Parkinson DiseasePhase 1/2NCT00547911
Augmenting Effects of L-DOPS With Carbidopa and Entacapone
A Phase 1/2 study testing Droxidopa, Carbidopa and Entacapone in people with Parkinson Disease and Multiple System Atrophy, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Parkinson Disease, Multiple System Atrophy, Autonomic Nervous System Diseases
- What is being tested?
- Droxidopa, Carbidopa and Entacapone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2007to Apr 2013
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: L-Dihydroxyphenylserine (L-DOPS) for Norepinephrine Deficiency: Interactions With Carbidopa and Entacapone
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.
Read more
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.
Read the 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
- Being tested
- Droxidopa, Carbidopa, Entacapone
- Keywords
- Entacapone, Carbidopa, Locus Ceruleus/Norepinephrine-Autonomic System, Norepinephrine, Adrenergic Nervous System
- Medical subject headings
- Parkinson Disease, Multiple System Atrophy, Autonomic Nervous System Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DroxidopaDrug
Also called L-DOPS, Northera, L-threo-dihydroxyphenylserine, SM-5688
CarbidopaDrug
Also called Lodosyn
EntacaponeDrug
Also called Comtan
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Droxidopa; Drug: Carbidopa; Drug: Entacapone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Systolic blood pressure was assessed at baseline and after drug administration at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours.
Measured: Up to 24 hours after receiving drug(s)
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.
Measured: Up to 24 hours after receiving drug(s)
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.
Measured: Up to 24 hours after receiving drug(s)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Oct 2007 (estimated)
- Study startOct 2007
- Primary completionApr 2013
- Study completionApr 2013
Why it stopped: Study terminated due to contamination droxidopa
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Parkinson DiseaseStudies of the same condition, open and under way.
- More trials run by National Institute of Neurological Disorders and Stroke (NINDS)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- David S Goldstein, M.D., Principal investigator, National Institute of Neurological Disorders and Stroke (NINDS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00547911
- Sponsor's protocol ID
- 080012
- Other IDs
- 08-N-0012
- Status last verified
- Jun 2014
- First submitted
- 19 Oct 2007
- Last updated
- 17 Jul 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 14777867Halliday 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.
PubMed 1972319Rajput 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.
PubMed 188990
Study at a glance
From the registry record, last updated by the sponsor on 17 Jul 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- L-Dihydroxyphenylserine (L-DOPS) for Norepinephrine Deficiency: Interactions With Carbidopa and Entacapone
- ClinicalTrials.gov ID
- NCT00547911
- Acronym / sponsor ID
- 080012
- Keywords
- Entacapone, Carbidopa, Locus Ceruleus/Norepinephrine-Autonomic System, Norepinephrine, Adrenergic Nervous System
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study terminated due to contamination droxidopa
- Enrolment
- 14 participants (actual)
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)US National Institutes of Health
- Study start
- Oct 2007
- Primary completion
- Apr 2013 (actual)
- Study completion
- Apr 2013 (actual)
- First posted
- 23 Oct 2007 (estimated)
- Results
- Posted 17 Jul 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| LDOPS + Placebo; LDOPS + CAR; LDOPS + ENT | Experimental | Drug: Droxidopa, Drug: Carbidopa, Drug: EntacaponeEach 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 | Experimental | Drug: Droxidopa, Drug: Carbidopa, Drug: EntacaponeThere 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 | Experimental | Drug: Droxidopa, Drug: Carbidopa, Drug: EntacaponeThere 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 | Experimental | Drug: Droxidopa, Drug: Carbidopa, Drug: EntacaponeThere 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 | Experimental | Drug: Droxidopa, Drug: Carbidopa, Drug: EntacaponeThere 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 | Experimental | Drug: Droxidopa, Drug: Carbidopa, Drug: EntacaponeThere 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DroxidopaAlso: L-DOPS, Northera, L-threo-dihydroxyphenylserine, SM-5688 | Drug | 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 |
| CarbidopaAlso: Lodosyn | Drug | 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 |
| EntacaponeAlso: Comtan | Drug | 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 |
Primary outcome
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)
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)
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)
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)
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.
3 secondary outcomes
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)
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)
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)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jul 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 14777867BLASCHKO 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.
- Background: PubMed 1972319Halliday 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.
- Background: PubMed 188990Rajput 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David S Goldstein, M.D. principal investigator
National Institute of Neurological Disorders and Stroke (NINDS)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Droxidopa, Carbidopa and Entacapone in people with Parkinson Disease and Multiple System Atrophy, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 17 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Jul 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00547911, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2014.