6 minutes assisted leg and arm cycling test: feasibility, validity, test-retest responsivity and responsivity in patients with neuromuscular and metabolic disorders

More and more clinical studies are performed in neuromuscular disorders, mostly
using rational therapies based on thorough knowledge of the pathophysiology and
molecular alterations.

To see the effect of these experimental interventions on the patient*s health
status, it is important to have reliable outcome measures. Functional outcome
measures reflect the functional abilities of the patient in daily life. These
outcome measures may be questionnaires, timed tests, dexterity tests and
exercise tests. Since exercise capacity is the most widely used functional
outcome in current clinical trials for neuromuscular and metabolic disorders 1
and endurance is in our opinion very sensitive to general disease progression,
it is important to validate feasible and sensitive exercise capacity outcomes
that are responsive to change.

In adults, the gold standard for measuring exercise capacity is an incremental
workload exercise test on an electronically braked, pedal rate-independent
cycle ergometer to measure peak working rate, parallel measuring oxygen
consumption and heart rate. In young or diseased children, this test is not
feasible and too burdensome. In addition, since most daily activities are
performed at submaximal levels of exertion, it has been proposed that
submaximal functional test are a better reflection of physical capacity and the
ability to perform the activities of daily life 2.

Currently, the 6-minute walking test (6MWT) is the most used measure to test
exercise tolerance. In this test, children are asked to walk (not run) as far
as possible in 6 minutes. The test has a high correlation with the standardized
maximum incremental exercise testing on a treadmill 2 in healthy adolescents,
and with aerobic fitness in healthy schoolchildren 3. The 6MWT also correlates
with aerobic fitness in children with Cystic Fibrosis 3 and had a high
reproducibility in boys with Duchenne Muscular Dystrophy (DMD) 4. However, even
ambulatory boys had a high likelihood of falls. Besides the risk of injuries
during the challenging test, most children with neuromuscular or mitochondrial
disorders are wheel chair bound or won*t be able to walk safely for 75 meters.
Above this in most children with neuromuscular disorders osteoporosis is
present with an increased risk of fractures while falling. This will limit the
amount of subjects to be included in studies using the 6MWT as an outcome
measure.

We developed an assisted 6 minutes cycling test (A6MCT) for arms and legs. This
test is also feasible for wheel chair bound patients. And, since it is an
assisted test, it is also suitable for patients who are not able to do a normal
cycling test, because of muscle weakness, hypotonia or severe exercise
intolerance. Heart rate and subjective level of fatigue are monitored and to
exclude bias from behaviour-tiredness and lack of motivation, the level of
fatigue is measured by surface EMG. Heart rate is also used for safety
monitoring. The a6MCT was validated in healthy boys aged 6-12 years of age and
compared to boys with DMD. In this study with healthy boys and in boys with
DMD, the a6MCT validity was good, repoducability was high and the test was
feasible and reliable for boys with DMD.

Since there is no gold standard for exercise capacity in children, we take the
6MWT because it is the most widely used test with a very good reliability and a
good correlation with the gold standard for exercise capacity in adults.
Therefore, we will correlate the distance walked in the 6MWT with the number of
revolutions on the A6MCTleg/arm to validate the A6MCT. A disadvantage of
choosing this test, is that we can only include ambulatory patients which are
able to walk safely for 75 meters. We use several other functional (secondary)
outcome measures to create a broader picture of the (dis)abilities of the
patients, which is interesting in interpreting the value of the A6MCT for the
general functional status of the patients. Especially the Motor Function
Measure is a well defined test of motor functions, not disease specific but
developed for disorders with flaccid paresis, and proven valid and sensitive
for change. Sample sizes are calculated per disease, using the percentage of
predicted achievement on the 6MWT and the expected variance to predict the
number of children needed. Since there is a widely used test to follow-up on
patients with patients with Friedreich Ataxia, namely the FARS (no gold
standard), we also perform this test in this group.

We choose to include a diverse pallet of diseases in our study. The main groups
are the muscular dystrophies and the mitochondrial disorders (including
Friedreich Ataxia (FRDA)). We also chose to include patients with Congenital
Disorders of Glycosylation (CDG), another multisystem disease with muscle
weakness, hypotonia and mild exercise intolerance. All diseases included in
this study are rare diseases, all of main interest in our centre. None of the
groups have adverse effects of exercise, other than tiredness and (possible)
muscle pain.

1.1 Goals and hypotheses

In this study, we aim to test the feasibility of the assisted six-minute
bicycle test in several groups of patients with neuromuscular and metabolic
disorders. Since the bicycle test is assisted, we hypothesize that the test is
feasible in children with severe muscle weakness or exercise intolerance. We
also hypothesize that in six minutes, a difference between the muscle weakness
and exercise intolerance will be revealed, without challenging to children with
exercise intolerance too much. In previous studies in healthy boys and boys
with DMD, the a6MCT has already shown to be feasible and therefore we hope that
the test will also be feasible in young children and children with cognitive
impairment or mild behavioural problems, since part of the tested boys had
comparable problems.

