Augmenting Effects of L-DOPS With Carbidopa and Entacapone

This study has been terminated.
(Study terminated due to contamination droxidopa)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
ClinicalTrials.gov Identifier:
NCT00547911
First received: October 19, 2007
Last updated: June 17, 2014
Last verified: June 2014
  Purpose

An experimental drug called L-DOPS increases production in the body of a messenger chemical called norepinephrine. Cells in the brain that make norepinephrine are often gone in Parkinson disease. The exact consequences of this loss are unknown, but they may be related to symptoms such as fatigue, depression, or decreased attention that occur commonly in Parkinson disease. This study will explore effects of L-DOPS in conjunction with carbidopa and entacapone, which are drugs used to treat Parkinson disease. We wish to find out what the effects are of increasing norepinephrine production in the brain and whether carbidopa and entacapone augment those effects.

Volunteers for this study must be at least 18 years of age and able to give consent to participate in the study. To participate in the study, volunteers must discontinue use of alcohol, tobacco, and certain herbal medicines or dietary supplements, and must also taper or discontinue certain kinds of medications that might interfere with the results of the study. Candidates will be screened with a medical history and physical exam.

Participants will be admitted to the National Institutes of Health Clinical Center for two weeks of testing. The study will have three testing phases in a randomly chosen order for each participant:

  • Single dose of L-DOPS
  • Single dose of L-DOPS in conjunction with carbidopa
  • Single dose of L-DOPS in conjunction with entacapone

Each phase will last two days, with a washout day between each phase in which no drugs will be given and no testing will be performed. In each phase, participants will undergo a series of tests and measurements, including blood pressure and electrocardiogram tests. Participants who are healthy volunteers will also have blood drawn and will undergo a lumbar puncture (also known as a spinal tap) to obtain spinal fluid for chemical tests.


Condition Intervention Phase
Parkinson Disease
Multiple System Atrophy
Autonomic Nervous System Diseases
Drug: Droxidopa
Drug: Carbidopa
Drug: Entacapone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: L-Dihydroxyphenylserine (L-DOPS) for Norepinephrine Deficiency: Interactions With Carbidopa and Entacapone

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone [ Time Frame: Up to 48 hours after receiving drug(s) ] [ Designated as safety issue: No ]
    Blood samples were obtained at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, 24 hours, and 48 hours to assess plasma droxidopa (LDOPS) concentrations.

  • Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone [ Time Frame: Up to 48 hours after receiving drug(s) ] [ Designated as safety issue: No ]
    Blood samples were obtained at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, 24 hours, and 48 hours to assess plasma norepinephrine concentrations.

  • Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone [ Time Frame: Up to 48 hours after receiving drug(s) ] [ Designated as safety issue: No ]
    Blood samples were obtained at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, 24 hours, and 48 hours to assess plasma droxymandelic acid (DHMA) concentrations.

  • Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone [ Time Frame: Up to 48 hours after receiving drug(s) ] [ Designated as safety issue: No ]
    Blood samples were obtained at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, 24 hours, and 48 hours to assess plasma dihydroxyphenylglycol (DHPG) concentrations.


Secondary Outcome Measures:
  • Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone [ Time Frame: Up to 24 hours after receiving drug(s) ] [ Designated as safety issue: No ]
    Systolic blood pressure was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.

  • Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone [ Time Frame: Up to 24 hours after receiving drug(s) ] [ Designated as safety issue: No ]
    Diastolic blood pressure was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.

  • Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone [ Time Frame: Up to 24 hours after receiving drug(s) ] [ Designated as safety issue: No ]
    Heart rate was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.


