Parkinson Disease
Conditions
Brief summary
The purpose of this study is to find out whether droxidopa, a medication that increases norepinephrine levels, may be effective in improving some aspects of cognition and movement in Parkinson's disease (PD).
Detailed description
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects 1 million people in the United States. PD causes a variety of disabling symptoms, which impact movement as well as cognition. Historically, we have relied on medications that increase dopamine levels to treat PD, although we are recognizing more and more that other chemicals in the brain are involved in PD as well. Droxidopa (Northera) is an approved drug for the treatment of low blood pressure in PD. It is a norepinephrine precursor, which is converted in the body to the neurotransmitter norepinephrine. This is a chemical that the body normally makes that has a variety of important activities in the brain and peripheral nervous system. In PD, the cells that make norepinephrine die off as part of the disease process. Therefore, people with PD often have low levels of norepinephrine in their blood and in their spinal fluid. Norepinephrine is important for maintaining blood pressure, which may be one reason that some people with PD have problems with their blood pressure falling too low when they stand up. This can lead to symptoms such as dizziness, lightheadedness, feeling faint, or sometimes passing out. Droxidopa has been approved by the FDA for the treatment of low blood pressure in Parkinson's disease. However, as norepinephrine is also important for a lot of processes that happen in the brain as well, we believe that this medication may be also helpful for some of the other symptoms of PD. In particular, norepinephrine plays a key role in brain networks that are important for attention, decision making, and controlling movements and actions. In order for norepinephrine to reach the brain, it must cross the blood-brain barrier. Therefore, in this study we will be giving droxidopa along with carbidopa, which stops your body from breaking down norepinephrine in the blood stream and allows it to get into the brain. This is a medication that is often given in Parkinson's disease along with levodopa in the form of carbidopa-levodopa, or Sinemet. This medication works the same way with levodopa in helping it get into the brain and improve the symptoms of PD. The only difference is that levodopa works like the chemical dopamine, whereas droxidopa works like norepinephrine. Up to this point, we have not had a way to correct the low norepinephrine levels in Parkinson's disease. Therefore, this study gives us the chance to investigate the effectiveness of a potential new treatment for PD patients.
Interventions
DRUGDroxidopa
Droxidopa will be started at 100mg twice a day and titrated up to a maximum of 600mg twice a day
DRUGCarbidopa
Carbidopa 200mg twice a day
Sponsors
H. Lundbeck A/S
American Academy of Neurology
Vanderbilt University Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
All patients will receive the same treatment.
Intervention model description
This is a single-arm study enrolling 15 patients that will all receive the experimental treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Nondemented man or woman 18 years of age or older with idiopathic PD based on the UK Parkinson Disease Society Brain Bank Clinical Diagnostic Criteria (refer to Appendix C for the criteria) 2. Unified Parkinson Disease Rating Scale (UPDRS) motor scores OFF medication consistent with postural instability gait difficulty (PIGD) subtype 3. Symptoms of freezing or falls 4. Able to walk at least 10 meters 5. Medically stable outpatient, based on the investigator's judgment 6. The patient must be willing and able to give written informed consent prior to performing any study procedures.