We also aim to test the validity of the test in the various groups of children
with neuromuscular and metabolic diseases. The validation however, is a
difficult part of the study, since there is no gold standard to measure
endurance or exercise capacity in children, nor a gold standard to measure
disease severity in any of the diseases. Since the six-minute walking test is a
valid and widely-used outcome measure for exercise capacity in children, we use
this test as a reference for the validation of the six minute assisted bicycle
test. A previous study has already shown that the A6MCT is positively
correlated to the 6MWT in healthy boys (manuscript in preparation). A small
sample of three boys with DMD, who performed the 6MWT and a6MCT, showed the
same trend. This limits our study population, since we can only investigate
ambulatory patients. To be able to recruit enough patients, we chose to have at
least 50% ambulatory patients in our population. Secondary, we will also
correlate the findings at the six minute assisted cycling test with the
widely-used timed up and go tests, disability tests and the Motor Function
Measure. The Motor Function Measure is the most reliable and widely used
outcome measure in children with flaccid paresis and proven valid for various
neuromuscular and metabolic disorders. All tests (6 minutes bicycling test with
arms and legs, the 6 minute walking test and the timed up and go test) are also
performed in stratified selected healthy girls aged 6-16 years and boys aged
13-16 years, since the data gathered at previous studies only include boys. We
will support our validity tests with details about the neurophysiology and
other parameters of endurance such as heart rate and subjective fatigue in
patients with pure muscle weakness (e.g. DMD) and combined muscle weakness with
profound exercise intolerance (mitochondrial disorders).

The test-retest reproducibility of the A6MCT will be assessed by repeating the
test within two weeks. Since this might be a burden for some patients and their
parents, this re-test is optional. Patients indicate after the first tests
whether they will proceed with the repeat test. At this day, only the A6MCT
will be repeated in patients with neuromuscular diseases since the other tests
have already been validated in this group. For the patients with metabolic
disorders, all tests, except for the MFM will be repeated.

The responsivity will be tested within one year, since the MFM is valid for
repetition within one year. At that day, all tests will be repeated, including
timed tests, 6MWT and MFM.

The feasibility tests will be performed in eight diseases, either neuromuscular
or metabolic diseases. The primary goal is to test the feasibility in either of
these populations, it is only a secondary goal to compare between groups and to
healthy individuals.

1.2 Relevance of the study

There is still no cure for Duchenne muscular dystrophy, Beckers muscular
dystrophy, Limb Girdle muscular dystrophy, Myotonic dystrophy, Spinal Musclar
Atrophy, Mitochondrial disorders, Friedreich ataxia, and Congenital Disorders
of Glycosylation. Worldwide, there is a lot of effort being done to provide a
cure for these rare diseases, but the lack of feasible and reliable outcome
measures for non-ambulatory patients causes the number of included patients
(and thus the power) in studies to be low. In this study, we aim to validate an
outcome measure that is, in our opinion, a promising outcome parameter for
neuromuscular diseases which limit muscle strength and endurance.

The scientific relevance will be high if the test proofs feasible and valid for
one or more groups of patients included in this study. Since exercise capacity
is one of the most important outcome measures for neuromuscular and (especially
for) mitochondrial disorders, the assisted cycling test might be a promising
primary outcome measure for future clinical trials. Many researchers around the
world face the lack of valid functional outcome measures for non-ambulatory
patients with neuromuscular or mitochondrial disorders. Especially since there
are more and more clinical trials performed in these patient groups, there is a
need for a feasible, valid, relevant and quantifiable outcome measure that is
easy to perform and can be used internationally.

This study will also provide information on the fatigability of patients with
neuromuscular disorders as well as reference values for children aged 6-18
years, both healthy and diseased. In boys with DMD there is a quite steady
walking velocity at the 6 minute walking test 4. We expect the same results in
the cycling test, which has been shown previously in healthy boys and boys with
DMD.

The study will be conducted in children, since all disorders are most prevalent
in childhood and severely impair children, already in their early teenage
years. Moreover, we specifically aim to study the feasibility of this outcome
measure in children since clinical trials in these diseases will also be
performed in the pediatric population.

2.1 Primary Objectives:

1) To test the feasibility of the six minute assisted leg and arm cycling test
in patients aged 6-18 years with Duchenne muscular dystrophy (DMD), Beckers
muscular dystrophy (BMD), Limb Girdle muscular dystrophy (LGMD), Myotonic
dystrophy (MyoD), Spinal Muscular Atrophy (SMA) Mitochondrial disorders (MiD),
Friedreich ataxia (FRDA), and Congenital Disorders of Glycosylation (CDG). The
test is successful if the test is completed (cycling the full 6 minutes,
possibly with pauses but restart within 15 seconds) without complications like
pain or stifness.

a) To give a detailed description of the patients in which the A6MCT is not
feasible (clinical condition; age; presence of spasticity, hypotonia, mental
retardation, behaviour problems; why the test failed; MFM; 6MWT; timed tests).

