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Clinical trials in children with Down syndrome Issues from a cognitive research perspective.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 142C:187 – 195 (2006)
A R T I C L E
Clinical Trials in Children With Down Syndrome:
Issues From a Cognitive Research Perspective
JAMES H. HELLER,* GAIL A. SPIRIDIGLIOZZI, BLYTHE G. CRISSMAN,
JENNIFER A. SULLIVAN-SAARELA, JENNIFER S. LI, AND PRIYA S. KISHNANI
Clinical and translational research play a key role in the transition of basic research discoveries to effective
therapies. In Down syndrome (DS), these research approaches are not well utilized or developed to test new
therapies to improve cognitive and/or adaptive function in this population. This article reviews the history of
clinical trial research in children with DS from a cognitive research perspective and discusses important issues
relevant to the conduct of well designed clinical trials for this population. Specific issues addressed include:
funding, study design, study medication, subject recruitment and retention, safety, and efficacy challenges. The
Duke Down Syndrome Research Team’s program of clinical research of cholinesterase inhibitors for individuals
with DS serves as the model application for the identified research principles. It is hoped that this article will raise
awareness of the unmet need for clinical research in the cognitive and adaptive function of individuals with DS,
especially children with DS. ß 2006 Wiley-Liss, Inc.
KEY WORDS: clinical trials; trisomy 21; cognitive deficit; language impairment; attention; memory; expressive language; rivastigmine
tartrate; donepezil hydrochloride; cholinergic therapy; pediatric; Down syndrome
How to cite this article: Heller JH, Spiridigliozzi GA, Crissman BG, Sullivan-Saarela JA, Li JS, Kishnani PS.
2006. Clinical trials in children with Down syndrome: Issues from a cognitive research perspective.
Am J Med Genet Part C Semin Med Genet 142C:187–195.
INTRODUCTION
Down syndrome (DS) results from
chromosomal aneuploidy (trisomy 21).
The consequent gene dosage imbalance
is believed to be the main cause of the
phenotype. Despite the fact that the
phenotype was described over 100 years
ago, much about the condition remains
unexplored [Jones, 1996]. Recent
advances in basic, translational, and
clinical research along with the development of subspecialty expertise have
yielded substantial improvements in the
medical care of individuals with DS.
These advances in DS investigation have
contributed to an increased understanding of the more complex medical and
developmental issues associated with
DS.
Clinical and translational research
play key roles in the transition of basic
research discoveries to effective therapies. The randomized, double-blind,
The Duke Down Syndrome Research Team (JH, GAS, BGC, JASS, PSK), established in 1997, is a collaborative group of medical sub specialists who
design and conduct clinical research including the investigation of potential therapeutic effects of cholinesterase inhibitors in adults and children with
Down syndrome.
James H. Heller M.A., M.S., C.C.C. is a Clinical Associate, Department of Surgery, Duke University Medical Center (DUMC). He has advanced
degrees in speech-language pathology (U of Minnesota) and in experimental psychology (Memorial U of Newfoundland, Canada). He is the former
director of the Child Development Unit, Department of Pediatrics, DUMC and has over 25 years clinical research experience in the field of
communication disorders.
Gail A. Spiridigliozzi, Ph.D. is a clinical child psychologist and Assistant Clinical Professor, based in the Duke Child Development and Behavioral
Health Clinic. She is also the psychologist for the Duke Down Syndrome Research Team. Her research and clinical interests include the psychoeducational profiles of children with Down syndrome, fragile X syndrome, metabolic disorders, and other genetic conditions.
Blythe G. Crissman, M.S., CGC is a genetic counselor in the Department of Pediatrics at Duke University Medical Center. She serves as the primary
genetic counselor and clinic coordinator of the Duke Comprehensive Down Syndrome Clinic, and is a clinical research coordinator for the Duke Down
Syndrome Research Team.
Jennifer A. Sullivan-Saarela, M.S., CGC is a senior genetic counselor in the Department of Pediatrics at Duke University Medical Center. She served
as the research coordinator of the Duke Down Syndrome Research Team from its inception, 1997–2002. She currently serves as the coordinator and
senior genetic counselor for the Duke Metabolic Clinic and Lysosomal Storage Disease Center. She is also Associate Editor of the Journal of Genetic
Counseling.
