Effects of Droxidopa When Measuring Gait Speed, Kyphosis, and Functional Reach in Parkinson's Disease

Gait disorders and balance impairments are one of the most incapacitating symptoms of
Parkinson's disease (PD). Gait impairment in Parkinson's disease exists despite the use of
dopinergic therapy. Motor phenotype associated with postural instability and ambulatory
dysfunction is related to greater risk of motor decline and may be influenced by
non-dopinergic pathology (Galna et al., 2015). Galna et al. (2015) conducted a study to
document the progression of gait impairment over 18 months in individuals with Parkinson's
disease with regard to phenotype and medication. Gait characteristics were measured in 121 PD
and 184 controls, and 18 months later in 108 PD participants (Galna, 2015). Sixteen gait
characteristics were examined with respect to five broad domains for PD and motor phenotype.
Correlations between change in levodopa (l-dopa) equivalent daily dose and gait were used to
identify dopa-responsive and nonresponsive characteristics (Galna, 2015). Pace and rhythm
deteriorated over 18 months in people with PD, with other gait domains remaining stable.
People with a postural instability and gait difficulty phenotype had more impaired gait at
baseline compared with a tremor-dominant phenotype, which was most evident in temporal
characteristics (Galna, 2015). In contrast, pace and variability deteriorated over the
subsequent 18 months in the tremor-dominant phenotype only (Galna, 2015). Weak but
statistically significant correlations were found between increased l-dopa medication and
less deterioration in pace and asymmetry. Significant gait impairment is evident in very
early disease despite optimal medication (Galna, 2015).

For people with Parkinson's disease, there are fall risk factors specific to PD. These
include changes in posture, postural instability, freezing of gait, dyskinesias, gait
changes, medication side effects, and decreased ability to react automatically to a loss of
balance. Health and cognitive factors such as cognitive decline and depression can also
greatly increase the risk of falling. Contreras and Grandas (2012) conducted a study in Spain
that included 160 people with Parkinson's disease who were being seen at a movement disorders
clinic in Madrid. It was found that that fallers were older and had longer disease duration
(Contreras & Grandas, 2012). Subjects also had increased disease severity according to the
UPDRS (part III) and the Hoehn and Yahr scale, and lower scores on the Schwab and England ADL
test (Contreras & Grandas, 2012). In addition, fallers scored worse in the Mini-Mental State
Examination and experienced a higher frequency of motor fluctuations, dyskinesia, and
freezing of gait (Contreras & Grandas, 2012).

Among people with PD, recurrent falls are more frequent, with one study reporting that more
than 50% of the study participants fell recurrently. In another study involving a survey of
100 people with PD, 13% reported falling more than once a week, with most of these people
falling multiple times a day (Allen et al., 2013). Several risk factors for falls have been
found to be more strongly associated with recurrent falls than single falls. Some of these
factors are potentially modifiable, including cognitive impairment, freezing of gait, fear of
falling, reduced mobility, reduced physical activity, and balance impairments (Allen et al.,
2013). There is substantial variability in the falling rates reported in various studies,
with the proportion of fallers (single and recurrent) ranging from 35% to 95%. Differences in
the method of monitoring falls could contribute to this variability (Allen et al., 2013).
Despite the fact that recurrent falls are a substantial problem for people with PD, the scope
of, and risk factors for, recurrent falls in PD are not clearly understood (Allen et al.,
2013).

Elbers et al. (2012) investigated the predictive value of gait speed for community walking in
Parkinson's disease. A total of 153 patients with Parkinson's disease were included in this
study. Community walking was evaluated using the mobility domain of the Nottingham Extended
Activities of Daily Living Index (NEAI). Patients who scored 3 points on item 1 ("Did you
walk around outside?") and item 5 ("Did you cross roads?") were considered community walkers
(Elbers et al., 2012). Gait speed was measured with the 6-m or 10-m timed walking test. Age,
gender, marital status, disease duration, disease severity, motor impairment, balance,
freezing of gait, fear of falling, previous falls, cognitive function, executive function,
fatigue, anxiety and depression were investigated for their contribution to the multivariate
model (Elbers et al., 2012). Results indicated seventy patients (46%) were classified as
community walkers. A gait speed of 0.88 m/s correctly predicted 70% of patients as community
walkers (Elbers et al., 2012). A multivariate model, including gait speed and fear of
falling, correctly predicted 78% of patients as community walkers (Elbers et al., 2012).
Elbers et al. concluded timed walking tests are valid measurements to predict community
walking in Parkinson's disease. However, evaluation of community walking should include an
assessment of fear of falling.

