Gait Impairment, Parkinson's Disease
Conditions
Keywords
freezing, gait, festination, shuffling, balance
Brief summary
The purpose of this research study is to examine whether Methylphenidate (MPD) can result in improvement of gait (walking) in a population of Parkinson's Disease (PD) patients whose main disability is freezing of gait. MPD (Ritalin®) is a drug which can excite or stimulate certain systems of the body that control motor function. This drug is FDA approved for the treatment of attention hyperactivity disorder, a condition unrelated to PD. The researchers hypothesize that daily treatment with a tolerable daily oral dose of MPD will improve gait velocity, stride length, cadence, and decrease freezing of gait, 3 months from treatment initiation in patients with moderately advanced PD, whose gait impairment is an important source of disability despite optimized antiparkinsonian treatment.
Detailed description
There are a total of six clinic visits involved in this study. All study-related assessments will take place first during the practically defined off period, that is, in the morning after at least 12 hours from the last dose of any antiparkinsonian medication, followed by a repeat assessment once the on state is clearly identified by the patient and examiner (approximately 30 to 60 minutes after taking your Parkinson's medication). This practically defined off period state is considered the desired state on which to report motor changes for any currently available or experimental intervention in PD. Patients will be off his or her Parkinson's medication for no more than 14 hours for each of the assessments. Studying patients in the off-period is the most widely used manner in which the value of new therapies can be fully measured. During the first visit, patients will be randomized into one of the study groups described below. Neither the participant nor the researcher conducting this study will choose what group he or she will be in. Participants will receive either placebo or a dose of 1 mg/kg of Methylphenidate capsules divided into three doses (at 8 am, 12 noon, and 4 pm). An increase in medication over a four week period will be used until a target dosage is reached, which may range from 5 to 8 10-mg capsules per day. A measure of balance will be taken during both patient's off and on motor states during each of the study visits. Patients will be asked to stand on a force plate (a piece of equipment that measures your balance and is located in the floor) for thirty seconds in a total of four conditions. The four sessions will be carried out as follows: (1) with eyes open while standing on firm surface, (2) with eyes closed while standing on firm surface, (3) with eyes open while standing on foam surface, and (4) with eyes closed while standing on foam surface. These sessions will be in random order and will be repeated up to 4 times. During all the study visits, the physician will ask patients to perform some physical tests during which the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H&Y) will be used to assess the severity of the patient's Parkinson's disease. Each assessment will take place during both patient's off and on motor states. Instruments that will also be used are the self-administered Freezing of Gait Questionnaire (FOGQ), to evaluate walking difficulties, and the Gait-Falls diary, to document all indoor and outdoor freezing, tripping, and falls. To assess changes in mood, patients will also complete the following instruments: the Montgomery-Asberg Depression scale (MADRS), the 15-item Geriatric Depression Scale (GDS-15) and the 20-item Zung Self-Rating Depression scale (Zung). To assess quality of life and activities of daily living, patients will complete the EQ-5D Health Questionnaire. Finally, patients will be asked to complete the Epworth Sleepiness Scale (ESS) to document any changes in sleep patterns. After the first visit, patients will begin a four week increase in medication in order to reach a target dose. At the fourth visit, patients will receive the opposite treatment of what was received the first time and another four-week increase in medication will take place. If Methylphenidate was given at the first visit, patients will receive placebo on the third visit and vice versa. There will be a three week period where patients will not take the study medication (either Methylphenidate or placebo), between the third and fourth visit. At all study visits, during both patient's off and on motor states, patients will have balance testing. The physician will evaluate the severity of patient's disease using the UPDRS and the H&Y. Patients will be asked to complete the FOGQ and the Gait-Falls diary.
Interventions
DRUGMethylphenidate (MPD)
Participants will be given 1 mg/kg of MPD divided in three doses (at 8 am, 12 noon, and 4 pm). A four-week titration period will be used, using 0.25-mg/kg increments per week until achieving the weight-adjusted target dosage, which may range from five to eight 10-mg tablets per day. The maximum daily dose will be 80 mg/day.
DRUGPlacebo
Participants will be given placebo instead of active MPD.
