Randomized, double-blind, placebo-controlled crossover study to validate finger tapping tasks for the quantification of levodopa/carbidopa effects in Parkinson*s Disease patients.

Prolonged dopamine (DA) replacement and DA agonist therapy for Parkinson*s
disease (PD) is associated with unwanted motor fluctuations. These motor
fluctuations tend to occur when DA medication is wearing off, referred to as ON
and OFF states. ON state is characterized by stable motor functioning at the
medication*s optimal efficacy level. OFF state is characterized by recurring
parkinsonian symptoms [1]. These motor fluctuations have a sudden or slow onset
[2]. Early in the treatment process, OFF states are predictably linked to
decreased DA plasma concentrations, however they can become unpredictable when
DA treatment is continued over the years [2].
Drawbacks of Current Clinical Endpoints. PD severity is assessed by the
Unified Parkinson*s Disease Rating Scale (UPDRS) and its Movement Disorder
Society (MDS-UPDRS)-revised version. Currently, the MDS-UPDRS is the *gold
standard* in clinical studies on PD. The MDS-UPDRS is a four-part scale
assessing (i) non-motor experiences of daily living, (ii) motor experiences of
daily living, (iii) motor examination and (iv) motor complications. The
MDS-UPDRS part III is often used to monitor therapeutic efficacy by assessing
motor function improvement in response to dopaminergic treatment or rate of
progression of motor function decline over time. However, as motor symptom
severity assessment occurs via observer ratings, the scale*s applicability
poses certain disadvantages. First, MDS-UPDRS assessment can be subject to
varying inter-rater reliability [3]-[5]. Second, patient visits and MDS-UPDRS'
examinations are time consuming and costly. Lengthy assessments are not
feasible when examining treatment effects of fast-acting dopaminergic agents.
Third, clinician-based rating scales lack sensitivity to precisely monitor
motor fluctuations throughout a day. Currently used patient reports and diaries
can be subject to recall bias or faulty self-assessment [4]. Taken together,
there is a need for a shorter and more reliable tool to assess dopaminergic
treatment effects.
Touchscreen based Alternate Finger Tapping. The alternate finger tapping task
(AFTT) is a short but sensitive test that differentiates between PD patients
and healthy controls. Additionally, the test can be used to detect ON versus
OFF states [6]-[11]. The test can be used to quantify symptoms of bradykinesia,
which is most responsive to dopaminergic treatment. Commonly used aspects to
quantify finger movement are the velocity, accuracy, total number of taps, and
the inter-tap interval. These clinical endpoints are related to the medication
state and the disease severity state. In addition, the variations of the AFTT
show good correlations with the MDS-UPDRS part III [7], [8].
Initially, arcade buttons were used in AFTT study setup [12]. This method has
been shown to detect ON/ OFF motor fluctuations [12]. However, an in-house
validation attempt failed at replicating these results. The experiment*s
failure is likely attributable to the configuration of the study. Arcade
buttons were found to be difficult for PD patients to press and while the total
number of taps can be measured, errors cannot be precisely assessed. One
advantage of touchscreens is that they are more sensitive to tap accuracy, and
are not dependent on the strength by which the subjects press the screen. In
turn, the touchscreen based interface can more efficiently and reliably
quantify PD upper limb motor movement and medication fluctuations than arcade
button setups. Therefore, a touchscreen-based setup is more appropriate to use
in future trials. As a future perspective, touchscreens are increasingly
available and potentially remote patient monitoring will become more feasible.
Taken together, there is a need for a validated, sensitive, and short test to
assess dopaminergic treatment effects. Literature suggests that finger tapping
tasks would be suitable for this purpose and would provide an additional
pharmacodynamic measure, which is shorter in duration than the gold standard
MDS-UPDRS part III. In this validation study, we chose a touchscreen based AFTT
and a goniometer since this is likely able to provide sensitive data regarding
tapping accuracy and speed and is not dependent on the strength by which the PD
patients can press the screen. The current aim of the study is therefore, to
assess whether the various finger tapping tasks is a sensitive measure in
discriminating between ON/OFF states, is responsive to dopaminergic (i.e.
levodopa/carbidopa) treatment and correlates with the MDS-UPDRS part III score.

Primary Objectives
Assess whether the finger tapping task endpoints:
• Differentiate between ON and OFF states in PD patients
• Correlate with the MDS-UPDRS part III total score
• Differentiate between placebo and levodopa/carbidopa treatment
Secondary Objectives
• Evaluate inter- and intra-subject variability of each endpoint of the finger
tapping tasks
• Evaluate user satisfaction of the AFT task and the goniometer

This is a randomized, double-blind, placebo-controlled, two-way crossover study
in PD patients with recognizable OFF episodes. Patients come to CHDR for two
treatment periods, each consisting of 2 days with 1 overnight stay. Between
treatment periods there is at least a one-week washout period. A maximum
washout of 3 weeks is allowed. Subjects are randomized 1:1 to one of the two
treatment sequences (either levodopa/carbidopa, followed by placebo or the
other way around). Subjects should withhold their own antiparkinsonian
medication in the evening prior to treatment in both treatment periods. Several
times prior and after dosing, finger tapping tasks and the MDS-UPDRS part III
will be performed.

Levodopa/carbidopa 100/25 mg, over-encapsulated oral tablets or placebo.

Levodopa/carbidopa 100/25 mg is a registered product and its side effects are
known. The most common side effects of are: dyskinesia, lack of appetite;
headache, paresthesia, muscle cramps, psychological disorders such as
hallucinations, confusion, daytime sleepiness, sudden sleep attacks, dizziness,
nightmares, insomnia and depression; chest pain, asthenia, heart palpitations,
orthostatic hypotension (especially when initiating treatment); dyspnea,
gastrointestinal disorders (nausea, vomiting, diarrhea, constipation, dry
mouth, dyspepsia). Patients that already use levodopa, or have used it in the
past, are included in this study, so side effects are expected to be limited
and/or known.
Even though the goal is to provide patients with a levodopa/carbidopa dose that
most closely matches their usual morning dose of Parkinson*s medication, there
is a risk of slightly under- or overdosing. This can lead to a prolonged OFF or
partial ON state, or dyskinesia. This is uncomfortable, but transient and
harmless.
On Day -1 of both treatment periods, patients are asked to withhold their usual
anti-Parkinson medication overnight. In the morning of Day 1 they will receive
the study treatment (placebo or levodopa/carbidopa). Due to withholding of the
medication, patients are expected to be OFF in the morning of Day 1. This is
characterized by increased Parkinson*s symptoms and generally perceived as
uncomfortable. Moreover, patients can experience some difficulty in returning
back to their normal disease state in the days thereafter.
There are no expected benefits for patients by participating in this study.