Norepinephrine-targeted Therapy for Action Control in Parkinson Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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Norepinephrine-targeted Therapy for Action Control in Parkinson Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Droxidopa
* Drug: Carbidopa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Unified Parkinson Disease Rating Scale (UPDRS) motor scores OFF medication consistent with postural instability gait difficulty (PIGD) subtype Symptoms of freezing or falls Able to walk at least 10 meters Medically stable outpatient, based on the investigator's judgment The patient must be willing and able to give written informed consent prior to performing any study procedures. Exclusion Criteria: Score of 21 or lower on Montreal Cognitive Assessment 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. 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. Diagnosis of hypertension that requires treatment with antihypertensive medications (short-acting antihypertensives to treat nocturnal supine hypertension are allowed in this study) Women of childbearing potential Any significant uncontrolled cardiac arrhythmia History of myocardial infarction, within the past 2 years Current unstable angina Congestive heart failure (NYHA Class 3 or 4) 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 History of stroke Gastrointestinal condition that may affect the absorption of study drug (e.g., ulcerative colitis, gastric bypass) Musculoskeletal disorders such as severe arthritis, post knee surgery, hip surgery, or any other condition that the investigators determine may impair assessment of gait History of myocardial infarction, uncontrolled cardiac arrhythmia, unstable angina, congestive heart failure, or stroke Untreated closed angle glaucoma Musculoskeletal or other disorders that may impair assessment of gait Any major surgical procedure within 30 days prior to the Baseline visit Previously treated with droxidopa within 30 days prior to the Baseline visit Currently receiving any other investigational drug or have received an investigational drug within 60 days prior to the Baseline visit Known or suspected alcohol or substance abuse within the past 12 months (DSM-IV definition of alcohol or substance abuse) 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-arm study enrolling 15 patients that will all receive the experimental treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Droxidopa 600mg by mouth twice a day and carbidopa 200mg by mouth twice a day for 4 weeks | Drug: Droxidopa<br>* Droxidopa will be started at 100mg twice a day and titrated up to a maximum of 600mg twice a day<br>Drug: Carbidopa<br>* Carbidopa 200mg twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 7 weeks | 
| 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. | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | The mean maximum tolerated dose of droxidopa reached by the study participants | Week 4 to Week 7 | 
| Percent Compliance | Percent compliance is defined as the percent of study participants who take greater than or equal to 70% of the assigned dosage | 7 weeks | 
| 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 | baseline and week 7 |