Jennifer S. Li, M.D., MHS is Associate Professor of Pediatrics (cardiology) and Director of Pediatric Clinical Trials at the Duke Clinical Research
Institute. She has a research focus in cardiac issues in patients with Down syndrome.
Priya S. Kishnani, M.D. is Associate Professor of Pediatrics and the Director of Clinical Trials in the Division of Medical Genetics at Duke University
Medical Center. Her primary focus has been the translation of laboratory science into the clinic arena to advance clinical care. She has also been the coDirector of the Duke Comprehensive Down Syndrome Clinic since 1995.
*Correspondence to: James H. Heller, DUMC Box 3528, 244 Bell Building, Duke University Medical Center, Durham, NC 27710.
E-mail: helle001@mc.duke.edu
DOI 10.1002/ajmg.c.30103
ß 2006 Wiley-Liss, Inc.
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placebo-controlled trial has become the
gold standard for establishing efficacy
and to a lesser extent safety [Alderman,
2005]. To date, clinical research in DS
has focused on the utility of treatments
for leukemia [Gamis, 2005]. This
research has led to best practice standards
that have extended the life span of
individuals with DS affected by hematologic malignancies.
However, as the lifespan of individuals with DS has increased significantly
[Yang et al., 2002] and more individuals
with DS are active members of the
community, maximizing functional
potential has become an immediate
need. The development of educational
policies, such as early intervention and
inclusion in the least restricted environment, have helped focus attention on
children’s abilities rather than their disabilities [Baker et al., 1994; Hollowood
et al., 1995; Hassold and Patterson,
1998]. These policies bring hope that
individuals with DS can lead relatively
independent and productive lives. In
light of the strong efforts and accomplishments in improving the lives of
individuals with DS, the cognitive
deficits associated with DS currently
loom as a formidable barrier to even
greater accomplishment.
There is a paucity of published
research in pharmacologic therapy for
improving cognitive function in individuals with DS. Most of the available
literature is based on anecdotal case
There is a paucity of published
research in pharmacologic
therapy for improving cognitive
function in individuals with
DS. Most of the available
literature is based on anecdotal
case reports and small, single
center, open-label, or placebo
control studies of agents such
as vitamin and mineral
supplements.
reports and small, single center, openlabel, or placebo control studies of agents
such as vitamin and mineral supplements. A listing of clinical trials investigating the potential enhancement of
cognitive function in children with DS
is provided in Table I.
It is the goal of researchers and
practitioners to develop strategies and
interventions to maximize the functional potential of all individuals with
DS. Due to many circumstances, including a shortage of funding and reluctance
of investigators and marketers to test
unproven therapies in rigorous clinical
trials, there is a limited history of shared
effort towards this goal. Thus far, interventions focusing on the cognitive
impairments of individuals with DS by
the medical community have been
notoriously slow. This may be due, in
part, to their adherence to two important principles: (1) do no harm and (2)
medical practice must be evidencebased. To date, there have been no
carefully designed and controlled studies
of a pharmacological agent that have
been proven effective in improving
cognitive function in children with DS.
Without this kind of study, the adoption
of any intervention to improve cognitive
function in individuals with DS in the
medical community is unlikely.
In an attempt to enhance cognitive
abilities, many parents choose to use
complementary and alternative therapies
and off-label medication for their children with DS. These parents are not
willing to lose time waiting for conclusive scientific data for their children
who may be at a critical stage in
cognitive and/or language development. Their decision whether or not to
actively seek a particular intervention is
pragmatic (i.e., do I think that this
intervention might help my child?). As
medical researchers and practitioners,
we face the dilemma of maintaining a
balance between evidence from conclusive scientific data to justify practice and
the need of parents to identify promising
treatments for their children while their
children are young enough to obtain
maximum benefit.
The most obvious solution for
medical researchers to resolve these
ARTICLE
competing needs is to initiate large-scale
double-blind, placebo-controlled clinical trials with potentially effective interventions. Ideally, therapies shown to be
ineffective in these trials can be eliminated from consideration and therapies
shown to be safe and efficacious can be
adopted. Unfortunately, this solution is
often not as simple as it seems. In the
following sections, we will identify and
discuss the clinical research issues that
make this solution so challenging.