Combs et al. (2013) conducted a study to determine test-retest reliability and responsiveness
of short-distance walking speed tests for persons with Parkinson disease (PD). Discriminant
and convergent validity of walking speed tests were also examined. Eighty-eight participants
with PD (mean age, 66 years) with mild to moderate severity (stages 1-4 on the Hoehn and Yahr
Scale) were tested on medications. Measures of activity included the comfortable and fast
10-m walk tests (CWT, FWT), 6-min walk test (6MWT), mini balance evaluations systems test
(mini-BEST Test), fear of falling (FoF), and the Activity-Specific Balance Confidence Scale
(ABC). The mobility subsection of the PD quality of life-39 (PDQ39-M) served as a
participation-based measure (Combs et al., 2013). Results indicated test-retest reliability
was high for both walking speed measures (CWT, ICC(2,1) = 0.98; FWT, ICC(2,1) = 0.99) (Combs
et al., 2013). Minimal detectable change (MDC(95)) for the CWT and FWT was 0.09 m/s and 0.13
m/s respectively (Combs et al., 2013). Participants at Hoehn & Yahr levels 3/4 demonstrated
significantly slower walking speed with the CWT and FWT than participants at Hoehn & Yahr
levels 1 and 2 (P < .01). The CWT and FWT were both significantly (P ≤ .002) correlated with
all activity and participation-based measures (Combs et al., 2013). In conclusion,
short-distance walking speed tests are clinically useful measures for persons with PD (Combs
et al., 2013). The CWT and FWT are highly reliable and responsive to change in persons with
PD (Combs et al., 2013). Short distance walking speed can be used to discriminate differences
in gait function between persons with mild and moderate PD severity (Combs et al., 2013). The
CWT and FWT had moderate to strong associations with other activity and participation based
measures demonstrating convergent validity (Combs et al., 2013).

Patients with Parkinson's disease (PD) or atypical parkinsonism often present with abnormal
posture. A retrospective observational study conducted by Doherty et al. (2011) showed that a
third of patients with PD had a deformity of their limbs, neck, or trunk. The most recognized
type of deformity is the classic stooped simian appearance, with flexion of the hips and
knees, and rounding of the shoulders (Doherty et al., 2011). Severe postural deformities
include kyphosis, camptocormia, antecollis, Pisa syndrome, and scoliosis. The underlying
pathophysiology of these deformities is largely unknown, and their management remains
difficult (Doherty et al., 2011).

Thoracic hyperkyphosis is one of the most common postural abnormalities. It is defined as
increased thoracic curvature in the sagittal plan of the vertebral column. Normal kyphosis
may range from 20º to 50º according to Cobb's radiographic method. The radiographic method is
the most popular kyphosis measuring method, but because it is an expensive method and it
exposes the individual to radiation, it is not the most appropriate method for periodic
patient follow-up. Routine clinical examinations such as physiotherapeutic evaluation of
thoracic kyphosis need to be valid, reliable, sensitive, practical and cheap.

A study by Teixeira and Carvalho (2007) assessed the reliability and validity of thoracic
kyphosis measurements using the flexicurve method. A cross-sectional study analyzed the
thoracic kyphosis of 56 people from sagittal radiography of the thoracic column using Cobb's
method and by means of the flexicurve method, by two evaluators. Results indicated he
intra-class correlation coefficient (ICC) between the measurements from the Cobb and
flexicurve methods was 0.906 (Teixeira & Carvalho, 2007). For diagnosing thoracic
hyperkyphosis, the sensitivity was 85% and the specificity was 97% (Teixeira & Carvalho,
2007). In conclusion, the flexicurve method was shown to be a suitable quantitative clinical
method for measuring the curvature of thoracic kyphosis (Teixeira & Carvalho, 2007).

