout 13,14,
J. Brazier 14, E. Stolk 15
1
OPEN Health, Patient-Centered Outcomes, Berlin, Ger-
many; 2 OPEN Health, Patient-Centered Outcomes, Ox-
ford, United Kingdom; 3 Les Laboratoires Servier, Internal
Medicines Franchise- Global Value and Access, Suresnes,
France; 4 OPEN Health, Patient-Centered Outcomes, Rot-
terdam, Netherlands- The; 5 University of Liège, Pub-
lic Health- Epidemiology and Health Economics, Liège,
Belgium; 6 SERFAN innovation, Strategic Economic Re-
search, Namur, Belgium; 7 Autism-Europe, MARS Autism,
Budapest, Hungary; 8 Autism-Europe, AFG Autisme, Paris,
France; 9 Medi-Qualité Omega, R&D and Health Tech-
nology Assessment, Paris, France; 10 King’s College Lon-
don, Institute of Psychiatry- Psychology & Neuroscience
IoPPN, London, United Kingdom; 11 Hospital General Uni-
 European Neuropsychopharmacology 53 (2021) S218–S288
versitario Gregorio Marañón, Child Psychiatry, Madrid,
Spain; 12 Hochschule Neubrandenburg, Health Economics
and Health Care Management, Neubrandenburg, Germany;
13
OPEN Health, Patient-Centered Outcomes, York, United
Kingdom; 14 The University of Sheffield, School of Health
and Related Research ScHARR, Sheffield, United Kingdom;
15
EuroQoL Research Foundation, Scientific Team, Rotter-
dam, Netherlands- The
Introduction: Exploration and elicitation of patient pref-
erences has gained increasing importance in pharmaceu-
tical registration, reimbursement, health technology as-
sessment, and clinical decision-making. Patient preference
studies aim at collecting information on the relative impor-
tance of health outcomes or other aspects of a condition,
so-called attributes, and the trade-offs between these at-
tributes. In childhood ASD, CARS2 is a condition-specific in-
strument to be filled out by clinicians, resulting in a score
for diagnosis and severity. CARS2 is often used in clinical tri-
als as outcome measure to assess treatment efficacy, mea-
sured through changes from baseline. However, it is un-
known which reduction in CARS2 score is perceived by pa-
tients as clinically meaningful improvement, and how this
perception aligns with clinicians’ perspective.
Aims: A health preference study will associate value with
changes in the CARS2 score and provide insight into the
relative importance of CARS2 items. With this research,
we aimed at assessing the appropriateness of a preference
study, specifically to determine whether CARS2 items can
be used as attributes, and to optimize the choice task de-
sign and attribute descriptions.
Methods: Clinicians, caregivers and autistic adults served as
proxies for children/adolescents with autism, since it was
considered unfeasible to conduct the study with children
who are very young, non-verbal, or have an intellectual dis-
ability. The 15 CARS2 items were assessed regarding their
relevance as attributes and adequacy of their wording for
non-expert users. Attributes with different levels of sever-
ity were combined to hypothetical profiles of autistic chil-
dren. These profiles were used to develop choice task de-
signs: The Best-Worst-Scaling (BWS) design presents three
different profiles and the respondent needs to select the
most and least preferred profiles. The Discrete Choice Ex-
periment (DCE) design shows two hypothetical profiles of
which the preferred one is chosen. The comprehensibility
of the CARS2 attributes and BWS/DCE choice task designs
were tested in individual interviews with four caregivers,
four clinicians, and two autistic high-functioning adults, fol-
lowed by an assisted informal pilot (three caregivers, two
clinicians, one payer expert, two methodological experts,
five colleagues).
Results: Thirteen of the 15 CARS2 items were deemed ap-
propriate attributes for the preference study, excluding the
items ‘level and consistency of intellectual response’ and
‘general impressions’. The attribute definitions and level
descriptions were shortened and refined to ensure compre-
hension for non-experts. The attributes were clear and un-
derstandable, caregivers and autistic adults identified with
the attributes and perceived them as comprehensive, but
the amount of information to process was high. The choice
tasks were challenging for participants and needed fur-
S255
ther explanation. However, 9/10 respondents could make
a choice. Interviewees favored a DCE with two profiles over
a BWS with three profiles. In the subsequent assisted infor-
mal pilot, participants favored a stacked visualization, in
which attributes with overlapping levels were grouped to-
gether, making it easier to discern differences between the
profiles.
Conclusion: A preference study in childhood ASD based
on the CARS2 instrument is feasible with caregivers and
clinicians as proxies for children’s preferences, as tested
with caregivers, clinicians, autistic adults, and payer and
methodological experts.
Conflict of interest
Disclosure statement:
Servier employee
doi: 10.1016/j.euroneuro.2021.10.332
P.0351
Amygdala connectivity as a mediator between
common genetic background for autism and social
functioning
G. Bussu 1, K. Haak 1, T. Bourgeron 2, F. Cliquet 2,
F. Campana 2, J. Tillmann 3, T. Charman 3, E. Loth 4,
D. Murphy 4, C. Beckmann 1, J. Buitelaar 1
1
Radboud University Medical Center Nijmegen- Donders In-
stitute for Brain- Cognition and Behaviour, Department
of Cognitive Neuroscience, Nijmegen, Netherlands- The;
2
Institut Pasteur, Human Genetics and Cognitive Functions,
Paris, France; 3 Institute of Psychiatry- Psychology and
Neuroscience- King’s College London, Department of Psy-
chology, London, United Kingdom; 4 Institute of Psychiatry-
Psychology and Neuroscience- King’s College London, De-
partment of Forensic and Neurodevelopmental Sciences,
London, United Kingdom
Background: Autism Spectrum Disorder (ASD) is a highly
heritable disorder with a complex polygenic architecture
[1]. Polygenic scores for ASD (PGS-ASD) measure the cumu-
lative effect of common genetic variants nominally associ-
ated to ASD, providing the opportunity to investigate neu-
roimaging markers influenced by genetic predisposition to
ASD. Previous studies have linked social symptoms of ASD to
structural and functional alterations of the amygdala [2].
However, our understanding of which amygdala pathways
may be altered in ASD is still very limited [3].
Objectives: This study investigates amygdalo-cortical con-
nectivity as a potential marker for social functioning in ASD,
testing the role of amygdala connectivity within large-scale
networks subserving social cognition as a mediator between
genetic load for ASD and adaptive social functioning.
Methods: PGS-ASD were computed on 343 ASD cases and 241
typically developed (TD) controls from the EU-AIMS Longitu-
dinal European Autism Project (LEAP [4]). We used resting-
state functional magnetic resonance imaging data on a sub-
sample of 406 individuals between 7 and 30 years of age (227
autistic) to define amygdala parcels based on its functional
connectivity within three large-scale networks subserving