FUNDING
Available funding of clinical trials for
enhancement of cognitive function in
DS is extremely limited both federally
and privately. Despite the FDA Modernization Act of 1997 [1998] and the Best
Pharmaceuticals for Children Act,
which include provisions for 6 months
of patent protection under pediatric
exclusivity, pharmaceutical companies
have been reluctant to support trials in a
population with special needs, particularly when the focus is on cognitive
deficits. Although small grants are of
merit when gathering pilot and preliminary data, more comprehensive and
rigorously designed studies, with larger
sample sizes or multiple site trials are
needed to get a medication approved for
a particular indication. These kinds of
studies require substantial financial support.
STUDY DESIGN
While funding is a critical factor in
establishing a double-blind placebocontrolled trial, it is not the only factor.
Necessary preliminary studies include
the establishment of an optimal dose and
titration schedule through pharmacokinetic studies, potential efficacy (and how
this should be measured with a robust
end point), and determination of the
relative toxicity of the drug. Without
these, it is unlikely that sufficient funding
for a definitive double-blind, placebocontrolled trial would become available.
And even if sufficient funding could be
obtained, without completing this preliminary work, the likelihood of a
conclusive result is low.
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
189
TABLE I. Pediatric Clinical Trials for Enhancing Cognitive Function in Individuals With DS
Investigator and year
Drug tested
Type of agent
Berg et al. [1961]
Pituitary extract
Heaton-Ward [1962]
Bumbalo et al. [1964]
Niacin
U series vitamin
Pueschel et al. [1980]
Vitamin B6,
5-hydroxytryptophan,
or both
Megavitamins and thyroid
hormone
Vitamins and Minerals
Vitamins and Minerals
Megavitamins
Vasopressin
Harrell et al. [1981]
Bennett et al. [1983]
Weathers [1983]
Smith et al. [1984]
Eisenberg et al. [1984]
Lonsdale and
Kissling [1986]
Bidder et al. [1989]
Thiamine
Coleman et al. [1985]
Lobaugh et al. [2001]
Multivitamins and
minerals
Vitamin B6
Piracetam
Heller et al. [2004]
Donepezil hydrochloride
Heller et al. [in press]
Rivastigmine tartrate
Small pilot studies provide the
essential background information for
the design of larger, better controlled
trials. Pilot studies provide perspective
on general safety and highlight specific
systems and effects that may require
more careful monitoring. Dose and
Small pilot studies provide the
essential background information
for the design of large, better
controlled trials. Pilot studies
provide perspective on general
safety and highlight specific
systems and effects that may
require more careful monitoring.
Study design
Open label
Number
of subjects
Placebo controlled
Placebo controlled
23
24
Placebo controlled
95
Vitamin compound
Open label
Vitamin supplement
Vitamin supplement
Vitamin supplement
Antidiuretic
hormone
Vitamin supplement
Placebo controlled
Placebo controlled
Placebo controlled
Open label
20
47
56
9
5–13 years
6–17 years
7–15 years
10–42 years
Placebo controlled
22
8–16 years
Vitamin supplement
Crossover
26
Vitamin supplement
Cyclic derivative
of gammaaminobutyric acid
Acetylcholinesterase
inhibitor
Acetyl and butyl
cholinesterase
inhibitor
Placebo Controlled
Double blind crossover
19
25
6 months–
5 years
10–42 years
6–13 years
Open label
7
8–13 years
Open Label
11
10–18 years
titration schedule effects can be investigated. These factors are particularly
important in children where wide variability in dose and titration tolerance can
be observed. While maximum dose and
titration schedules are determined in the
study planning stage, these targets may
not be reached by particular subjects if
the subjects demonstrate a significantly
increased adverse event profile at a lower
dose level or on a faster titration rate. It is
important to build in flexibility in dose
and/or titration rate to minimize adverse
events. The loss of subjects, particularly
in small sample trials, reduces the study’s
internal validity [Katz, 2005].
In our studies of cholinesterase
inhibitors [Heller et al., in press;
Kishnani et al., 1999; Heller et al.,
2003, 2004], the dose level was increased
gradually and subject response to the
3
Age range
Bovine pituitary
extract
Vitamin supplement
Compound of 48
agents
Vitamin
4
16 months- 4
years
6–36 years
3 months-11
years
Newborn
5–9 years
increased dose was carefully monitored.