The Get Up and Go test, the predecessor of the Timed Up and Go test (TUG), was developed by
Mathias and Nayak as a tool to screen for balance problems, primarily in the frail elderly.
The test measures how long it takes for a person to rise from a chair, walk 3 meters (about
10 feet) to a line on the floor, and return to the chair. The test correlates well with the
Berg Balance Scale, the Barthel Index of activities of daily living, and gait speed tests.
The Timed Up and Go modified the earlier version of the test by adding a timing component. An
adult who is independent in balance and mobility can perform the TUG in less than 10 seconds
(Shumway-Cook & Woollacott, 2007). In a study of older adults with a range of neurologic
pathologies, people taking 30 seconds or more to complete the TUG were more likely to need an
assistive device, walk too slowly for community ambulation, and score lower on the Berg
Balance scale. In contrast, a person completing the test in less than 20 seconds was more
likely to be independent in daily living activities, score higher on the Berg Balance scale,
and walk at a speed sufficient for community mobility (Podsiadlo & Richardson, 1991).
Shumway-Cook and Woollacott (2012) noted that the TUG can be used to predict the risk of
falls in older adults. In a study, 30 community-dwelling frail elderly adults were tested
using the TUG, and researchers found that those taking longer than 14 seconds to complete the
task were at high risk for falls. In the same study, the TUG was modified by adding a
cognitive task (counting backward by threes) and a manual task (carrying a full cup of
water). The addition of a secondary task increased the time need to complete the TUG by 22%
to 25% (Shumway-Cook & Woollacott, 2012).

Inclusion Criteria:

Inclusion Criteria:

1. 18 years of age or older.

2. Clinical diagnosis of Parkinson's disease.

3. Stable dose of current Parkinson's disease medication(s) for the past 2 weeks.

4. Stable deep brain stimulator settings for the past 2 weeks.

5. Provide written informed consent to participate in the study.

Exclusion Criteria:

1. Concomitant use of vasoconstricting agents for the purpose of increasing blood
pressure.

Patients taking vasoconstricting agents such as ephedrine, dihydroergotamine, or
midodrine must stop taking these drugs at least 2 days prior to baseline and
throughout the duration of the study.

2. Concomitant use of the following medications:

3. Anti-hypertensive medication for the treatment of essential hypertension

4. Vasoconstricting agents such as ephedrine, dihydroergotamine, or midodrine.
Concomitant treatment for symptomatic NOH (with the exception of vasoconstricting
agents) will be permitted during the study. This includes fludrocortisone, which is
permitted during the study. Medications for the treatment of PD will be permitted
during the study.

5. Sumatriptan-like drugs, (for example, naratriptan, zolmitriptan, rizatriptan)

6. Cyclopropane or halothane, or other halogen-containing inhalational anesthetics

7. Catecholamine-containing preparations (e.g. isoprenaline)

8. Non-selective monoamine oxidase inhibitors (MAOIs)

9. Ergotamine derivatives (except if anti-Parkinsonian medication)

10. Any investigational medication.

11. Uncontrolled depression.

12. Prior history of neuroleptic malignant syndrome.

13. History of suicide attempt within the previous 2 years.

14. Known or suspected alcohol or substance abuse within the past 12 months (DSM-IV
definition of alcohol or substance abuse).

15. Women who are pregnant or breastfeeding.

16. Women of child bearing potential (WOCP) who are not using at least one method of
contraception with their partner.

17. Male patients who are sexually active with a woman of child bearing potential (WOCP)
and not using at least one method of contraception.

18. Untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion
of an ophthalmologist, might result in an increased risk to the patient.

19. Sustained severe hypertension (BP ≥ 180 mmHg systolic or ≥ 110 mmHg diastolic in the
seated or supine position which is observed in 3 consecutive measurements over an
hour).

20. Any significant uncontrolled cardiac arrhythmia.

21. History of myocardial infarction, within the past 2 years.

22. Current unstable angina.

23. Congestive heart failure (NYHA Class 3 or 4).

24. Diabetic autonomic neuropathy.

25. History of cancer within the past 2 years other than a successfully treated,
non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in
situ.

26. Gastrointestinal condition, which in the Investigator's judgment, may affect the
absorption of study drug (e.g. ulcerative colitis, gastric bypass).

27. Any major surgical procedure within 30 days of the baseline visit

28. Previous or current treatment with droxidopa.

29. Current participation in individual physical therapy, specifically for balance or
gait.

30. Any condition or laboratory test result, which in the Investigator's judgment, might
result in an increased risk to the patient, or would affect their participation in the
study.

31. Additionally the Investigator has the ability to exclude a patient if for any reason
they feel the subject is not a good candidate for the study or will not be able to
follow study procedures.