anxiety disorder will be excluded from this trial. Insomnia is also
exclusionary, but it would be interesting to know how they intend to
differentiate the psychiatric disorder of insomnia from unrefreshing
sleep and other sleep issues associated with ME and CFS.
The following Phase II study from Columbia University has been
registered with Clinical Trials.gov, but is not yet recruiting.
Chronic Fatigue Syndrome: A Presumptive Mitochondrial Disorder (CFS:M)
NCT01471652
Purpose:
Detailed Description:
Chronic fatigue syndrome (CFS), also known as myalgic encephalitis
(ME), is clinically characterized as a multisystem illness exhibiting
debilitating fatigue, musculoskeletal pain, disturbed sleep, and
impaired memory and concentration. Its diagnosis is non-specific and
symptom based, with no real biomarkers yet identified. The etiology
and pathophysiology of CFS remain obscure.
There is a long-standing hypothesis that individuals with CFS have
normal metabolism and their fatigue is psychological, with energy
being wasted through the processes of anxiety, stress, and depression.
The more CFS is investigated, however, the clearer it becomes that
this is incorrect, and that it is probably a metabolic dysfunction
resulting in insufficient energy production.
A number of studies have suggested that there may be a genetic
contribution to CFS. In addition, a severe viral illness frequently
predisposes the onset of CFS, while a number of pathogens have been
linked to CFS (2, 3, 6). Although some patients develop CFS after an
acute infection such as mononucleosis, some investigators believe it
arises from the reactivation of a latent virus in the host, both
resulting in a chronic low-level activation of the immune system.
As more data are acquired, we and others believe that CFS is actually
a metabolic mitochondrial dysfunction resulting in insufficient energy
production. Mounting evidence indicates that viral infections in
genetically susceptible individuals can cause changes in mitochondrial
function. Many features observed in CFS are similar to those seen in
genetic mitochondrial disorders. Firstly, some muscle biopsies in
patients with CFS have shown both abnormal mitochondrial degeneration
and severe deletions of mitochondrial DNA genes. Mitochondrial
dysfunction increases the production of free radicals and reactive
oxygen species (ROS), which cause oxidative damage, believed to
contribute to CFS pathogenesis. Carnitine is required for metabolic
reactions including mitochondrial fatty acid oxidation. A deficiency
of serum acylcarnitine has been observed in CFS patients, suggesting
that there is increased utilization of carnitine in CFS, thereby
decreasing energy production. In mitochondrial disorders, utilization
of pyruvate is decreased, resulting in higher circulating and muscle
levels of lactate, as well as decreased oxidative phosphorylation and
energy production. Brain ventricular cerebrospinal lactate is
elevated, and brain glutathione is decreased, in both mitochondrial
disorders and CFS. In CFS patients cerebrospinal lactate is increased
by approximately 300% compared to that found in generalized anxiety
disorder and healthy individuals. Using brain NMR spectroscopy, the
distinction between CFS and psychological disorders can be
demonstrated.
The pathogenesis of chronic fatigue syndrome (CFS) is poorly
understood and no effective therapy has been developed. Recent studies
suggest that a preceding viral infection causes mitochondrial
dysfunction of the brain and skeletal muscle of genetically
susceptible individuals. There is no specific laboratory test to
identify patients with CFS. However, certain clinical manifestations
are similar to those seen in mitochondrial disorders. Both patients
with mitochondrial disorders and CFS manifest elevated serum lactate
levels after exercise, and demonstrate elevated brain cerebrospinal
fluid levels and decreased brain glutathione levels on nuclear
magnetic resonance (NMR) spectroscopy.
Therapy consisting of daily conditioning exercise, dietary
recommendations, and nutraceutical supplements (ENT) has been show to
be beneficial in treating patients with mitochondrial disorders.
Similar therapy has been instituted in individual patients with CFS
and has been shown to also improve their clinical conditions.
A placebo-controlled trial will be undertaken in 24 CFS patients aged
25-55. Patients fulfilling the CDC criteria for CFS will participate
in this 6 month study. Other medical causes for fatigue will be
excluded. Half the patients will receive treatment consisting of daily
conditioning exercise plus nutraceutical supplements (ENT), that has
been shown to be beneficial for patients with mitochondrial
dysfunction, while the other half will receive daily conditioning
exercise and placebo tablets.
Response to ENT will be evaluated by maximum oxygen consumption
(VO2max) and circulating lactate levels during & after treadmill
exercise, a 6-minute walk test, and a fatigue questionnaire. In
addition, whether ENT corrects the elevated brain cerebrospinal fluid
levels and decreased brain glutathione levels will be measured. To
ensure compliance to therapy patients will be monitored frequently.
The objective of this study is to assess the safety and efficacy of
ENT and whether ENT leads to sustained improvement of CFS patients
compared to their baseline status, and compared to an exercised group
of patients not receiving supplements.
Further study details as provided by Columbia University:
Primary Outcome Measures:
Change in rate of fatigue status and other CFS symptoms [ Time Frame:
0, 3, and 6 months ] [ Designated as safety issue: No ]
Rate of decrease in fatigue and other CFS symptoms, as measured by
SF-36 and The Fatigue Assessment Instrument.
Secondary Outcome Measures:
Change in brain lactate and glutathione levels [ Time Frame: 0 and 6
months ] [ Designated as safety issue: No ]
Patients will undergo nuclear magnetic resonance spectroscopy of the
brain prior to starting therapy (baseline) and repeat it after 6
months of therapy.
Estimated Enrollment: 24
Study Start Date: February 2012
Estimated Study Completion Date: April 2013
Estimated Primary Completion Date: April 2013 (Final data collection
date for primary outcome measure)
http://clinicaltrials.gov/ct2/show/NCT01471652
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