Dose tolerance is affected by titration
rate [Kishnani et al., 2001]. If the subject
could not tolerate the increased dose at
the slow rate of titration, the dose was
backed down to the previously tolerable
level.
Efficacy is a key element of clinical
trial design that directly affects the
external validity of the study [Pajonk,
2005]. In order for the study drug to be
incorporated into standard practice,
positive study results must be generalizable to real-world practice. In pilot
studies, the inherent weakness of knowing that a subject is on the experimental
medication and the absence of a placebo
control group creates bias in data interpretation including: (a) the potential to
associate all change with the study
medication; and (b) the potential to
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observe change that is not really there.
Thus, despite positive pilot study outcomes, the off-label use of medications
for cognitive enhancement should be
discouraged [Salman, 2002].
In an attempt to maximize the
external validity of a clinical trial of an
experimental medication for individuals
with DS, one might target general
measures of adaptive function or quality
of life as a primary endpoint. For
individuals with DS and other groups
with cognitive impairments, the definition and subsequent measurement of
efficacy may be contingent upon the
baseline developmental level. However,
this benefit may not be perceived as a
benefit for individuals who are not
employed or for individuals who have
been placed in supportive settings like
sheltered workshops. With such individuals, it is conceivable that drug-related
improvements in cognitive function may
not be noticed in the home and/or work
setting. It is also conceivable that drugrelated improvements in cognitive function may decrease the individual’s quality
of life and adaptive function in these
settings. For example, an individual may
become more expressive and assertive
while taking the study medication. For
school-aged children faced with daily
academic challenges, these cognitive
improvements may have a profound
positive effect on quality of life, ability
to perform within the classroom and at
home, and with improved self esteem.
However, for the adult who is living at
home or working in a sheltered workshop setting, these same improvements
in cognitive function may lead to
increased confrontations with caregivers
and co-workers and a breakdown of
established social networks. Thus, the
whole concept of efficacy and subject
selection must be carefully considered in
the study design.
We have adopted a multiple outcome approach to efficacy analysis in our
investigation of cholinergic therapy in an
attempt to understand the drug effect on
specific cognitive domains. The reason
for this approach arose from the preliminary findings by Kishnani et al.
[1999] of improved adaptive function
in some adults with DS treated with
donepezil hydrochloride. The study was
based on the hypothesis that acetylcholine plays a critical role in learning,
We have adopted a multiple
outcome approach to efficacy
analysis in our investigation
of cholinergic therapy in an
attempt to understand the drug
effect on specific cognitive
domains. The reason for
this approach arose from the
preliminary findings by
Kishnani et al. [1999] of
improved adaptive function in
some adults with DS treated
with donepezil hydrochloride.
memory and mood [Nadel, 2003; Pennington et al., 2003] and that individuals
with DS have lower levels of acetylcholine [Sacks and Smith, 1989; Florez et al.,
1990]. These investigators reasoned that
increasing the level of this neurotransmitter in individuals with DS may
enhance cognition.
Our subsequent work has investigated the effects of cholinergic treatment
on multiple cognitive domains using
multiple performance measures. While
this approach can lead to errors in
hypothesis testing, a secondary analysis
of the types of measures that consistently
approach and/or reach statistical significance can provide interesting insights
into the drug effect mechanisms. For
example, one can investigate whether
improvement in one particular domain,
such as attention or memory, appears to
define the entire drug effect or whether
processes such as associative or auditory
processing improve across cognitive
domains. Much preliminary work at this
level is necessary to define the efficacy
parameters before pivotal double-blind
placebo-controlled trials are undertaken
in the DS population.
ARTICLE
STUDY MEDICATION
There are two important features to the
selection of a study medication, which
can be a pharmacological agent or a
nutritional supplement. First and foremost, the study medication must be safe.
Second, there must be some reasonable
expectation (scientific rationale) that the
medication will have a positive effect on
the targeted behavior and/or condition.
Safety is a relative concept based on the
degree of risk versus anticipated benefit.
A higher degree of risk can be tolerated
when the benefit is life saving. When the
targeted benefit is improved functional
ability, the medication risks (side effects)
must be relatively minor (i.e., greater
than the physical and/or psychological
risk ordinarily encountered in daily
life or during the performance of
routine physical or psychological examinations) and present the prospect of
direct benefit to the individual subject
[Duke University Medical Center,
unpublished].
