Parkinson Disease, Multiple System Atrophy, Autonomic Nervous System Diseases
Conditions
Keywords
Entacapone, Carbidopa, Locus Ceruleus/Norepinephrine-Autonomic System, Norepinephrine, Adrenergic Nervous System
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
Interventions
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Volunteer Subjects in good general health | 2 |
| Pure Autonomic Failure Subjects with Pure Autonomic Failure | 7 |
| Multiple System Atrophy Subjects with autonomic failure and a history of Multiple System Atrophy | 2 |
| Parkinson's Disease Subjects with autonomic failure and a history of Parkinson's Disease | 3 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Healthy Volunteer | Pure Autonomic Failure | Multiple System Atrophy | Parkinson's Disease | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 1.5 | 68.6 years STANDARD_DEVIATION 8.1 | 57.0 years STANDARD_DEVIATION 0 | 65.0 years STANDARD_DEVIATION 7.1 | 64.0 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 1 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 3 | 0 / 3 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 0 / 2 | 1 / 2 | 0 / 3 | 0 / 3 |
Outcome results
Primary
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.
Time frame: Up to 48 hours after receiving drug(s)
Population: Data for Healthy Volunteers and all Patient groups was combined for analysis due to the low N-value because of premature study termination, which is further described in the Limitations and Caveats section. In addition, some subject data was unable to be analyzed due to unreliable measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDOPS + Placebo | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 0.9 nmol/L | Standard Error 0.4 |
| LDOPS + Placebo | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 10.1 nmol/L | Standard Error 5.7 |
| LDOPS + Placebo | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 1.4 nmol/L | Standard Error 0.8 |
| LDOPS + Placebo | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 0.1 nmol/L | Standard Error 0.1 |
| LDOPS + Placebo | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 11.0 nmol/L | Standard Error 5.1 |
| LDOPS + Placebo | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 15.7 nmol/L | Standard Error 4.3 |
| LDOPS + Placebo | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 4.0 nmol/L | Standard Error 1 |
| LDOPS + CAR | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 1.74 nmol/L | Standard Error 0.33 |
| LDOPS + CAR | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 3.24 nmol/L | Standard Error 0.54 |
| LDOPS + CAR | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 2.54 nmol/L | Standard Error 0.49 |
| LDOPS + CAR | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 3.00 nmol/L | Standard Error 0.58 |
| LDOPS + CAR | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 1.66 nmol/L | Standard Error 0.48 |
| LDOPS + CAR | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 1.52 nmol/L | Standard Error 0.49 |
| LDOPS + CAR | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 1.70 nmol/L | Standard Error 0.28 |
| LDOPS + ENT | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 0.90 nmol/L | Standard Error 0.47 |
| LDOPS + ENT | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 19.91 nmol/L | Standard Error 4.59 |
| LDOPS + ENT | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 0.97 nmol/L | Standard Error 0.4 |
| LDOPS + ENT | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 4.58 nmol/L | Standard Error 1.37 |
| LDOPS + ENT | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 15.04 nmol/L | Standard Error 3.76 |
| LDOPS + ENT | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 33.03 nmol/L | Standard Error 10.91 |
| LDOPS + ENT | Plasma DHMA Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 2.21 nmol/L | Standard Error 1.11 |
Primary
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.
Time frame: Up to 48 hours after receiving drug(s)
Population: Data for Healthy Volunteers and all Patient groups was combined for analysis due to the low N-value because of premature study termination, which is further described in the Limitations and Caveats section. In addition, some subject data was unable to be analyzed due to unreliable measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDOPS + Placebo | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 4.1 nmol/L | Standard Error 0.6 |
| LDOPS + Placebo | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 5.7 nmol/L | Standard Error 0.8 |
| LDOPS + Placebo | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 6.1 nmol/L | Standard Error 0.8 |
| LDOPS + Placebo | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 3.4 nmol/L | Standard Error 0.4 |
| LDOPS + Placebo | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 3.4 nmol/L | Standard Error 0.4 |
| LDOPS + Placebo | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 3.4 nmol/L | Standard Error 0.5 |
| LDOPS + Placebo | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 5.4 nmol/L | Standard Error 0.9 |
| LDOPS + CAR | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 3.6 nmol/L | Standard Error 0.6 |
| LDOPS + CAR | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 3.4 nmol/L | Standard Error 0.4 |
| LDOPS + CAR | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 3.5 nmol/L | Standard Error 0.4 |
| LDOPS + CAR | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 3.3 nmol/L | Standard Error 0.5 |
| LDOPS + CAR | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 3.5 nmol/L | Standard Error 0.8 |
| LDOPS + CAR | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 3.8 nmol/L | Standard Error 0.4 |
| LDOPS + CAR | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 3.7 nmol/L | Standard Error 0.5 |
| LDOPS + ENT | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 10.7 nmol/L | Standard Error 1.6 |
| LDOPS + ENT | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 8.0 nmol/L | Standard Error 1.2 |
| LDOPS + ENT | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 3.8 nmol/L | Standard Error 0.3 |
| LDOPS + ENT | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 4.1 nmol/L | Standard Error 0.4 |
| LDOPS + ENT | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 19.3 nmol/L | Standard Error 3.2 |
| LDOPS + ENT | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 16.6 nmol/L | Standard Error 2.3 |
| LDOPS + ENT | Plasma DHPG Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 3.5 nmol/L | Standard Error 0.3 |
Primary
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.
