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Norepinephrine-targeted Therapy for Action Control in Parkinson Disease

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ClinicalTrials.gov Identifier: NCT03115827
Recruitment Status : Completed
First Posted : April 14, 2017
Last Update Posted : February 25, 2019
Sponsor:
Collaborators:
H. Lundbeck A/S
American Academy of Neurology
Information provided by (Responsible Party):
Katherine Eder McDonell, Vanderbilt University Medical Center

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).

Condition or disease Intervention/treatment Phase
Parkinson Disease Drug: Droxidopa Drug: Carbidopa Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single-arm study enrolling 15 patients that will all receive the experimental treatment.
Masking: None (Open Label)
Masking Description: All patients will receive the same treatment.
Primary Purpose: Treatment
Official Title: Norepinephrine-targeted Therapy for Action Control in Parkinson Disease
Actual Study Start Date : April 18, 2017
Actual Primary Completion Date : December 21, 2018
Actual Study Completion Date : December 21, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm 1
Droxidopa 600mg by mouth twice a day and carbidopa 200mg by mouth twice a day for 4 weeks
Drug: Droxidopa
Droxidopa will be started at 100mg twice a day and titrated up to a maximum of 600mg twice a day

Drug: Carbidopa
Carbidopa 200mg twice a day




Primary Outcome Measures :
  1. 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 ]
    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.

  2. Number of patients who discontinue the study drug due to adverse effects during the 7-week treatment period. [ Time Frame: 7 weeks ]
    Tolerability will be defined by the number of patients who discontinue the study drug due to adverse effects.


Secondary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: Week 4 to Week 7 ]
    The mean maximum tolerated dose of droxidopa reached by the study participants

  2. Percent compliance [ Time Frame: 7 weeks ]
    Percent compliance is defined as the percent of study participants who take greater than or equal to 70% of the assigned dosage

  3. Change in Stop-Signal reaction time from Baseline to Week 7 [ Time Frame: 7 weeks ]
    The Stop-Signal reaction time is a computerized test that assesses reaction time and response inhibition

  4. Change in performance on Simon task from Baseline to Week 7 [ Time Frame: 7 weeks ]
    The Simon task is a computerized test that assesses reaction time in the setting of irrelevant visual information.

  5. Change in performance on attentional blink task from Baseline to Week 7 [ Time Frame: 7 weeks ]
    The attentional blink task measures the ability to respond to two different stimuli presented in close temporal sequence.

  6. Change in gait as evaluated by GAITRite assessment from Baseline to Week 7 [ Time Frame: 7 weeks ]
    The GAITRite is a computerized assessment that measures several different parameters of walking and balance.

  7. Change in oxygen extraction on MRI from Baseline to Week 7 [ Time Frame: 7 weeks ]
    Measurement of the oxygen extraction fraction on MRI can be used as a surrogate for cerebral blood flow.

  8. Change in autonomic function parameters from Baseline to Week 7 [ Time Frame: 7 weeks ]
    Autonomic function tests including posture study, heart rate variability, valsalva maneuver, and blood catecholamine measurements will be performed.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03115827


Locations
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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University Medical Center
H. Lundbeck A/S
American Academy of Neurology
Investigators
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Principal Investigator: Katherine McDonell, MD Vanderbilt Medical Center

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Responsible Party: Katherine Eder McDonell, Assistant Professor of Neurology, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT03115827     History of Changes
Other Study ID Numbers: VUMC54580
First Posted: April 14, 2017    Key Record Dates
Last Update Posted: February 25, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Norepinephrine
Carbidopa
Droxidopa
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Aromatic Amino Acid Decarboxylase Inhibitors
Enzyme Inhibitors