Due to ethical and liability issues, it
is unlikely that a new drug would be
directly introduced to a pediatric population, much less a pediatric DS population. However, it is reasonable to
consider the off-label use of drugs
approved for adult use, particularly when
those drugs target cognitive function.
When considering nutritional supplements or the off-label use of an adult
drug in children, it is important to realize
that too much of a good thing may be
harmful. Megavitamins in large doses,
for example, can be toxic to a child
[Litovitz et al., 1994; Barrueto et al.,
2005].
The DS condition adds another
layer of complexity to the dosing question. Specifically, what is the effect of the
extra chromosome and the genes in
triplicate on the targeted therapeutic
pathway? Animal models of therapeutic
pathways, such as the mouse model of
DS, may contribute to our understanding of the therapeutic pathway, but
animal models in general cannot model
the extent of human complexity. In
order for an animal model to recapitulate
the phenotypic consequences in DS, all
interacting genes must be present in
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
three copies. Segmental trisomy mouse
models of DS that include the Ts65Dn,
Ts1Cje, and Ts1Rhr [Sago et al., 1998;
Costa et al., 1999; Olson et al., 2005], are
trisomic for regions of mouse chr16, but
not for all genes. Due to the lack of a
mouse model with all features of DS, a
number of studies need to be done
directly in patients.
Adequately designed, well-controlled pharmacokinetic (PK) studies of
the target population provide critical
data for dosing decisions. In the case of
children with DS, the PK studies need to
be completed with the same-aged children as targeted in the efficacy trials,
because developmental changes influence absorption [Yaffe and Aranda,
1992]; distribution [Gilman, 1990];
metabolism [Brown and CampoliRichards, 1989]; excretion [Brown and
Campoli-Richards, 1989]; and protein
binding [Rane et al., 1971]. PK studies
can determine tolerability and blood–
serum levels. However, blood–serum
levels are not necessarily predictive of
medication levels in the brain due to the
blood–brain barrier.
Positron emission tomography
(PET) provides the opportunity to document dose–response according to overall
brain uptake and on targeted locations,
such as the cerebellum, amygdala and
hippocampus; where decreased volume
has been considered the neuroatomical
basis for functional deficits in individuals
with DS [Aylward et al., 1999; Pinter
et al., 2001a,b]. Functional MRI (fMRI)
offers the potential for the ultimate dose–
response analysis, that is, the analysis of
the dose versus specific neuropathway
function associated with the cognitive
tasks under investigation. However,
fMRI requires an extended period of
interaction while the patient is positioned
within a MRI scanner; a challenge that
even many adults cannot tolerate.
In our investigation of cholinesterase inhibitors (ChEIs) including donepezil hydrochloride [Heller et al., 2004]
and rivastigmine tartrate [Heller et al.,
in press] for treating cognitive deficits in
children with DS, we have found that
the effective dose for children with DS
can vary between subjects and that the
relationship between dose and thera-
peutic effect is not linear, that is, once an
effective level is reached, the higher dose
only produces more adverse effects, not
higher performance. In our trial of
rivastigmine tartrate, a significantly
lower dose of drug (compared to
recommended adult levels) with a slower
titration schedule was better tolerated
and produced fewer adverse effects. The
availability of a liquid formulation of the
study medication (rivastigmine tartrate)
helped include children with DS in the
study who have difficulty swallowing
pills and also provided flexibility in
dosing and titration.
SUBJECTS
In clinical research, the selection of the
subject sample directly relates to the trial
success and to the generalizability of the
results. However, when investigating the
pharmacological effects of a study drug
on a vulnerable population such as
individuals with DS, the generalizability
In clinical research, the
selection of the subject
sample directly relates to
the trial success and to the
generalizability of the results.
However, when investigating
the pharmacological effects of
a study drug on a vulnerable
population such as individuals
with DS, the generalizability
of results must be secondary
to safety.
of results must be secondary to safety.