Time frame: Up to 48 hours after receiving drug(s)
Population: Data for Healthy Volunteers and all Patient groups was combined for analysis due to the low N-value because of premature study termination, which is further described in the Limitations and Caveats section. In addition, some subject data was unable to be analyzed due to unreliable measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDOPS + Placebo | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 2246 nmol/L | Standard Error 611 |
| LDOPS + Placebo | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 6843 nmol/L | Standard Error 1080 |
| LDOPS + Placebo | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 8695 nmol/L | Standard Error 1659 |
| LDOPS + Placebo | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 0 nmol/L | Standard Error 0 |
| LDOPS + Placebo | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 8 nmol/L | Standard Error 4 |
| LDOPS + Placebo | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 211 nmol/L | Standard Error 103 |
| LDOPS + Placebo | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 7067 nmol/L | Standard Error 1955 |
| LDOPS + CAR | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 9059 nmol/L | Standard Error 1447 |
| LDOPS + CAR | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 0.003 nmol/L | Standard Error 0.003 |
| LDOPS + CAR | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 1731 nmol/L | Standard Error 440 |
| LDOPS + CAR | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 7077 nmol/L | Standard Error 1324 |
| LDOPS + CAR | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 7242 nmol/L | Standard Error 1749 |
| LDOPS + CAR | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 188 nmol/L | Standard Error 51 |
| LDOPS + CAR | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 7 nmol/L | Standard Error 2 |
| LDOPS + ENT | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 7172 nmol/L | Standard Error 891 |
| LDOPS + ENT | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 2068 nmol/L | Standard Error 413 |
| LDOPS + ENT | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 6 nmol/L | Standard Error 1 |
| LDOPS + ENT | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 331 nmol/L | Standard Error 203 |
| LDOPS + ENT | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 12008 nmol/L | Standard Error 2294 |
| LDOPS + ENT | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 9114 nmol/L | Standard Error 1962 |
| LDOPS + ENT | Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 0.897 nmol/L | Standard Error 0.753 |
Primary
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.
Time frame: Up to 48 hours after receiving drug(s)
Population: Data for Healthy Volunteers and all Patient groups was combined for analysis due to the low N-value because of premature study termination, which is further described in the Limitations and Caveats section. In addition, some subject data was unable to be analyzed due to unreliable measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDOPS + Placebo | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 0.87 nmol/L | Standard Error 0.19 |
| LDOPS + Placebo | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 0.85 nmol/L | Standard Error 0.16 |
| LDOPS + Placebo | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 0.70 nmol/L | Standard Error 0.13 |
| LDOPS + Placebo | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 0.89 nmol/L | Standard Error 0.14 |
| LDOPS + Placebo | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 1.17 nmol/L | Standard Error 0.15 |
| LDOPS + Placebo | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 1.27 nmol/L | Standard Error 0.15 |
| LDOPS + Placebo | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 1.26 nmol/L | Standard Error 0.18 |
| LDOPS + CAR | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 0.98 nmol/L | Standard Error 0.19 |
| LDOPS + CAR | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 0.87 nmol/L | Standard Error 0.16 |
| LDOPS + CAR | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 0.89 nmol/L | Standard Error 0.15 |
| LDOPS + CAR | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 0.85 nmol/L | Standard Error 0.15 |
| LDOPS + CAR | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 0.98 nmol/L | Standard Error 0.19 |
| LDOPS + CAR | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 0.85 nmol/L | Standard Error 0.16 |
| LDOPS + CAR | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 1.12 nmol/L | Standard Error 0.19 |
| LDOPS + ENT | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 48 Hour | 0.84 nmol/L | Standard Error 0.15 |
| LDOPS + ENT | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 1.69 nmol/L | Standard Error 0.16 |
| LDOPS + ENT | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 1.08 nmol/L | Standard Error 0.23 |
| LDOPS + ENT | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 1.49 nmol/L | Standard Error 0.16 |
| LDOPS + ENT | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 1.62 nmol/L | Standard Error 0.13 |
| LDOPS + ENT | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 1.09 nmol/L | Standard Error 0.19 |
| LDOPS + ENT | Plasma Norepinephrine Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 1.06 nmol/L | Standard Error 0.16 |
Secondary
Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone
Diastolic blood pressure was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.