Enrollment: 14
Study Start Date: October 2007
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT
Each subject received 400 mg of droxidopa (LDOPS) with three separate interventions, i.e., LDOPS with 200 mg placebo, LDOPS with 200 mg carbidopa (CAR), and LDOPS with 200 mg entacapone (ENT). The order of the three interventions was randomly assigned prior to drug administration and each intervention was followed by a wash out period of at least two days. This arm received the three interventions in the order of: LDOPS + Placebo, followed by LDOPS + CAR, followed by LDOPS + ENT.
Drug: Droxidopa
N/A
Other Names:
  • L-DOPS
  • Northera
  • L-threo-dihydroxyphenylserine
  • SM-5688
Drug: Carbidopa
Other Name: Lodosyn
Drug: Entacapone
Other Name: Comtan
Experimental: LDOPS + Placebo; LDOPS + ENT; LDOPS + CAR
There are three interventions that every subject orally received over the duration of the study; 400 mg of droxidopa (LDOPS) + 200 mg placebo, 400 mg of droxidopa (LDOPS) + 200 mg carbidopa (CAR), and 400 mg of droxidopa (LDOPS) + 200 mg entacapone (ENT). The order of the three interventions was randomly assigned prior to drug administration and each intervention was followed by a wash out period of at least two days to clear previous intervention from subject's systems. This arm received the three interventions in the order of: LDOPS + Placebo, followed by LDOPS + ENT, and lastly LDOPS + CAR.
Drug: Droxidopa
N/A
Other Names:
  • L-DOPS
  • Northera
  • L-threo-dihydroxyphenylserine
  • SM-5688
Drug: Carbidopa
Other Name: Lodosyn
Drug: Entacapone
Other Name: Comtan
Experimental: LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT
There are three interventions that every subject orally received over the duration of the study; 400 mg of droxidopa (LDOPS) + 200 mg placebo, 400 mg of droxidopa (LDOPS) + 200 mg carbidopa (CAR), and 400 mg of droxidopa (LDOPS) + 200 mg entacapone (ENT). The order of the three interventions was randomly assigned prior to drug administration and each intervention was followed by a wash out period of at least two days to clear previous intervention from subject's systems. This arm received the three interventions in the order of: LDOPS + CAR, followed by LDOPS + Placebo, and lastly LDOPS + ENT.
Drug: Droxidopa
N/A
Other Names:
  • L-DOPS
  • Northera
  • L-threo-dihydroxyphenylserine
  • SM-5688
Drug: Carbidopa
Other Name: Lodosyn
Drug: Entacapone
Other Name: Comtan
Experimental: LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo
There are three interventions that every subject orally received over the duration of the study; 400 mg of droxidopa (LDOPS) + 200 mg placebo, 400 mg of droxidopa (LDOPS) + 200 mg carbidopa (CAR), and 400 mg of droxidopa (LDOPS) + 200 mg entacapone (ENT). The order of the three interventions was randomly assigned prior to drug administration and each intervention was followed by a wash out period of at least two days to clear previous intervention from subject's systems. This arm received the three interventions in the order of: LDOPS + CAR, followed by LDOPS + ENT, and lastly LDOPS + Placebo.
Drug: Droxidopa
N/A
Other Names:
  • L-DOPS
  • Northera
  • L-threo-dihydroxyphenylserine
  • SM-5688
Drug: Carbidopa
Other Name: Lodosyn
Drug: Entacapone
Other Name: Comtan
Experimental: LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR
There are three interventions that every subject orally received over the duration of the study; 400 mg of droxidopa (LDOPS) + 200 mg placebo, 400 mg of droxidopa (LDOPS) + 200 mg carbidopa (CAR), and 400 mg of droxidopa (LDOPS) + 200 mg entacapone (ENT). The order of the three interventions was randomly assigned prior to drug administration and each intervention was followed by a wash out period of at least two days to clear previous intervention from subject's systems. This arm received the three interventions in the order of: LDOPS + ENT, followed by LDOPS + Placebo, and lastly LDOPS + CAR.
Drug: Droxidopa
N/A
Other Names:
  • L-DOPS
  • Northera
  • L-threo-dihydroxyphenylserine
  • SM-5688
Drug: Carbidopa
Other Name: Lodosyn
Drug: Entacapone
Other Name: Comtan
Experimental: LDOPS + ENT; LDOPS + CAR; LDOPS + Placebo
There are three interventions that every subject orally received over the duration of the study; 400 mg of droxidopa (LDOPS) + 200 mg placebo, 400 mg of droxidopa (LDOPS) + 200 mg carbidopa (CAR), and 400 mg of droxidopa (LDOPS) + 200 mg entacapone (ENT). The order of the three interventions was randomly assigned prior to drug administration and each intervention was followed by a wash out period of at least two days to clear previous intervention from subject's systems. This arm received the three interventions in the order of: LDOPS + ENT, followed by LDOPS + CAR, and lastly LDOPS + Placebo.
Drug: Droxidopa
N/A
Other Names:
  • L-DOPS
  • Northera
  • L-threo-dihydroxyphenylserine
  • SM-5688
Drug: Carbidopa
Other Name: Lodosyn
Drug: Entacapone
Other Name: Comtan