Because of the variability in health status,
comorbidities, and educational placements in children with DS, it is important to establish strict inclusion and
exclusion criteria. To this regard, all
subjects recruited into our series of trials
investigating the cognitive effects of
cholinergic agents have had a documented diagnosis of trisomy 21 and were
191
8 years of age or older, verbal and
intelligible (capable of reporting pain
or other adverse events) with IQs within
the mild to moderate range of mental
retardation.
This focus on subject safety extends
beyond subject selection criteria. In
order to be enrolled in research, the
subject’s family/caregiver must provide
informed consent and be willing to
participate actively in the study. This
commitment includes a willingness to:
(a) attend multiple visits; (b) store and
dispense the appropriate daily dose of
study medication; (c) clearly communicate any concerns that they may have
about the study; (d) attentively observe
and report changes in the health and
behavior of their child; and (e) maintain
open and frequent contact with the
study team. This contact is particularly
important when side effects occur or
dose changes are made.
Recruiting subjects and their
families with these extensive enrollment
criteria introduces bias into the sample.
Individuals who are unintelligible, nonverbal, functioning below a moderate
level of mental retardation or who are not
fluent in English are excluded. Similarly,
the requirements for caregiver support
selectively include families with sufficient
resources to attend multiple sessions and
remain committed to their roles of
observation and reporting. Recruiting
efforts add additional bias. In an attempt
to obtain a large and diverse pool of
potential subjects, we advertise for subjects through local and regional DS clinics
and support groups and through the
National Down Syndrome Society. Our
published work and presentations at
regional and national conferences also
serve to elicit family interest in participating in new studies. Through these
recruiting efforts, there is a tendency to
enroll subjects from families who are
more highly educated, more sophisticated regarding patient advocacy, and
more highly motivated to anticipate the
possibly of change in their children.
SAFETY
The overarching goal in conducting
clinical research in children is to protect
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them from harm, but also give them the
opportunity to participate in research
from which they may benefit [Society
for Adolescent Health Research, 2003].
Data establishing the safety of an investigational agent in the adult population
cannot be extrapolated to children;
therefore, there is a pressing need for
studies involving children as research
subjects.
All aspects of the study design
identify subject safety. The subject
inclusion and exclusion criteria identify
subjects capable of reporting pain or
poor health, eliminate subjects at particular risk due a compromised medical
condition, and reduce and/or eliminate
potential drug interactions due to concomitant medications. Dose and titration schedules are designed to minimize
adverse effects. In addition, regular clinic
visits, caregiver training for adverse
event reporting and an extensive monitoring schedule minimize the impact of
adverse events should they occur. However, despite careful inclusion criteria,
adverse events will occur. It is essential
that all potential adverse events are
recorded and considered in terms of
the subject’s continued role in the study.
The adverse event analysis is critical to
determining the relative safety of the
experimental medication.
Capturing adverse events in an
objective way is a difficult task. In regard
to study design, objective thresholds for
adverse events should be determined
prior to conducting the study. An
adverse event may be identified by
abnormal laboratory parameters, symptoms showing toxicity, or significant
changes in health or behavior. A serious
adverse event is one that is life-threatening, causes a congenital defect, or that
leads to hospitalization or a prolongation
of hospitalization.
Whenever a change in dose is made,
careful monitoring of the subject must
occur, especially following the initiation
of the first dose. Expected side effects,
based on the available study medication
package insert, should be systematically
reviewed with the caregiver and
included in the safety data analysis for
each visit. It is also important to
complete a thorough review of systems
to capture unexpected side effects that
may or may not be related to the study
drug. In addition to a systems review at
study visits, adverse events must be
captured also between study visits. There
are standard approaches to collecting and
analyzing adverse events, examples
include the Adverse Drug Reaction
probability scale [Naranjo et al., 1981]
and the Common Terminology Criteria
for Adverse Events version 3.0 [Trotti
et al., 2003]. Individual institutional
review boards also have rules as to how
adverse events must be reported. The
adverse event analysis completed in our
research involves documenting each
adverse event and then rating that event
in terms of severity (mild, moderate, or
severe), expected or unexpected and
related or unrelated to the study. Our
safety analyses include a detailed investigation of severe adverse events (should
they occur) and the reason why subjects
drop out of studies. Mild and moderate
adverse events are documented and
reported. Comparisons of adverse events
across drug and placebo conditions are
completed in double-blind, placebocontrolled studies.
