SELECTING OUTCOME MEASURES IN PAEDIATRIC MITOCHONDRIAL ENCEPHALOPATHY: A PILOT STUDY

At this moment, there is no cure for mitochondrial disease, but drug
development is quickly progressing(1, 2). We have just completed a phase 2
trial in adults with the m.3234A>G mutation in our centre, of which the results
are pending. Parallel to the execution of this trial, we are preparing for
paediatric trials for which the outcomes of this pilot study are crucial.
The phenotype of mitochondrial disorders is extremely heterogeneous, even
between patients with the same syndrome or genetic diagnosis and varies in
time. Therefore, choosing a population and/or endpoints for these studies is
exceptionally challenging. Pure mitochondrial myopathies, which are part of an
ongoing validation study, are extremely rare. The majority of the children
suffer most from involvement of the brain (mitochondrial encephalopathy). The
clinical and genetic spectrum of mitochondrial encephalopathies varies widely,
ranging from children with near-normal functional abilities to children who
barely make contact to their environment (3). Besides the functional abilities,
the genetic, biochemical and clinical profile also differ, almost from patient
to patient (4). Common symptoms include: mental retardation, autism or autistic
like spectrum, epilepsy (focal or generalized), diminished consciousness, optic
neuropathies, movement disorders (extrapyramidal, pyramidal or cerebellar
leading to e.g. tremors, dystonia and ataxia) and spasticity.
The clinical trials in paediatric mitochondrial disease that have been
performed so far have all failed to reach their primary endpoint. Next to the
possible lack of effect of the drugs evaluated, this could be due to
inappropriate study design and selection of a population which was so limited
in their abilities to follow instructions that measuring outcome reliably was
virtually impossible. Therefore, most of the studies that are performed by
international colleagues focus on adults with mitochondrial disease, mostly
suffering from a pure mitochondrial myopathy like in CPEO plus like syndromes.
Although clinical research is more challenging in children, especially in those
with disabilities, the Radboud Centre for Mitochondrial Medicine aims to
continue its efforts to also make the paediatric studies more robust. In this
study, we aim to gain more experience with the most common phenotype of
mitochondrial diseases: children with mitochondrial encephalopathy.

We hypothesize that by executing these pilot studies, we will be able to only
include relevant, feasible, reliable and valid outcome measures in our natural
history study. The psychometric data obtained in this study will be used to
select outcome measures for an international multicentre natural history study
in a key-opinion leader workshop.

Primary Objective:
Determine the relevance, feasibility, reliability (test-retest, inter- and
intra-rater) and validity of a selected set of outcome measures in children
with mitochondrial encephalopathy.

Secondary Objective:
Determine in- and exclusion criteria for the international multicentre natural
history study, based on the experience in the pilot study

This is an observational study to test the properties of the selected
instruments in the targeted patient group.

Participants will be asked to visit the outpatient clinic of the RCMM three
times; the study visits will last about 5 hours. The training session, baseline
measurement and re-test visit will be planned at three subsequent visits at the
same time of the same day of the week (2 weeks between training and baseline
and 1 week between baseline and retest). The training session is included
because most of these tests are already known to be subject to learning
effects. The baseline and the re-test visit are used to test the stability of
the measurement over time while the condition of the child does not change
(test-retest reliability). During the baseline measurement, children will be
seen by two physiotherapists (inter-rater reliability) and videotaped (for
intra-rater reliability). The validity of the measures will be determined by
correlating to patient- and physiotherapist-rated anchors. During the
measurements, relevance and feasibility will be determined, in close dialogue
with patients and their caretakers.

Participants will be asked to visit the outpatient clinic of the RCMM three
times; the study visits will last about 5 hours each, but the patients will
only be actively involved for less than 2 hours (lots of breaks and
questionnaires for parents). The time and the program for the baseline and
retest measurement will be determined at the training session. None of the
measurements will be painful or hazardous to patients. We aim to study the
measurement properties of these instruments in this group of patients. This
study is a preparation for a clinical trial in this condition and may
facilitate the proper conduction of the clinical trial in this condition. For
the patient, the conduction of so many tests is without any doubt burdensome.
Therefore, we reduced the number of test to to-our-opinion the absolute
minimum. When discussing our protocol with a parent of a patient with a mild
and a parent with a child with a mild encephalopathy, they felt that the
protocol was feasible. We will make a summary of the measurements after the
first measurement and at the end of the stud, when indicated answering a
question from clinical care.
This study must be conducted in minors and incapacitated subjects because we
assess the measurement properties of these tests in this population.