Augmenting Effects of L-DOPS With Carbidopa and Entacapone

Phase 1

Terminated

Conditions: Autonomic Nervous System Diseases
Parkinson Disease
Multiple System Atrophy

Interventions: Drug: Droxidopa
Drug: Carbidopa
Drug: Entacapone

Registration Number: NCT00547911

Lead Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

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.

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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT	Droxidopa	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.
LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT	Carbidopa	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.
LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT	Entacapone	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.
LDOPS + Placebo; LDOPS + ENT; LDOPS + CAR	Droxidopa	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.
LDOPS + Placebo; LDOPS + ENT; LDOPS + CAR	Carbidopa	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.
LDOPS + Placebo; LDOPS + ENT; LDOPS + CAR	Entacapone	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.
LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT	Droxidopa	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.
LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT	Entacapone	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.
LDOPS + CAR; LDOPS + Placebo; LDOPS + ENT	Carbidopa	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.
LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo	Droxidopa	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.
LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo	Carbidopa	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.
LDOPS + CAR; LDOPS + ENT; LDOPS + Placebo	Entacapone	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.
LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR	Entacapone	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.
LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR	Droxidopa	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.
LDOPS + ENT; LDOPS + Placebo; LDOPS + CAR	Carbidopa	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.
LDOPS + ENT; LDOPS + CAR; LDOPS + Placebo	Droxidopa	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.
LDOPS + ENT; LDOPS + CAR; LDOPS + Placebo	Carbidopa	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.
LDOPS + ENT; LDOPS + CAR; LDOPS + Placebo	Entacapone	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.

Primary Outcome Measures

Name	Time	Method
Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone	Up to 48 hours after receiving drug(s)	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.
Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone	Up to 48 hours after receiving drug(s)	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	Up to 48 hours after receiving drug(s)	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	Up to 48 hours after receiving drug(s)	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.

Secondary Outcome Measures

Name	Time	Method
Diastolic 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 pressure was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.
Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone	Up to 24 hours after receiving drug(s)	Systolic 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	Up to 24 hours after receiving drug(s)	Heart rate was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.