EFFICACY
Efficacy, the critical element of a clinical
trial that determines whether or not the
study medication is beneficial, has two
key aspects. First of all, does the experi-
Efficacy, the critical element
of a clinical trial that
determines whether or
not the study
medication is beneficial, has
two key aspects. First of all,
does the experimental drug
have an effect on the intended
outcome? And second, if the
experimental medication does
have an effect, is this effect
clinically relevant?
ARTICLE
mental drug have an effect on the
intended outcome? And second, if the
experimental medication does have an
effect, is this effect clinically relevant? In
terms of the study of cognitive function
in individuals with DS, these issues boil
down to: (a) whether the study medication improves cognitive function in some
measurable way, and (b) whether or not
this improvement in cognitive function
will improve the individual’s quality of
life. On the surface, these issues seem
quite straightforward, but in practice they
are not. In fact, a given study medication
may indeed have an effect on cognitive
function, but unless this effect can be
measured, the medication effect will
never be known. In order to demonstrate change across a group of subjects,
the medication must have the capacity to
effect change, the subjects must have the
ability to demonstrate change, and the
investigators must have the capability of
measuring the change through structured interactions with the subjects and/
or the subject’s caregivers.
An ongoing task of the Duke DS
Research Team has been to assemble a
test battery that is appropriate for the
subjects’ developmental skill levels and
sensitive to the effects of cholinesterase
inhibitors. In order to minimize psychometric testing issues such as content
validity, construct validity, concurrent
validity, and test–retest reliability, standardized test measures are used to a large
extent. It is important to note that most
measures of cognitive function have
been standardized on the general population. Age-matched individuals with
DS fall on the extreme end of the
performance scale on these tests, typically below the first percentile. The use
of age appropriate scales for individuals
with DS in clinical trials is not particularly useful because these scales are
generally insensitive to performance
change in the DS population. Rather
than using a test battery composed of
age appropriate scales, developmentally
appropriate scales are used. Typically
these tests have more items at or near the
subject’s functional level and thus are
more sensitive to change. Unfortunately, the standardized scores, adjusted for
the age of the typically developing
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
individual upon whom the test was
normed, are most often not appropriate
for individuals with DS.
An alternative approach to measuring performance change is the use of raw
scores (the total number of items correct)
rather than standard scores. With the use
of raw scores, the investigator links
performance change over time to specific test items. This can provide additional insight into the study medication
effect. However, raw scores (unlike
standard scores) do not factor some
psychometric test error, such as test–
retest reliability, into the analysis. Therefore, when using raw scores in the
efficacy analysis, it is particularly important to select test measures that are well
designed, that is, contain minimal test
error, and are extremely sensitive to the
developmental level of the subject. In
that way, the impact of psychometric test
error on performance change is minimized. Additionally, the careful selection of tests that are highly sensitive to
performance change in individuals with
DS can eliminate test ceiling and floor
effects which can cause an investigator to
conclude that there is no medication
effect when one really exists (Type II
error) [Heller et al., in press].
When working with children with
DS, it is also important to understand
that while the performance measurement system may be exquisitely
designed, the quality of the analysis is
contingent upon the quality of the data.
In this case, the old adage of ‘‘garbage in
garbage out’’ holds true. If the subject is
not motivated to provide his/her optimal performance at any given session,
then the results of that session are
compromised. Because determinations
of medication effects are based on
performance change across sessions, it
is critical that these performance changes
are not contaminated by subject motivational factors. It is an important and
substantial challenge for a research team
to elicit optimal performance from
individuals with DS at each test session.
Based on the experience of the Duke DS
Research Team, there are a number of
factors necessary to optimize the performance of individuals with DS at each test
session (Table II).
To this point, we have discussed the
importance of establishing a test battery
that is sensitive to performance change
in individuals with DS and the importance of obtaining optimal performance
from the subjects at each session to
accurately quantify the effect of the
medication on performance. However,
we have yet to define cognitive function
and how it should be measured. Cognitive function is a broad term encompassing multiple functional domains.
