Parkinson's Disease
Conditions
Keywords
Freezing of gait, gait dysfunction
Brief summary
The purpose of this study is to explore the efficacy of the drug Amantadine for the treatment of freezing of gait in patients with Parkinson's Disease. The investigators hypothesize that amantadine is useful for management of freezing of gait in subjects with Parkinson's Disease.
Detailed description
Subjects who meet the eligibility requirements for the study will be randomized to Amantadine versus a matching placebo.
Interventions
DRUGAmantadine
Amantadine 100mg daily, for a week, if it is tolerated Amantadine will increase to 1 tab twice a day. Amantadine will then be administered orally twice daily in the morning with breakfast and at noon with lunch (AM and NN).
DRUGPlacebo
Sugar Pill
Sponsors
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects with idiopathic PD as determined by UK brain bank diagnostic criteria 2. H&Y stage 2.5-3 3. Presence of freezing of gait (FOG) as determined by UPDRS Part I score \> 2 4. Ability to walk for 2 minutes in the ON and OFF state 5. Stable regimen of PD medications for 30 days prior to screening 6. Ability to comply with the study procedures 7. If female, be either post menopausal for at least 2 years, surgically sterilized or have undergone hysterectomy or, if of child bearing potential they must be willing to avoid pregnancy by using an adequate method of contraception as defined in Section 6.4.10 for four weeks prior to, during and four weeks after the last dose of trial medication. For the purposes of this trial, women of childbearing potential are defined as all female subjects after puberty unless they are post-menopausal for at least two years, are surgically sterile or are sexually inactive. 8. Willing and able to provide informed consent.
Exclusion criteria
1. Presence of other co morbid conditions that can contribute to gait dysfunction (orthopedic, rheumatologic, cardiac, other) 2. Presence of freezing of gait (FOG) ONLY in medications ON state 3. Presence of freezing of gait (FOG) ONLY in medications OFF state 4. Presence of significant cognitive dysfunction as determined by Montreal Cognitive Assessment (MoCA) \<20 5. Presence of clinically significant depression as determined by geriatric depression scale (GDS)- 15\>5 6. Presence of clinically significant hallucinations 7. Inability to sign informed consent 8. Participation in the physical therapy aimed at management of PD for the duration of the study (PT for orthopedic issues will be allowed) 9. Contraindications for use of Amantadine ( prior history of allergic reaction, history of known renal insufficiency with Cr \> 2) 10. If female, be pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Timed Up and Go (TUG) - ON Usual Medication | Baseline, change at 4 weeks | This is a walking assessment. The subject will begin in the seated position, stand up, walk 7 meters, turn around, and sit back down. The entire process from leaving the chair to returning to the chair will be timed. Also, the Timed Up and Go (TUG) will be done both in the ON and OFF states. |
| Timed Up and Go (TUG) - OFF Usual Medication | Baseline, change at 4 weeks | This is a walking assessment. The subject will begin in the seated position, stand up, walk 7 meters, turn around, and sit back down. The entire process from leaving the chair to returning to the chair will be timed. Also, the Timed Up and Go (TUG) will be done both in the ON and OFF states. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Freezing of Gait Questionnaire | Baseline, change in 4 weeks | A questionnaire that is used to assess the likelihood of the subject freezing in a number of different scenarios. 0=No freezing of gait to 24=severe freezing of gait |
| Clinical Global Impression (CGI) | 4 weeks | Global Improvement is the second scale in the clinical global impression (CGI). Total overall improvement is judged by whether or not, in the judgment of the assessor, the improvement is entirely due to the drug treatment. It is also a 1-7 point weighted scale, going from very much improved (1) to very much worse (7). A zero score is assigned if the score is not assessed. |
| Parkinson's Disease Questionnaire-39 (PDQ-39) | Baseline, week 4 | The Parkinson's Disease Questionnaire-39 (PDQ39) is a copyrighted instrument to assess symptoms of Parkinson's disease (PD) with 39 questions relating to mobility, activities of daily living, emotional well-being, social support, cognition, communication and bodily discomfort. The test asks subjects to rate each question regarding their Parkinson's disease symptoms over the past month. (range 0 to 100, lower scores reflect better quality of life) |