Exclusion criteria
1. Score of 21 or lower on Montreal Cognitive Assessment 2. Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 mmHg diastolic, or have these measurements at their Baseline Visit (Visit 2). Sustained is defined as measurements persistently greater at 2 separate measurements at least 10 minutes apart with the subject supine and at rest for at least 5 minutes. 3. Concomitant use of vasoconstricting agents such as ephedrine, dihydroergotamine, or midodrine. Concomitant use of other noradrenergic medications, such as serotonin-norepinephrine reuptake inhibitors (SNRI's) is also contraindicated. Patients must stop taking these drugs at least 2 days or 5 half-lives (whichever is longer) prior to their baseline visit and throughout the duration of the study. 4. Diagnosis of hypertension that requires treatment with antihypertensive medications (short-acting antihypertensives to treat nocturnal supine hypertension are allowed in this study) 5. Women of childbearing potential 6. Any significant uncontrolled cardiac arrhythmia 7. History of myocardial infarction, within the past 2 years 8. Current unstable angina 9. Congestive heart failure (NYHA Class 3 or 4) 10. 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 11. History of stroke 12. Gastrointestinal condition that may affect the absorption of study drug (e.g., ulcerative colitis, gastric bypass) 13. Musculoskeletal disorders such as severe arthritis, post knee surgery, hip surgery, or any other condition that the investigators determine may impair assessment of gait 14. History of myocardial infarction, uncontrolled cardiac arrhythmia, unstable angina, congestive heart failure, or stroke 15. Untreated closed angle glaucoma 16. Musculoskeletal or other disorders that may impair assessment of gait 17. Any major surgical procedure within 30 days prior to the Baseline visit 18. Previously treated with droxidopa within 30 days prior to the Baseline visit 19. Currently receiving any other investigational drug or have received an investigational drug within 60 days prior to the Baseline visit 20. Known or suspected alcohol or substance abuse within the past 12 months (DSM-IV definition of alcohol or substance abuse) 21. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Develop an Adverse Event During the 7-week Treatment Period That is Determined to be Likely Related to the Study Medications. | 7 weeks | Safety will be defined by the percent of subjects who develop an adverse event during the 7-week treatment period that is determined to be likely related to the study medications. |
| Number of Participants Who Discontinue the Study Drug Due to Adverse Effects During the 7-week Treatment Period. | 7 weeks | Tolerability will be defined by the number of patients who discontinue the study drug due to adverse effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose | Week 4 to Week 7 | The mean maximum tolerated dose of droxidopa reached by the study participants |
| Percent Compliance | 7 weeks | Percent compliance is defined as the percent of study participants who take greater than or equal to 70% of the assigned dosage |
| Change in Stop-Signal Reaction Time From Baseline to Week 7 | baseline and week 7 | The Stop-Signal reaction time is a computerized test that assesses reaction time and response inhibition |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 Droxidopa 600mg by mouth twice a day and carbidopa 200mg by mouth twice a day for 4 weeks
Droxidopa: Droxidopa will be started at 100mg twice a day and titrated up to a maximum of 600mg twice a day
Carbidopa: Carbidopa 200mg twice a day | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Arm 1 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 69.6 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 10 / 15 |
| serious Total, serious adverse events | 2 / 15 |
Outcome results
Primary
Number of Participants Who Discontinue the Study Drug Due to Adverse Effects During the 7-week Treatment Period.
Tolerability will be defined by the number of patients who discontinue the study drug due to adverse effects.
Time frame: 7 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 | Number of Participants Who Discontinue the Study Drug Due to Adverse Effects During the 7-week Treatment Period. | Participants that discontinued due to SAEs | 2 Participants |
| Arm 1 | Number of Participants Who Discontinue the Study Drug Due to Adverse Effects During the 7-week Treatment Period. | Participants that discontinued due to mild AEs | 1 Participants |
| Arm 1 | Number of Participants Who Discontinue the Study Drug Due to Adverse Effects During the 7-week Treatment Period. | Participants that did not discontinue | 12 Participants |
Primary
Number of Subjects Who Develop an Adverse Event During the 7-week Treatment Period That is Determined to be Likely Related to the Study Medications.
Safety will be defined by the percent of subjects who develop an adverse event during the 7-week treatment period that is determined to be likely related to the study medications.
Time frame: 7 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 | Number of Subjects Who Develop an Adverse Event During the 7-week Treatment Period That is Determined to be Likely Related to the Study Medications. | 8 Participants |
Secondary
Change in Stop-Signal Reaction Time From Baseline to Week 7
The Stop-Signal reaction time is a computerized test that assesses reaction time and response inhibition
Time frame: baseline and week 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Change in Stop-Signal Reaction Time From Baseline to Week 7 | -14.38 change in SSRT in seconds | Standard Deviation 40.42 |
p-value: 0.6t-test, 2 sided
Secondary
Maximum Tolerated Dose
The mean maximum tolerated dose of droxidopa reached by the study participants
Time frame: Week 4 to Week 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Maximum Tolerated Dose | 1053 mg/day | Standard Deviation 267 |
Secondary
Percent Compliance
Percent compliance is defined as the percent of study participants who take greater than or equal to 70% of the assigned dosage
Time frame: 7 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 | Percent Compliance | 11 Participants |