Sponsors
Michael J. Fox Foundation for Parkinson's Research
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients with a definite diagnosis of Parkinson's disease for at least 5 years. * Patients with mild to severe gait disturbance. * Patients on a stable dose of anti-parkinsonian medications that will not be expected to require medication adjustments. * Mini-Mental State Examination (MMSE) score of 25 or greater.
Exclusion criteria
* Patients with musculoskeletal disorders such as severe arthritis, post knee surgery, hip surgery, or any other condition that the investigators determine may impair assessment of gait. * Previous treatment with DBS (deep brain stimulation). * Those with history of stroke. * Those with cerebellar, vestibular, or sensory ataxia. * Concurrent use of, or within two weeks from discontinuing, MAO inhibitor drugs (selegiline, rasagiline). * Women of childbearing potential.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Outcome Measure Was Change in a Gait Stride Length Between Groups at 12 and 27 Weeks. | Week 12 and 27 | Gait stride length is the distance between two consecutive steps in the on state. This will be measured by the GAITRite System, which is an electronic walkway utilized to measure the temporal (timing) and spatial (two dimension geometric position) parameters of its pressure activated sensors. |
| The Primary Outcome Measure Was Change in Gait Velocity Between Groups at 12 and 27 Weeks. | Week 12 and 27 | Gait velocity is a measure of distance over time in the on state. This will be measured by the GAITRite System, which is an electronic walkway utilized to measure the temporal (timing) and spatial (two dimension geometric position) parameters of its pressure activated sensors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Freezing of Gait Questionnaire (FOGQ) Scores Between Groups at 12 and 27 Weeks. | Week 12 and 27 | FOGQ is a questionnaire that quantifies severity of gait and falls. It contains 16 items with a 0-4 severity scale for each, for a range of 0 (normal) to 64 (most severe impairment). |
| Montgomery-Åsberg Depression Rating Scale (MADRS) Between Groups at 12 and 27 Weeks. | Week 12 and 27 | MADRS is a questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 |
| The Unified Parkinson Disease Rating Scale (UPDRS) Between Groups at 12 and 27 Weeks | At week 12 and 27 | Patients will have a mild to severe gait disturbance with score \>1 on the motor subscale of the Unified Parkinson's disease rating scale (UPDRS) but without need for a continuous ambulatory aid such as walker or wheelchair (Hoehn & Yahr 2-3). The highest score possible for the UPDRS is 108 which indicates severe motor impairment. The lowest score for the UPDRS is 0 which indicates no motor impairment. |
| The 5-item EuroQoL (EQ-5D) Quality of Life Generic Instrument Between Groups at 12 and 27 Weeks. | Week 12 and 27 | The EQ-5D comprises five questions on mobility, self care, pain, usual activities, and psychological status with three possible answers for each item (1=no problem, 2=moderate problem, 3=severe problem; see appendix). A summary index with a maximum score of 1 can be derived from these five dimensions by conversion with a table of scores. The range is from 0 to 100, with 100 indicating the best health status. |
| The Epworth Sleepiness Scale (ESS) Between Groups at 12 and 27 Weeks | Week 12 and 27 | The Epworth Sleepiness Scale (ESS) is a scale intended to measure daytime sleepiness that is measured by use of a very short questionnaire. The questionnaire asks the subject to rate his or her probability of falling asleep on a scale of increasing probability from 0 to 3 for eight different situations that most people engage in during their daily lives, though not necessarily every day. The scores for the eight questions are added together to obtain a single number. A number in the 0-9 range is considered to be normal while a number in the 10-24 range indicates excessive daytime sleepiness. Higher scores imply worse sleepiness. |
| Duration of Freezing and Shuffling Episodes Between Groups at 12 and 27 Weeks. | Week 12 and 27 | Freezing and shuffling are measures of ambulatory impairment. |
Countries
United States
Participant flow
Recruitment details
Twenty-three subjects with PD and moderate gait impairment were enrolled for this 6-month placebo-controlled, double-blind study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants were randomized to receive both MPD and placebo. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period - 12 Weeks | Withdrawn | 0 | 3 |
| Second Intervention Period - 12 Weeks | Withdrawn | 2 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 67.6 years STANDARD_DEVIATION 9.6 |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 20 | 5 / 23 |
| serious Total, serious adverse events | 0 / 20 | 0 / 23 |
Outcome results
Primary
The Primary Outcome Measure Was Change in a Gait Stride Length Between Groups at 12 and 27 Weeks.
