Augmenting Effects of L-DOPS With Carbidopa and Entacapone

NCT00547911 | Terminated Phase 1 Results

• 2 other identifiers: 08001208-N-0012
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Parkinson Disease; Multiple System Atrophy; Autonomic Nervous System Diseases

Keywords

Entacapone; Carbidopa; Locus Ceruleus/Norepinephrine-Autonomic System; Norepinephrine; Adrenergic Nervous System

Outcome Measures

Primary Outcomes (4)

• Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone

  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.

  Up to 48 hours after receiving drug(s)

• Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone

  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.

  Up to 48 hours after receiving drug(s)

• Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone

  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.

  Up to 48 hours after receiving drug(s)

• Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone

  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.

  Up to 48 hours after receiving drug(s)

Secondary Outcomes (3)

• Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone

  Up to 24 hours after receiving drug(s)

• Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone

  Up to 24 hours after receiving drug(s)

• Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone

  Up to 24 hours after receiving drug(s)

Study Arms (6)

LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT

EXPERIMENTAL

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; Drug: Carbidopa; Drug: Entacapone

LDOPS + Placebo; LDOPS + ENT; LDOPS + CAR

EXPERIMENTAL

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; Drug: Carbidopa; Drug: Entacapone

LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT

EXPERIMENTAL

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; Drug: Carbidopa; Drug: Entacapone

LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo

EXPERIMENTAL

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; Drug: Carbidopa; Drug: Entacapone

LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR

EXPERIMENTAL

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; Drug: Carbidopa; Drug: Entacapone

LDOPS + ENT; LDOPS + CAR; LDOPS + Placebo

EXPERIMENTAL

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; Drug: Carbidopa; Drug: Entacapone

Interventions

Droxidopa DRUG

Also known as: L-DOPS, Northera, L-threo-dihydroxyphenylserine, SM-5688

LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT; LDOPS + ENT; LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR; LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo; LDOPS + ENT; LDOPS + CAR

Carbidopa DRUG

Also known as: Lodosyn

LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT; LDOPS + ENT; LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR; LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo; LDOPS + ENT; LDOPS + CAR

Entacapone DRUG

Also known as: Comtan

LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT; LDOPS + ENT; LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR; LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo; LDOPS + ENT; LDOPS + CAR

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• BLASCHKO H, BURN JH, LANGEMANN H. The formation of noradrenaline from dihydroxyphenylserine. Br J Pharmacol Chemother. 1950 Sep;5(3):431-7. doi: 10.1111/j.1476-5381.1950.tb00593.x. No abstract available.

  PMID: 14777867 BACKGROUND

• Halliday GM, Li YW, Blumbergs PC, Joh TH, Cotton RG, Howe PR, Blessing WW, Geffen LB. Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease. Ann Neurol. 1990 Apr;27(4):373-85. doi: 10.1002/ana.410270405.

  PMID: 1972319 BACKGROUND

• Rajput AH, Rozdilsky B. Dysautonomia in Parkinsonism: a clinicopathological study. J Neurol Neurosurg Psychiatry. 1976 Nov;39(11):1092-100. doi: 10.1136/jnnp.39.11.1092.

  PMID: 188990 BACKGROUND

MeSH Terms

Conditions

Parkinson Disease; Multiple System Atrophy; Autonomic Nervous System Diseases

Interventions

Droxidopa; Carbidopa; entacapone

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Primary Dysautonomias

Intervention Hierarchy (Ancestors)

Norepinephrine; Catecholamines; Amines; Organic Chemicals; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins; Methyldopa; Dihydroxyphenylalanine; Hydrazines

Limitations and Caveats

Study was prematurely terminated due to a small amount of DOPAL contamination in the droxidopa. Because of the early termination only a small number of subjects were enrolled in each condition. Recently, the FDA has approved droxidopa.

Results Point of Contact

• Title: Dr. David Goldstein
• Organization: National Institutes of Health

goldsteind@ninds.nih.gov

301-496-1115

Study Officials

• David S Goldstein, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 19, 2007
• First Posted: October 23, 2007
• Study Start: October 1, 2007
• Primary Completion: April 1, 2013
• Study Completion: April 1, 2013
• Last Updated: July 17, 2014
• Results First Posted: July 17, 2014

Record last verified: 2014-06

Locations

US (1)