Time frame: Up to 24 hours after receiving drug(s)
Population: Data for Healthy Volunteers and all Patient groups was combined for analysis due to the low N-value because of premature study termination, which is further described in the Limitations and Caveats section. In addition, some subject data was unable to be analyzed due to unreliable measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDOPS + Placebo | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 80 mmHg | Standard Error 4 |
| LDOPS + Placebo | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 88 mmHg | Standard Error 7 |
| LDOPS + Placebo | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 86 mmHg | Standard Error 6 |
| LDOPS + Placebo | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 84 mmHg | Standard Error 3 |
| LDOPS + Placebo | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 89 mmHg | Standard Error 5 |
| LDOPS + Placebo | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 85 mmHg | Standard Error 5 |
| LDOPS + CAR | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 84 mmHg | Standard Error 5 |
| LDOPS + CAR | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 81 mmHg | Standard Error 4 |
| LDOPS + CAR | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 80 mmHg | Standard Error 5 |
| LDOPS + CAR | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 81 mmHg | Standard Error 6 |
| LDOPS + CAR | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 82 mmHg | Standard Error 5 |
| LDOPS + CAR | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 81 mmHg | Standard Error 4 |
| LDOPS + ENT | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 78 mmHg | Standard Error 4 |
| LDOPS + ENT | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 81 mmHg | Standard Error 3 |
| LDOPS + ENT | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 89 mmHg | Standard Error 5 |
| LDOPS + ENT | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 91 mmHg | Standard Error 6 |
| LDOPS + ENT | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 91 mmHg | Standard Error 5 |
| LDOPS + ENT | Diastolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 85 mmHg | Standard Error 5 |
Secondary
Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone
Heart rate was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.
Time frame: Up to 24 hours after receiving drug(s)
Population: Data for Healthy Volunteers and all Patient groups was combined for analysis due to the low N-value because of premature study termination, which is further described in the Limitations and Caveats section. In addition, some subject data was unable to be analyzed due to unreliable measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDOPS + Placebo | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 67 BPM | Standard Error 3 |
| LDOPS + Placebo | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 65 BPM | Standard Error 3 |
| LDOPS + Placebo | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 66 BPM | Standard Error 3 |
| LDOPS + Placebo | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 68 BPM | Standard Error 4 |
| LDOPS + Placebo | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 67 BPM | Standard Error 4 |
| LDOPS + Placebo | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 66 BPM | Standard Error 3 |
| LDOPS + CAR | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 66 BPM | Standard Error 3 |
| LDOPS + CAR | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 66 BPM | Standard Error 3 |
| LDOPS + CAR | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 64 BPM | Standard Error 3 |
| LDOPS + CAR | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 62 BPM | Standard Error 2 |
| LDOPS + CAR | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 68 BPM | Standard Error 4 |
| LDOPS + CAR | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 65 BPM | Standard Error 3 |
| LDOPS + ENT | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 65 BPM | Standard Error 2 |
| LDOPS + ENT | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 65 BPM | Standard Error 3 |
| LDOPS + ENT | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 68 BPM | Standard Error 4 |
| LDOPS + ENT | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 64 BPM | Standard Error 3 |
| LDOPS + ENT | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 67 BPM | Standard Error 3 |
| LDOPS + ENT | Heart Rate After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 67 BPM | Standard Error 2 |
Secondary
Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone
Systolic blood pressure was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.
Time frame: Up to 24 hours after receiving drug(s)
Population: Data for Healthy Volunteers and all Patient groups was combined for analysis due to the low N-value because of premature study termination, which is further described in the Limitations and Caveats section. In addition, some subject data was unable to be analyzed due to unreliable measurements.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDOPS + Placebo | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 140 mmHg | Standard Error 7 |
| LDOPS + Placebo | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 148 mmHg | Standard Error 8 |
| LDOPS + Placebo | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 163 mmHg | Standard Error 10 |
| LDOPS + Placebo | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 165 mmHg | Standard Error 10 |
| LDOPS + Placebo | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 161 mmHg | Standard Error 9 |
| LDOPS + Placebo | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 149 mmHg | Standard Error 7 |
| LDOPS + CAR | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 143 mmHg | Standard Error 6 |
| LDOPS + CAR | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 143 mmHg | Standard Error 6 |
| LDOPS + CAR | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 148 mmHg | Standard Error 8 |
| LDOPS + CAR | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 146 mmHg | Standard Error 8 |
| LDOPS + CAR | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 144 mmHg | Standard Error 7 |
| LDOPS + CAR | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 144 mmHg | Standard Error 11 |
| LDOPS + ENT | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 1 Hour | 149 mmHg | Standard Error 8 |
| LDOPS + ENT | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 2 Hour | 158 mmHg | Standard Error 10 |
| LDOPS + ENT | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 24 Hour | 144 mmHg | Standard Error 7 |
| LDOPS + ENT | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 3 Hour | 161 mmHg | Standard Error 12 |
| LDOPS + ENT | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | Baseline | 139 mmHg | Standard Error 5 |
| LDOPS + ENT | Systolic Blood Pressures After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone | 6 Hour | 159 mmHg | Standard Error 9 |