Detailed Description:

Objective: L-DOPS is a synthetic chemical that can be converted to norepinephrine (NE). NE is a key messenger of the sympathetic nervous system. Failure of the sympathetic nervous system results in orthostatic hypotension (OH), a fall in blood pressure when the person stands up. Patients with Parkinson disease (PD) often have OH that is related to loss of sympathetic nerves and to NE deficiency. L-DOPS can help treat OH in these patients. Drugs used commonly to treat PD, however, probably influence effects of L-DOPS. Carbidopa, which combined with levodopa (brand name Sinemet) is a standard treatment for PD, might prevent L-DOPS from being turned into NE outside the brain and therefore interfere with effects of L-DOPS on blood pressure. Entacapone (brand name Comtan) might augment production of NE after a dose of L-DOPS, by decreasing metabolic breakdown of L-DOPS. The first goal of this study is to test these hypotheses in patients with neurogenic OH. NE is also a chemical messenger in the brain and is thought to participate in a variety of neuropsychiatric phenomena such as vigilance, mood, memory, and transmission of pain sensation. Patients with OH can have evidence of central NE deficiency. A second goal of this study is to determine whether depressed mood, apathy, fatigue, or pain improve with L-DOPS treatment in these patients. A third goal is to test whether carbidopa and entacapone, which both should enhance delivery of L-DOPS to the brain, augment L-DOPS effects on these symptoms. Finally, a fourth goal is to verify that carbidopa and entacapone augment neurochemical indices of central neural production of NE after a dose of L-DOPS.

Study Population: The subjects are patients with PD+NOH, MSA+NOH, or pure autonomic failure (PAF); and healthy volunteers. A total of 55 patients and 15 healthy volunteers are to be enrolled.

Design: Patients and healthy volunteers enter this Protocol after undergoing clinical laboratory evaluation under NIH Clinical Protocol 03-N-0004, to confirm the diagnosis, identify NOH, and provide data related to central or peripheral NE production. Each subject serves as his or her own control. Subjects are tested after taking a single oral dose of 400 mg of L-DOPS in a randomized crossover design study of three treatment conditions L-DOPS alone, L-DOPS after carbidopa (200 mg), and L-DOPS after entacapone (200 mg). Healthy volunteers have CSF drawn by lumbar puncture under fluoroscopic guidance about 3 hours after administration of each drug combination.

Outcome Measures:

Primary: Hemodynamics, plasma catechols and their metabolites, non-motor symptom checklists

Secondary: (In healthy volunteers) CSF catechols and their metabolites

Other: (In patients with dysarthria) Speech

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

All subjects in this Protocol will have already undergone clinical laboratory evaluations called for in Clinical Protocol 03-N-0004, "Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure.

EXCLUSION CRITERIA:

Age: People younger than 18 years old are excluded.