| Modified Timed Up and Go (mTUG) | Baseline, change in 4 weeks | The subject sits in the chair approximately 3 1/2 meters away from doorway with the door closed. Subject then stands up and walks one meter to a 40cm X 40cm box taped on the floor. Within the box the patient turns clockwise (360 degrees), then turns counterclockwise (360 degrees). Walk to open the door and walk through the doorway, turn around and return to the chair. Modified Timed Up and Go (mTUG) completed in three components including walking the course without additional tasks, carrying a tray with a cup of water, and counting backwards from 100, in both ON and OFF state. |
| Fatigue Severity Scale (FSS) | Baseline, change in 4 weeks | A questionnaire used to discriminate between Parkinson Disease (PD) patients with fatigue and those without fatigue. Range 9 to 63, higher scores indicate greater fatigue severity. |
| Number Who Completed Medication as Randomized | week 4 | Tolerability analysis as determined by the number of subjects completing each arm of the study. |
| Number of Participants With Drug Safety Reports | Week 4 | Analyzing the safety of the medication, Amantadine. Data regarding the medication will be collected from the patient on each visit including any adverse events since the last visit, frequency and severity of falls. This is done in order to determine the safety of Amantadine. |
| Gait Analysis Testing | Baseline, week 4, week 7, week 11 | Use of an accelerometer such as Motorola Droid and wireless acceleration sensors to record gait parameters step time, walking speed, and cadence during the timed up and go (TUG) and modified timed up and go (mTUG) components. The sensors will be attached to the subject's legs and trunk using Velcro straps. The accelerometer will be held or clipped onto the subject in order to measure his or her acceleration. This is done within clinic and during the visit time. |
| Analysis of Motor Functioning Using the Parkinson's Home Diaries | Baseline, change in 4 weeks | Subject will record motor activity as OFF, ON (mobility improved) or asleep on the diary every half hour for two days. Subjects further define ON time according to dyskinesia categories none, non-troublesome or troublesome. The home diaries are used as an evaluation measure of the intervention by assessing the change in off time and change in on time with troublesome dyskinesia. The difference in time experiencing dyskinesia while ON meds relative to the time OFF meds at baseline and at 4 weeks is compared. |
Countries
United States
Participant flow
Pre-assignment details
There was a total of 3 participants enrolled into the study. All 3 participants were randomized to receive either Amantadine or Placebo and crossed over after a washout period.
Participants by arm
| Arm | Count |
|---|---|
| Amantadine Crossover to Placebo For first 4 weeks of study Amantadine 100mg daily, for a week, if it is tolerated Amantadine will increase to 1 tab twice a day
Amantadine: Amantadine 100mg daily, for a week, if it is tolerated Amantadine will increase to 1 tab twice a day. Amantadine will then be administered orally twice daily in the morning with breakfast and at noon with lunch (AM and NN).
Crossover to Placebo (sugar pill) at week 7 | 2 |
| Placebo Crossover to Amantadine For first 4 weeks of study, Placebo (sugar pill)
Crossover to Amantadine at week 7 Amantadine 100mg daily, for a week, if it is tolerated Amantadine will increase to 1 tab twice a day
Amantadine: Amantadine 100mg daily, for a week, if it is tolerated Amantadine will increase to 1 tab twice a day. Amantadine will then be administered orally twice daily in the morning with breakfast and at noon with lunch (AM and NN). | 1 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 |
Baseline characteristics
| Characteristic | Amantadine Crossover to Placebo | Placebo Crossover to Amantadine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 2 participants | 1 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 0 / 3 | 0 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 2 |
Outcome results
Primary
Timed Up and Go (TUG) - OFF Usual Medication
This is a walking assessment. The subject will begin in the seated position, stand up, walk 7 meters, turn around, and sit back down. The entire process from leaving the chair to returning to the chair will be timed. Also, the Timed Up and Go (TUG) will be done both in the ON and OFF states.
