Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01399905 |
| Other study ID # |
IRB00004133 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
March 2009 |
| Est. completion date |
May 2011 |
Study information
| Verified date |
December 2019 |
| Source |
Oregon Health and Science University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Hypothesis: We hypothesize that carbidopa in daily doses of 450mg will enter the central
nervous system and partially inhibit AAAD, thereby reducing the decarboxylation of exogenous
levodopa to dopamine, and thereby blunt the therapeutic effects of levodopa in PD subjects.
The purpose of this study is to see how low dose vs. high dose of the study drug, carbidopa
effect movement in subjects with Parkinson's disease. The low dose of the study drug is 75 mg
and the high dose is 450mg.
Subjects will be recruited from the investigators clinic when they are seen for treatment for
Parkinson's disease. Subjects will also be recruited through flyers hung at OHSU and at the
VA.
Subjects will take part in 2 screening visits one week apart to determine eligibility.
Subjects will be randomly chosen to start either high or low dose carbidopa and take it for 4
weeks. Subjects will be called 2, 4, and 6 or 7 days after this visit to ask how they are
doing after starting this dose of study drug. We will leave them a message if we cannot reach
them. If there are any problems, we will schedule them to come to the clinic within the next
2 days.
Subjects will have an outpatient visit 2 weeks after screening and a hospital admission 2
weeks after that. At the hospital, subjects will stay for 3 days. They will have blood drawn
and their Parkinson's disease assessed by a finger tapping exercise, timing their walking,
and looking at their uncontrolled movements.
The subject will then receive the opposite dose of carbidopa for 4 weeks. Subjects will be
called 2, 4, and 6 or 7 days after this visit to ask how they are doing after starting this
dose of study drug. We will leave them a message if we cannot reach them. If there are any
problems, we will schedule them to come to the clinic within the next 2 days.
The outpatient visit and hospital admission will repeat again. At the end of the second
hospital admission, treatment on the study is over and subjects will go back to their
original Parkinson's disease medications. The study will end with a follow up phone call or
clinic visit 2 - 4 weeks after the final hospital admission.
Subjects will fill out a daily diary that asks about their movement throughout the day for 3
days before they come to the Oregon Clinical and Translational Research Institute.
Carbidopa is used for the treatment of Parkinson's disease with levodopa. This protocol is
using a high dose of 450mg of carbidopa. This study is also using IV levodopa, which is a
different route than is normally given.
Finger tapping rates will be compared between high and low dose study drug use to see if one
group has slower rates than the other.
Description:
A. Specific Aims:
Parkinson's disease is a common neurodegenerative disorder characterized by the progressive
motor symptoms of tremor, rigidity, and bradykinesia. The prevalence is estimated at
102-109/100,000 and increases with age. It is the second most common neurodegenerative
disorder after Alzheimer's disease, and the annual cost in the US is estimated to be $14.3
billion dollars per year.
In Parkinson's disease (PD) dopamine containing neurons in the substantia nigra are
selectively lost, which causes motor dysfunction. Dopamine levels may be increased by giving
oral levodopa, which improves motor function in PD. After oral administration, levodopa is
taken into the brain and converted into dopamine by aromatic amino acid decarboxylase (AAAD)
enzyme in the striatum , resulting in improved dopaminergic neurotransmission. AAAD is found
in the peripheral tissues as well as in the brain, and prior to passage into the central
nervous system levodopa may be decarboxylated to dopamine in the small bowel and liver.
Peripheral metabolism of levodopa to dopamine significantly reduces the amount of levodopa
that reaches the brain and therefore dopamine available for neurotransmission. The presence
of dopamine in the periphery also produces anorexia and nausea. Carbidopa is an AAAD
inhibitor that reduces the conversion of levodopa to dopamine. It is thought to not cross the
blood-brain barrier and to affect only peripheral AAAD. This concept is of fundamental
importance in the current treatment of PD. Carbidopa potentiates levodopa so that a much
lower dose is effective. It also reduces anorexia and nausea, which often occur after giving
levodopa alone. For this reason, almost all levodopa is marketed as carbidopa/levodopa
tablets. This combination drug has become the standard of care for PD. As the disease
progresses, increasingly high amounts of the carbidopa/levodopa combination are given to
ensure adequate motor functioning, though the response to treatment becomes much less
predictable with frequent fluctuations in motor ability.
Though conventional wisdom and older pharmacological studies suggest carbidopa does not
penetrate the blood-brain barrier, recent animal studies contradict this. This is very
important because if carbidopa entered the central nervous system in humans it could
significantly inhibit levodopa conversion into dopamine, and thus reduce its therapeutic
effects. A single large dose of carbidopa given to a normal rat, or a rat chemically lesioned
to mimic PD, resulted in carbidopa entrance into the central nervous system, and inhibition
of brain AAAD and conversion of levodopa to dopamine (1, 2). It is not known whether
prolonged use of high dose carbidopa worsens motor function over time in humans. A small
series of patients with PD and motor fluctuations that were switched from carbidopa/levodopa
to levodopa alone were reported to have improvement in motor features(3). Carbidopa is
typically given in a one to four ratio of carbidopa to levodopa in each pill, and chronic
high dosing of caribopa and levodopa is common in PD. If carbidopa penetrates into the
central nervous system in humans it could lead to decreased conversion of levodopa to
dopamine in the central nervous system, and decrease the therapeutic response to administered
levodopa.