Risk: A candidate subject is excluded if, in the judgment of the Principal Investigator or Clinical Director, Protocol participation would place the subject at substantially increased acute medical risk. This includes the risks associated with air travel to the NIH. A candidate subject is excluded if, in the opinion of the Principal Investigator or Clinical Director, the medical risk outweighs the potential scientific benefit.

Disqualifying Conditions: A candidate subject is excluded if there is a disqualifying condition. Examples of disqualifying conditions are hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, and symptomatic coronary heart disease. Persons with dementia interfering with their ability to provide informed consent are excluded. If dementia is suspected, such as by score on the mini-mental examination of less than 24, then a bioethics consult will be obtained.

Medications: A candidate subject is excluded if clinical considerations require that the patient continue treatment with a drug likely to interfere with the scientific results. Examples would be treatment with levodopa/carbidopa or a tricyclic antidepressant. Patients with known or suspected allergy or hypersensitivity to any test drug are excluded. Patients unable to discontinue nicotine or alcohol temporarily are excluded. Patients are not to discontinue any medications before the patient or the patient s doctor discusses this with Dr. Goldstein, the Principal Investigator, or Sandra Pechnik, the Research Nurse. If it is decided that discontinuing medications would be unsafe, then the patient is excluded from the study. Subjects must discontinue use of alcohol and tobacco throughout the period of testing. PD patients who have difficulty tolerating withdrawal of levodopa/carbidopa treatment may be treated with a dopamine receptor agonist during the study, with the dosing remaining the same.

Tricyclic antidepressants, drugs that inhibit L-aromatic-amino-acid decarboxylase or catechol-O-methyltransferase, levodopa, and carbidopa will be withdrawn throughout the period of study. Withdrawal of antiparkinsonian medications may worsen rigidity, bradykinesia, or tremor. These effects are not thought to adversely influence the long-term course of the disease. Withdrawal of tricyclic antidepressants may worsen depression. Drug withdrawal will be done only in inpatients. Alternative drugs, such as serotonin reuptake blockers, anti-anxiety agents, or dopamine receptor agonists, may be used at constant doses during the study.

Herbal Medicines and Dietary Supplements: Certain herbal medicines or dietary supplements are known or suspected to interfere with the experimental results, and such herbal medicines or dietary supplements must be discontinued before enrollment in the study. For many herbal medicines or dietary supplements, the mechanisms of action and therefore the possible effects on the experimental results are unknown. In cases where the subjects wish to continue their herbal medicines or dietary supplements while on study, and search of the available medical literature fails to identify effects that are known or expected to interfere with the experimental results, then the subjects may participate.

Practical Limitations: Subjects in whom we feel it would be difficult to insert a catheter into a vein are excluded. Subjects who are not expected clinically to tolerate lying still supine during the testing are excluded.

Pregnancy: Pregnant or lactating women are excluded. Women of childbearing potential must have a negative urine or blood test for pregnancy done within 24 hours before any testing involving radioactivity or an experimental drug.

Post-Lumbar Puncture Headache: Candidate Healthy Volunteers are excluded if they had a headache requiring a blood patch after lumbar puncture under fluoroscopic guidance.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00547911

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: David S Goldstein, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
  More Information

Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
ClinicalTrials.gov Identifier: NCT00547911     History of Changes
Other Study ID Numbers: 080012, 08-N-0012
Study First Received: October 19, 2007
Results First Received: June 17, 2014
Last Updated: June 17, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Entacapone
Carbidopa
Locus Ceruleus/Norepinephrine-Autonomic System
Norepinephrine
Adrenergic Nervous System

Additional relevant MeSH terms:
Autonomic Nervous System Diseases
Primary Dysautonomias
Nervous System Diseases
Parkinson Disease
Multiple System Atrophy
Shy-Drager Syndrome
Atrophy
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Hypotension
Vascular Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Droxidopa
Carbidopa
Entacapone
Norepinephrine
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on July 20, 2014