Time frame: Baseline, change at 4 weeks
Population: participants who could complete the task.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Amantadine | Timed Up and Go (TUG) - OFF Usual Medication | Baseline | 23 seconds |
| Amantadine | Timed Up and Go (TUG) - OFF Usual Medication | Change at 4 weeks | -3.5 seconds |
| Placebo | Timed Up and Go (TUG) - OFF Usual Medication | Baseline | 19.5 seconds |
| Placebo | Timed Up and Go (TUG) - OFF Usual Medication | Change at 4 weeks | 8.6 seconds |
Primary
Timed Up and Go (TUG) - ON Usual Medication
This is a walking assessment. The subject will begin in the seated position, stand up, walk 7 meters, turn around, and sit back down. The entire process from leaving the chair to returning to the chair will be timed. Also, the Timed Up and Go (TUG) will be done both in the ON and OFF states.
Time frame: Baseline, change at 4 weeks
Population: participants who could complete the task. Note: for the 2 participants who were tested while on placebo, one did not complete baseline, and one did not complete week 4, so a change could not be computed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Amantadine | Timed Up and Go (TUG) - ON Usual Medication | Baseline | 16.7 seconds |
| Amantadine | Timed Up and Go (TUG) - ON Usual Medication | Change at 4 weeks | 0.04 seconds |
| Placebo | Timed Up and Go (TUG) - ON Usual Medication | Baseline | 17.4 seconds |
Secondary
Analysis of Motor Functioning Using the Parkinson's Home Diaries
Subject will record motor activity as OFF, ON (mobility improved) or asleep on the diary every half hour for two days. Subjects further define ON time according to dyskinesia categories none, non-troublesome or troublesome. The home diaries are used as an evaluation measure of the intervention by assessing the change in off time and change in on time with troublesome dyskinesia. The difference in time experiencing dyskinesia while ON meds relative to the time OFF meds at baseline and at 4 weeks is compared.
Time frame: Baseline, change in 4 weeks
Population: patients who report being ON and OFF medication and experience dyskinesia under either condition at baseline and after 4 weeks of either Amantadine or Placebo.~NOTE: only one patient reported both dyskinesia at baseline and 4 weeks and only under the placebo condition. Others did not report any OFF time, so the difference could not be calculated.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Amantadine | Analysis of Motor Functioning Using the Parkinson's Home Diaries | Baseline | 90 minutes | Standard Deviation 0 |
| Placebo | Analysis of Motor Functioning Using the Parkinson's Home Diaries | Baseline | 150 minutes | Standard Deviation 0 |
| Placebo | Analysis of Motor Functioning Using the Parkinson's Home Diaries | Change at 4 weeks | 450 minutes | Standard Deviation 0 |
Secondary
Clinical Global Impression (CGI)
Global Improvement is the second scale in the clinical global impression (CGI). Total overall improvement is judged by whether or not, in the judgment of the assessor, the improvement is entirely due to the drug treatment. It is also a 1-7 point weighted scale, going from very much improved (1) to very much worse (7). A zero score is assigned if the score is not assessed.
Time frame: 4 weeks
Population: number completing study up to assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amantadine | Clinical Global Impression (CGI) | 2 score on a scale |
| Placebo | Clinical Global Impression (CGI) | 4.5 score on a scale |
Secondary
Fatigue Severity Scale (FSS)
A questionnaire used to discriminate between Parkinson Disease (PD) patients with fatigue and those without fatigue. Range 9 to 63, higher scores indicate greater fatigue severity.