The domains of interest in our studies
of cholinesterase inhibitors are: Adaptive
Function, Language (expressive and
receptive), Attention, Memory, and
Associative Processing. Within each
domain, we have included several different measures or subtests in an effort to
capture and better understand a potential
medication effect. The inclusion of
multiple measures also helps address the
193
obvious complexity inherit in each
domain, such as the different aspects
of language (receptive versus expressive)
or memory (visual versus auditory,
short-term versus long-term). As discussed in the Study Design section
above, there is a trade-off between
investigating the potential medication
effect across multiple cognitive domains
and the statistical power to demonstrate
that the experimental medication has a
statistically significant effect on the
functional capability of individuals with
DS.
We would argue that in the current
exploratory stage of research that it is
is important to consider the broad
potential effect of the study medication
We would argue in the current
exploratory stage of the research
that it is important to consider
the broad potential effect of the
study medication in order to
identify the possible mechanisms of action and to better
understand the potential of the
study medication for use in
individuals with DS.
in order to identify the possible mechanisms of action and to better understand
the potential of the study medication for
TABLE II. Factors Important for Eliciting Optimal Performance From Individuals With DS
1. A clinically trained research team with substantial experience in testing children and adults with cognitive disabilities.
2. Establishing a positive relationship so that the individual looks forward to additional visits. In this regard, we have learned to design a
screening session into our trials where no efficacy data are collected. The purpose of this visit is to provide a second review to ensure
that the subject and his/her family meet the inclusion criteria and are fully informed about the study and to establish the rapport
between the examiners and the subject. The screening visit is particularly useful in reducing the anxiety level of the subject and the
subject’s family.
3. Eliminate all distracters from the test environment, including interruptions, noise, and observers of the performance.
4. Insert as few changes as possible across sessions, that is, maintain the same examiner, maintain order of testing, test in the same room in
the same orientation with the same decorating scheme, provide the same auxiliary services, that is, snack and/or lunch at the same time
each session.
5. Communicate a positive expectation of optimum performance from the very start of the study and maintain that expectation
throughout.
194
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
use in individuals with DS. However, it
is also important not to lose sight of the
goal of clinical relevance, because ultimately, clinical relevance will determine
whether or not a particular medication is
used. For example, in our research, we
are eager to demonstrate that a cholinesterase inhibitor, such as donepezil
hydrochloride or rivastigmine tartrate,
improves the expressive language ability
of individuals with DS. However, unless
we can demonstrate how an increase in
language function of this magnitude
improves the quality of life for individuals with DS, it is unlikely that the
clinical use of this medication with
individuals other than the study subjects
would be endorsed.
To this end, we include multiple
measures of overall function (i.e., adaptive function) as well as measures of
specific cognitive domains in our
research. We are particularly excited
when study results demonstrate performance improvement in particular
cognitive domains and simultaneous
improvement in adaptive function. This
type of result not only strengthens the
hypothesis that cholinergic therapy can
improve aspects of cognitive function in
children with DS; it also suggests a
potential mechanism for this result.
Another challenge is the potential
impact of floor and/or ceiling effects in
the measures comprising a domain. At
the very least, the investigators must be
mindful of the subjects’ estimated mental
age in choosing their measures. Including tasks that are too difficult can often
lead to behavior problems, such as
increased frustration and refusals to
continue working. Tasks which are too
easy for the majority of the subjects may
eliminate the possibility of observing a
drug effect.
SUMMARY
The issues of clinical trials for the
enhancement of cognitive function in
children with DS are challenging and
complex, but they are not insurmountable. As with the development of
leukemia research in DS, research successes are incremental and are achieved
through the collaborative efforts of
multiple stakeholders. Funding for clinical research in cognitive function in DS
will increase when families, caregivers,
The issues of clinical trials for
the enhancement of cognitive
function in children with DS
are challenging and complex,
but they are not insurmountable.
As with the development
of leukemia research in DS,
research successes are
incremental and are achieved
through the collaborative efforts
of multiple stakeholders.
and individuals with DS aggressively
seek private and public support for
answers to optimizing functional ability
and quality of life. New therapy alternatives will arise as private industry
tackles comparable issues in conditions
such as Alzheimer disease, stroke, and
head injury. Similarly, new research ideas
will evolve as the research community
comes together to tackle these issues
from many different perspectives. We
hope that this discussion will raise awareness of the need for clinical research in
the cognitive function of children with
DS and the value of experienced multidisciplinary research teams who design
and manage these types of trials.
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