We propose a randomized, double blind, controlled trial with crossover to explore two
mechanisms by which carbidopa may accumulate in the CNS.
If given in high doses over 4 weeks, carbidopa may slowly accumulate in the central nervous
system and impair dopamine synthesis and thereby motor function in PD.
Aim #1: Compare motor response to 2 hour levodopa infusion after 4 weeks of high dose
carbidopa and after 4 weeks of low dose carbidopa.
After 4 weeks of high dose carbidopa, subjects may notice more "off" time than after 4 weeks
of low dose carbidopa. Changes in response to levodopa can be evaluated by a patient diary
and by the need to increase daily levodopa.
Aim 2: Determine the clinical response to oral levodopa at the end of a 4 weeks treatment
with high dose carbidopa and with low dose carbidopa measured by an "on/off" diary and with
total daily levodopa dose.
An alternate reason for carbidopa to enter the central nervous system (CNS) is through a
blood-brain barrier that has become abnormal as a result of age and PD. In this case a single
large dose of carbidopa may enter the CNS and reduce the conversion of levodopa to dopamine.
Aim #3: Compare the clinical response to 2 hour levodopa infusion administered with 25mg
carbidopa or 150mg carbidopa.
Demonstrating that high doses of carbidopa diminishe the response to levodopa would alter
current practice, as clinicians presently are not concerned about the quantity of carbidopa
administered to patients with PD. As a result of this study, a significant insight into the
management of advanced PD will be gained. The overall goal is to better understand if use of
high dose carbidopa may paradoxically complicate treatment. A positive or negative finding
will have important therapeutic implications. This study has potential to fundamentally
change how we treat PD.
B. Background and Significance:
B. 1 Parkinson's Disease
PD is a common neurodegenerative disorder that results in progressive tremor, rigidity, and
bradykinesia. The risk for developing PD increases with age. The prevalence ranges from
102-109/100,000 in Western countries and incidence rate of 1.7 per 1000 person years(4, 5).
There is increased direct cost to the individual and a substantial indirect cost to the
family(6, 7). The overall estimated cost of PD in the US is $14.3 billion dollars
annually(8).
Though PD is associated with a variety of clinical features, patients typically present with
motor dysfunction. Motor signs are caused by loss of dopaminergic neurons in the substantia
nigra. The mainstay of treatment for motor signs is correction of dopaminergic
neurotransmission by oral administration of levodopa, a precursor of dopamine. The risk of
death in PD is significantly reduced by the use of levodopa and responsiveness to levodopa
treatment is a strong predictor of survival(9, 10).
B. 2. Pharmacology of Levodopa and Carbidopa Levodopa is taken up by the small bowel and
heavily metabolized by AAAD located in the intestinal mucosa, and to a lesser degree by the
liver. As a result of this first pass peripheral metabolism, the bioavailability of levodopa
in the serum after oral administration is approximately 30%(11) and peripheral metabolism of
levodopa continues after the first pass metabolism so that only a small amount of levodopa
enters the CNS if AAAD is not inhibited. Carbidopa is an AAAD inhibitor and can be given
along with levodopa to prevent the peripheral conversion of levodopa to dopamine, and
increase the overall bioavailability of levodopa by two to fourfold. Higher doses of
carbidopa produce higher plasma levels of levodopa. Carbidopa is also of clinical importance
since carbidopa reduces anorexia and nausea related to the effects of dopamine on the area
postrema which is effectively outside the blood-brain barrier.
Traditional clinical thinking assumes carbidopa does not penetrate the blood brain barrier,
and by this virtue will not interfere with central conversion of levodopa to dopamine (12).
The studies supporting this assumption rely on animal models and utilize single doses of
carbidopa (13)(14). Clinical dictum indicates a minimum of 75 milligrams of carbidopa be
given daily to produce reasonable inhibition of the AAAD. Aside from the primary effect of
inhibiting the decarboxylation of levodopa in the periphery and potentiating the effects of
levodopa, carbidopa has no demonstrated pharmacological effect. Since carbidopa is not
thought to penetrate the blood brain barrier it is considered a peripheral decarboxylase
inhibitor.