Gait stride length is the distance between two consecutive steps in the on state. This will be measured by the GAITRite System, which is an electronic walkway utilized to measure the temporal (timing) and spatial (two dimension geometric position) parameters of its pressure activated sensors.
Time frame: Week 12 and 27
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1. MPD | The Primary Outcome Measure Was Change in a Gait Stride Length Between Groups at 12 and 27 Weeks. | 107.66 centimeters | Standard Deviation 26.03 |
| 2. Placebo | The Primary Outcome Measure Was Change in a Gait Stride Length Between Groups at 12 and 27 Weeks. | 112.29 centimeters | Standard Deviation 21.85 |
| Baseline | The Primary Outcome Measure Was Change in a Gait Stride Length Between Groups at 12 and 27 Weeks. | 103.35 centimeters | Standard Deviation 24.24 |
Primary
The Primary Outcome Measure Was Change in Gait Velocity Between Groups at 12 and 27 Weeks.
Gait velocity is a measure of distance over time in the on state. This will be measured by the GAITRite System, which is an electronic walkway utilized to measure the temporal (timing) and spatial (two dimension geometric position) parameters of its pressure activated sensors.
Time frame: Week 12 and 27
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1. MPD | The Primary Outcome Measure Was Change in Gait Velocity Between Groups at 12 and 27 Weeks. | 96.96 centimeters/second | Standard Deviation 22.38 |
| 2. Placebo | The Primary Outcome Measure Was Change in Gait Velocity Between Groups at 12 and 27 Weeks. | 99.24 centimeters/second | Standard Deviation 15.16 |
| Baseline | The Primary Outcome Measure Was Change in Gait Velocity Between Groups at 12 and 27 Weeks. | 95.76 centimeters/second | Standard Deviation 25.38 |
Secondary
Duration of Freezing and Shuffling Episodes Between Groups at 12 and 27 Weeks.
Freezing and shuffling are measures of ambulatory impairment.
Time frame: Week 12 and 27
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1. MPD | Duration of Freezing and Shuffling Episodes Between Groups at 12 and 27 Weeks. | Shuffling | 7.67 hours | Standard Deviation 5.02 |
| 1. MPD | Duration of Freezing and Shuffling Episodes Between Groups at 12 and 27 Weeks. | Freezing | 3.07 hours | Standard Deviation 2.99 |
| 2. Placebo | Duration of Freezing and Shuffling Episodes Between Groups at 12 and 27 Weeks. | Shuffling | 6.15 hours | Standard Deviation 4.05 |
| 2. Placebo | Duration of Freezing and Shuffling Episodes Between Groups at 12 and 27 Weeks. | Freezing | 3.25 hours | Standard Deviation 3.02 |
| Baseline | Duration of Freezing and Shuffling Episodes Between Groups at 12 and 27 Weeks. | Shuffling | 9.1 hours | Standard Deviation 3.7 |
| Baseline | Duration of Freezing and Shuffling Episodes Between Groups at 12 and 27 Weeks. | Freezing | 5.4 hours | Standard Deviation 4.11 |
Secondary
Freezing of Gait Questionnaire (FOGQ) Scores Between Groups at 12 and 27 Weeks.
FOGQ is a questionnaire that quantifies severity of gait and falls. It contains 16 items with a 0-4 severity scale for each, for a range of 0 (normal) to 64 (most severe impairment).
Time frame: Week 12 and 27
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1. MPD | Freezing of Gait Questionnaire (FOGQ) Scores Between Groups at 12 and 27 Weeks. | 12.31 units on a scale | Standard Deviation 2.73 |
| 2. Placebo | Freezing of Gait Questionnaire (FOGQ) Scores Between Groups at 12 and 27 Weeks. | 12.56 units on a scale | Standard Deviation 4.11 |
| Baseline | Freezing of Gait Questionnaire (FOGQ) Scores Between Groups at 12 and 27 Weeks. | 12.71 units on a scale | Standard Deviation 3.87 |
Secondary
Montgomery-Åsberg Depression Rating Scale (MADRS) Between Groups at 12 and 27 Weeks.