Time frame: Baseline, change in 4 weeks
Population: Participants who completed questionnaire
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Amantadine | Fatigue Severity Scale (FSS) | Baseline | 27 score on a scale |
| Amantadine | Fatigue Severity Scale (FSS) | change in 4 weeks | 1.5 score on a scale |
| Placebo | Fatigue Severity Scale (FSS) | Baseline | 26 score on a scale |
| Placebo | Fatigue Severity Scale (FSS) | change in 4 weeks | -5 score on a scale |
Secondary
Freezing of Gait Questionnaire
A questionnaire that is used to assess the likelihood of the subject freezing in a number of different scenarios. 0=No freezing of gait to 24=severe freezing of gait
Time frame: Baseline, change in 4 weeks
Population: Participants who completed questionnaire
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Amantadine | Freezing of Gait Questionnaire | Baseline | 10 score on a scale |
| Amantadine | Freezing of Gait Questionnaire | Change at 4 weeks | -2 score on a scale |
| Placebo | Freezing of Gait Questionnaire | Baseline | 15 score on a scale |
| Placebo | Freezing of Gait Questionnaire | Change at 4 weeks | 1 score on a scale |
Secondary
Gait Analysis Testing
Use of an accelerometer such as Motorola Droid and wireless acceleration sensors to record gait parameters step time, walking speed, and cadence during the timed up and go (TUG) and modified timed up and go (mTUG) components. The sensors will be attached to the subject's legs and trunk using Velcro straps. The accelerometer will be held or clipped onto the subject in order to measure his or her acceleration. This is done within clinic and during the visit time.
Time frame: Baseline, week 4, week 7, week 11
Population: No data was collected from the portable devices that were used.
Secondary
Modified Timed Up and Go (mTUG)
The subject sits in the chair approximately 3 1/2 meters away from doorway with the door closed. Subject then stands up and walks one meter to a 40cm X 40cm box taped on the floor. Within the box the patient turns clockwise (360 degrees), then turns counterclockwise (360 degrees). Walk to open the door and walk through the doorway, turn around and return to the chair. Modified Timed Up and Go (mTUG) completed in three components including walking the course without additional tasks, carrying a tray with a cup of water, and counting backwards from 100, in both ON and OFF state.
Time frame: Baseline, change in 4 weeks
Population: participants who completed task
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amantadine | Modified Timed Up and Go (mTUG) | Baseline - ON | 14 seconds | Standard Deviation 0 |
| Amantadine | Modified Timed Up and Go (mTUG) | change in 4 weeks - ON | 1 seconds | Standard Deviation 0 |
| Amantadine | Modified Timed Up and Go (mTUG) | Baseline - OFF | 16 seconds | Standard Deviation 0 |
| Amantadine | Modified Timed Up and Go (mTUG) | change in 4 weeks - OFF | 2 seconds | Standard Deviation 0 |
| Placebo | Modified Timed Up and Go (mTUG) | change in 4 weeks - OFF | 1 seconds | Standard Deviation 0 |
| Placebo | Modified Timed Up and Go (mTUG) | Baseline - ON | 16 seconds | Standard Deviation 0 |
| Placebo | Modified Timed Up and Go (mTUG) | Baseline - OFF | 20 seconds | Standard Deviation 0 |
| Placebo | Modified Timed Up and Go (mTUG) | change in 4 weeks - ON | -1 seconds | Standard Deviation 0 |
Secondary
Number of Participants With Drug Safety Reports
Analyzing the safety of the medication, Amantadine. Data regarding the medication will be collected from the patient on each visit including any adverse events since the last visit, frequency and severity of falls. This is done in order to determine the safety of Amantadine.
Time frame: Week 4
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amantadine | Number of Participants With Drug Safety Reports | 0 Participants |
| Placebo | Number of Participants With Drug Safety Reports | 0 Participants |
Secondary
Number Who Completed Medication as Randomized
Tolerability analysis as determined by the number of subjects completing each arm of the study.
Time frame: week 4
Population: participants who completed study to time of assessment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amantadine | Number Who Completed Medication as Randomized | 3 Participants |
| Placebo | Number Who Completed Medication as Randomized | 2 Participants |
Secondary
Parkinson's Disease Questionnaire-39 (PDQ-39)
The Parkinson's Disease Questionnaire-39 (PDQ39) is a copyrighted instrument to assess symptoms of Parkinson's disease (PD) with 39 questions relating to mobility, activities of daily living, emotional well-being, social support, cognition, communication and bodily discomfort. The test asks subjects to rate each question regarding their Parkinson's disease symptoms over the past month. (range 0 to 100, lower scores reflect better quality of life)
Time frame: Baseline, week 4
Population: Participants completing questionnaire
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Amantadine | Parkinson's Disease Questionnaire-39 (PDQ-39) | Baseline | 38 score on a scale |