B. 3. Carbidopa Acts Centrally to Prevent Formation of Dopamine Evidence from laboratory
studies has appeared in recent years suggesting carbidopa penetrates the blood brain barrier
to a greater extent than realized. One piece of evidence is based on single injection models
using microdialysate techniques for drug level measurement in normal rats (1). A single high
dose of carbidopa 50mg/kg may inhibit the aromatic amino acid decarboxylase activity in the
striatum of normal rats by 75% (2). Benserazide is a peripheral AAAD inhibitor similar to
carbidopa. Benserazide administration 50mg/kg prolongs the time to reach peak dopamine level
by 60 minutes centrally. Administration of benserazide 10mg/kg and 50mg/kg decreases striatal
AAAD activity in normal rats by 28% and 78% respectively, and in rats modeled to mimic PD
benserazide 10mg/kg and 50mg/kg decreases striatal AAAD activity 75% and 88%, respectively
(15). Even if a small percent of each dose of carbidopa enters the CNS, long-term use could
allow carbidopa to accumulate if clearance of carbidopa is not rapid. A small study suggests
that motor fluctuations improve in advanced PD when patients receive levodopa without an
aromatic amino acid decarboxylase inhibitor (3). It was demonstrated in an earlier study with
an experimental formulation of extended release carbidopa/levodopa that some patients had
worse motor function with three times the dose of carbidopa/levodopa despite an adequate
plasma levodopa level (16). High dose carbidopa is typically used in advanced PD. When high
dose carbidopa is given chronically this may create a situation where carbidopa accumulates
in the central nervous system and could thereby worsen motor function.
B. 4. Alteration of the Blood Brain Barrier in PD May Be a Mechanism by Which Carbidopa
Inhibits Central AAAD Another consideration is that the blood brain barrier is altered in PD
and could allow entry of substances previously sequestered to the periphery (17). As PD
progresses patients receive larger doses of carbidopa along with levodopa in order to manage
motor fluctuations. Chronic levodopa administration often results in dyskinesias in these
circumstances. Histochemical evidence from animal models of levodopa induced dyskinesia
suggests there is dysfunction of the blood brain barrier. Signs of angiogenesis and serum
albumin leakage were two findings supporting vascular alteration in this model (18). Chronic
administration of MPTP to primates increases VEGF-expressing neurons and increases the number
of blood vessels in the substantia nigra pars comptacta (19). Similarly, in the
6-hydroxydopamine model of PD, primates had patchy loss of blood brain barrier in the same
regions associated with angiogenesis (20). In a small autopsy study humans with PD had
vascularity present in the substantia nigra pars compacta compared with controls (21). Blood
brain barrier alteration could lead to increased penetration of carbidopa from the periphery
over time in two different scenarios. Firstly, carbidopa clearing mechanisms and transport
pumps may be overwhelmed if small amounts accumulate over time. Secondly, the degree of
blood-brain barrier alteration may be so great that even a single large dose of carbidopa may
enter the CNS.
Carbidopa penetrates the blood brain barrier to a limited extent after a single injection in
normal rats. Since the blood brain barrier could be altered in PD there might be significant
inhibition of central AAAD. Either the effect of long-term multiple daily doses of carbidopa
or a single large dose of carbidopa could lead to a significant decrease in the amount of
available dopamine, thereby worsening the clinical features of PD.
C. Preliminary Studies / Experience of the Investigators:
Our group has extensive experience in randomized controlled clinical trials and proof of
principle studies in PD. This includes a large number of levodopa infusion protocols similar
to that proposed for the current study. We have recently completed studies examining the dose
effect of apomorphine on motor fluctuations (Gunzler in press), clinical testing of
concomitantly dosed levodopa and methylphenidate (22), and evolution of response to levodopa
over the course of PD (23). We have conducted pilot studies involving both outpatient and
Clinical Translational Research Center (CTRC formerly GCRC) admissions for both levodopa and
carbidopa (16, 24). Furthermore we have been involved in research on the basic pharmacology
and clinical effects of levodopa (25-35).
D. Research Design and Methods
D. 1. Overall Study Design This study will be a randomized, double-blind, \controlled,
crossover trial of four week outpatient treatment periods with levodopa and either carbidopa
450mg daily or carbidopa 75mg daily plus placebo (figure 1). Levodopa will be dosed
separately in individual capsules at doses and intervals that maximize motor function.
Subjects will be selected based on inclusionary and exclusionary criteria and randomized to
start in either high dose carbidopa group or low dose carbidopa group. After randomization
subjects will be given four weeks of outpatient treatment with levodopa and either high dose
carbidopa or low dose carbidopa plus placebo. After this four week treatment phase subjects
will be brought into the Clinical Translational Research Center at OHSU (CTRC) for a total of
three days. Included in this will be two days measuring objective motor function with
levodopa infusion along with a different dose of carbidopa on each of the two days. The
evening of admission to the CTRC subjects will turn in ratings of outpatient clinical state
collected in a structured diary. After this visit they will crossover and alternately receive
either high dose carbidopa or low dose of carbidopa for another four weeks. They will again
be brought into the CTRC for a second two day measurement of motor function with levodopa
infusion and a different dosing schedule of carbidopa on each of the two days. They will
again turn in ratings of outpatient clinical state collected in a structured diary. Both
subjects and investigators will remain blinded to the dose of carbidopa for both outpatient
phases and one of the two days of each inpatient phase of the study.
Other known NCT identifiers
