Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01323374 |
| Other study ID # |
Droxidopa FMS201 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
January 2009 |
| Est. completion date |
October 2011 |
Study information
| Verified date |
February 2024 |
| Source |
Chelsea Therapeutics |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
A correlation between increased norepinephrine concentration in the central nervous system
(CNS) and a decrease in fibromyalgia pain has been suggested in clinical studies. Therefore,
as a pro-drug of norepinephrine, droxidopa could potentially benefit fibromyalgia patients by
reducing pain as a result of increasing CNS levels of norepinephrine.
As this benefit is presumed to be a central effect, the addition of carbidopa, a peripheral
DOPA decarboxylase (DDC) inhibitor, may favorably impact the drug's treatment profile.
Carbidopa is utilized as a blocker of peripheral DDC, an enzyme required for the conversion
of droxidopa into norepinephrine. Therefore, inhibition of peripheral DDC should result in a
reduction of any side effects resulting from the peripheral production of norepinephrine,
whilst allowing for increased central levels, and hence, increased centrally mediated
benefits.
The purpose of the study is the obtain information regarding the proper dosing, effectiveness
and safety of droxidopa and combination droxidopa/carbidopa treatments in patients with
fibromyalgia.
Description:
Fibromyalgia syndrome (FMS) and Chronic widespread pain (CWP) are two syndromes within a
broader class known as functional somatic syndromes. Chronic widespread pain (CWP) is defined
according to the American College of Rheumatology (ACR), as pain both above and below the
waist involving both sides of the body and lasting for at least 3 months. Fibromyalgia
syndrome (FMS), a subset of CWP, is a multisystem disease characterized by sleep disturbance,
fatigue, headache, morning stiffness, paresthesias, and anxiety.
While there is debate as to specific etiology and pathogenesis, fibromyalgia is generally
believed to be the result of a perturbation of central pain processing, specifically the
neuroendocrine system. Fibromyalgia patients have been shown to have lower levels of
metabolites from three neurotransmitters (serotonin, norepinephrine, and dopamine) in their
cerebrospinal fluid (CSF) compared to healthy controls. The low rate of turnover of these
neurotransmitters supports the hypothesis of a metabolic defect in fibromyalgia and suggests
that the defect occurs at a neuroregulatory level. Results of a study that examined the
effect of a permanent reduction in the noradrenergic innervation of the spinal cord suggested
that the antinociceptive effects of norepinephrine are closely linked to opioidergic and
tachykinergic neurotransmission.
Droxidopa [also, known as L-threo-3,4-dihydroxyphenylserine, L-threo-DOPS, or L-DOPS] is the
International non-proprietary name (INN) for a synthetic amino acid precursor of
norepinephrine (NE), which was originally developed by Sumitomo Pharmaceuticals Co., Limited,
Japan. It has been approved for use in Japan since 1989. Droxidopa has been shown to improve
symptoms of orthostatic hypotension that result from a variety of conditions including Shy
Drager syndrome (Multiple System Atrophy), Pure Autonomic Failure, and Parkinson's disease.
There are four stereoisomers of DOPS; however, only the L-threo-enantiomer (droxidopa) is
biologically active. Data from clinical studies and post-marketing surveillance programs
conducted in Japan show that the most commonly reported adverse drug reactions with droxidopa
are increased blood pressure, nausea, and headache. In clinical studies to date, data
suggests that droxidopa is well-tolerated and effective as a norepinephrine precursor.
Pre-clinical and clinical studies suggest that droxidopa has an analgesic effect in patients
with chronic pain. An increase in central nervous system (CNS) levels of norepinephrine has
been shown to correlate with an analgesic effect. Based on the pre-clinical and clinical
findings to date, it is hypothesized that droxidopa can provide pain reduction in
fibromyalgia patients through increasing the CNS levels of norepinephrine.
Carbidopa is a DOPA decarboxylase (DDC) inhibitor. At therapeutic doses carbidopa does not
cross the blood-brain barrier and therefore should not inhibit CNS metabolism of droxidopa to
NE. Decreasing the activity of DDC in the periphery enables droxidopa metabolism to be
focused in the CNS. This CNS focus should increase CNS response while also limiting the
increase in blood pressure associated with peripheral droxidopa metabolism. In addition, as
DDC is an enzyme required for the conversion of droxidopa into its active metabolite
norepinephrine, inhibition of peripheral DDC, utilizing Carbidopa, should result in a
reduction of any side effects resulting from the peripheral production of NE, whilst allowing
for increased central levels, and hence, increased centrally mediated benefits.
The primary objective of this study is to determine the efficacy of droxidopa and
droxidopa/carbidopa in the treatment of pain associated with fibromyalgia. Secondary
objectives include: evaluation of the effect of droxidopa and combinations of
droxidopa/carbidopa on signs and symptoms of fibromyalgia, evaluation of the effect of
droxidopa and combinations of droxidopa/carbidopa on the overall quality of life of
fibromyalgia patients, evaluation of the dose-response relationship for droxidopa between
different doses of droxidopa, carbidopa and combinations of droxidopa/carbidopa in
fibromyalgia patients, evaluation of the clinical benefit of treatment with different doses
of droxidopa, carbidopa and combinations of droxidopa/carbidopa in fibromyalgia patients,
estimation of the optimal dose for relief of fibromyalgia pain using response surface
methodology, and evaluation of the safety of droxidopa and droxidopa/carbidopa treatments.