MADRS is a questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60
Time frame: Week 12 and 27
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1. MPD | Montgomery-Åsberg Depression Rating Scale (MADRS) Between Groups at 12 and 27 Weeks. | 5.79 units on a scale | Standard Deviation 5.24 |
| 2. Placebo | Montgomery-Åsberg Depression Rating Scale (MADRS) Between Groups at 12 and 27 Weeks. | 6.71 units on a scale | Standard Deviation 6.2 |
| Baseline | Montgomery-Åsberg Depression Rating Scale (MADRS) Between Groups at 12 and 27 Weeks. | 9.44 units on a scale | Standard Deviation 5.93 |
Secondary
The 5-item EuroQoL (EQ-5D) Quality of Life Generic Instrument Between Groups at 12 and 27 Weeks.
The EQ-5D comprises five questions on mobility, self care, pain, usual activities, and psychological status with three possible answers for each item (1=no problem, 2=moderate problem, 3=severe problem; see appendix). A summary index with a maximum score of 1 can be derived from these five dimensions by conversion with a table of scores. The range is from 0 to 100, with 100 indicating the best health status.
Time frame: Week 12 and 27
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1. MPD | The 5-item EuroQoL (EQ-5D) Quality of Life Generic Instrument Between Groups at 12 and 27 Weeks. | 65 units on a scale | Standard Deviation 25.7 |
| 2. Placebo | The 5-item EuroQoL (EQ-5D) Quality of Life Generic Instrument Between Groups at 12 and 27 Weeks. | 63.94 units on a scale | Standard Deviation 20.71 |
| Baseline | The 5-item EuroQoL (EQ-5D) Quality of Life Generic Instrument Between Groups at 12 and 27 Weeks. | 68.67 units on a scale | Standard Deviation 13.56 |
Secondary
The Epworth Sleepiness Scale (ESS) Between Groups at 12 and 27 Weeks
The Epworth Sleepiness Scale (ESS) is a scale intended to measure daytime sleepiness that is measured by use of a very short questionnaire. The questionnaire asks the subject to rate his or her probability of falling asleep on a scale of increasing probability from 0 to 3 for eight different situations that most people engage in during their daily lives, though not necessarily every day. The scores for the eight questions are added together to obtain a single number. A number in the 0-9 range is considered to be normal while a number in the 10-24 range indicates excessive daytime sleepiness. Higher scores imply worse sleepiness.
Time frame: Week 12 and 27
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1. MPD | The Epworth Sleepiness Scale (ESS) Between Groups at 12 and 27 Weeks | 11.05 units on a scale | Standard Deviation 4.55 |
| 2. Placebo | The Epworth Sleepiness Scale (ESS) Between Groups at 12 and 27 Weeks | 10.71 units on a scale | Standard Deviation 3.7 |
| Baseline | The Epworth Sleepiness Scale (ESS) Between Groups at 12 and 27 Weeks | 11.24 units on a scale | Standard Deviation 3.53 |
Secondary
The Unified Parkinson Disease Rating Scale (UPDRS) Between Groups at 12 and 27 Weeks
Patients will have a mild to severe gait disturbance with score \>1 on the motor subscale of the Unified Parkinson's disease rating scale (UPDRS) but without need for a continuous ambulatory aid such as walker or wheelchair (Hoehn & Yahr 2-3). The highest score possible for the UPDRS is 108 which indicates severe motor impairment. The lowest score for the UPDRS is 0 which indicates no motor impairment.
Time frame: At week 12 and 27
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1. MPD | The Unified Parkinson Disease Rating Scale (UPDRS) Between Groups at 12 and 27 Weeks | 21.18 units on a scale | Standard Deviation 12.73 |
| 2. Placebo | The Unified Parkinson Disease Rating Scale (UPDRS) Between Groups at 12 and 27 Weeks | 20.33 units on a scale | Standard Deviation 10.48 |
| Baseline | The Unified Parkinson Disease Rating Scale (UPDRS) Between Groups at 12 and 27 Weeks | 18.39 units on a scale | Standard Deviation 8.21 |