2) To validate the six minute assisted leg and arm cycling test compared to the
6 minute walking test (widely accepted test for endurance in children) as a
functional outcome measure in patients aged 6-18 years with healthy controls,
DMD, BMD, LGMD, MyoD, SMA, MiD, FRDA and CDG if still ambulant. If the patients
is non-ambulatory, we will use the MFM to test construct validity.

3) To determine the test-retest reproducibility and responsivity of the six
minute assisted leg and arm cycling test in patients aged 6-18 years with DMD,
BMD, LGMD, MyoD, SMA, MiD, FRDA and CDG.

2.2 Secondary Objectives:

1) To compare the number of revolutions on the A6MCTleg/arm, the objective
(sEMG amplitude and frequency) and subjective fatigue, and the heart rate at 3
and 6 minutes of patients with neuromuscular disorders (muscle weakness) and
mitochondrial disorders (exercise intolerance).

2) To correlate the number of revolutions on the A6MCTleg/arm to the Motor
Function measure (lower extremity part).

3) To correlate the number of revolutions on the A6MCTleg/arm to the Motor
Function measure (upper extremity part).

4) To obtain reference values for the six minute assisted leg and arm cycling
test in healthy girls aged 6-18 years and healthy boys aged 13-16 years.

5) To correlate the number of revolutions on the A6MCTleg/arm to the Friedreich
Ataxia Rating Scale (FARS) in patients with FRDA.

6) To compare the slope of the the number of revolutions on the A6MCTleg/arm
between neuromuscular and metabolic diseases.

In this study, patients with various neuromuscular and metabolic disorders
(DMD, BMD, LGMD, MyoD, MiD, FRDA and CDG) as well as healthy controls will be
included.

3.1 Controls
Control girls and adolescent boys will be recruited by approaching local
schools. If too many controls subscribe, a randomized subset will be drawn,
stratifying for gender and age. After informed consent (see 8.2 Recruitment),
patients are stratified randomized in two groups. First, they are asked to
cycle on the Dynamic bicycle in 6 minutes (A6MCT), as far as possible,
randomized for arms of legs first. There will be a pause of 15 minutes between
arms and legs. In all children, heart rate will be monitored and subjective
fatigue will be monitored. After a break of 30 minutes and a glass of lemonade,
controls are asked to walk as far as possible in 6 minutes (6MWT). After a
break of 10 minutes, the timed up and go and 10 meter walking test will be
performed in both groups.

3.2 Patients
Patients will be recruited at our outpatient departments or via patients*
organizations (see 8.2 Recruitment). Patients will be asked to come to our
outpatient department. If the patient has a wheelchair for long distances, they
are asked to use it to come to the outpatient clinic to decrease the
possibility of fatigue on forehand. After informed consent, patients are
included in the study. The Brooke and Vignos scale is filled in. Patients are
stratified randomized in two groups, arms first or legs first. First, patients
are asked to perform both A6MCTs. There will be a pause between the leg and arm
tests of 15 minutes. Fatigue will be monitored by surface EMG to monitor
fatigue in the thigh muscles, heart rate and a subjective fatigue scale. After
a break of 30 minutes, the 6MWT is performed. In this test, it is allowed to
rest against the wall but not to take a sit. After a break of 10 minutes, the
timed tests and the MFM will be performed in both groups. The validation tests
will also be performed in children in whom the A6MCT was not feasible, to
define the group in which the A6MCT cannot be used.
With all tests, two researchers will be present to support the children and to
catch them if they might fall during the 6MWT.

Both healthy controls and patients will be asked to call in case of serious
adverse events, such as severe muscle pain or exhaustion. Patients will be
called one week after the tests to ask for adverse effects of the exercise.

Children will not benefit from this study. However, for the future of
therapeutic trials in children with neuromuscular and metabolic diseases, this
study will be of great value. Since endurance is an outcome which is relevant
to the patient and his quality of life, and it is a non-invasive outcome
measure, it is a promising technique to be used in future clinical trials. The
outcomes of this study can be used for advices concerning training in regular
physiotherapy.
Since most patients we study don*t survive into adulthood or their functional
abilities are quite different in adulthood compared to childhood, we depend on
children to perform our study. In previous studies patients enjoyed the cycling
test.
We don*t expect major risks in our study. Since we select patients who can
safely walk for 75 meters, also the 6 minute walking test will be quite safe.
However, there is always a risk of falling. Also, patients with severe
cardiomyopathy are excluded. There are no serious adverse effects of short
exercise in any of the groups, apart from tiredness and muscle pains. The
effort of the exercises can be compared to playing outside or having
physiotherapy. Since we select patients based on their ability to walk safely
for 75 meters, we think they will walk further distances in daily life. Also,
we try to prevent adverse effects of the exercises by regular pauses.
Patients are asked to come to the Rehabilitation outpatient clinic for three
hours, if possible combined with another appointment in the hospital. The tests
together take about 45 minutes in total, there is time to rest and have a drink
between all tests.