Autism Clinical Trial
Official title:
Treatment of Childhood Regressive Autism With Minocycline: an Anti-Inflammatory Agent Active Within the CNS
There is a subgroup of children with autism that appears to develop typically for a period
of time, and then loses social or language skills, or regresses. A recent study by Vargas
and co-workers at Johns Hopkins has demonstrated that this regressive type of autism is
associated with chronic brain inflammation as shown by an abnormal production of
inflammatory cytokines among other abnormalities.
This present study will test the effectiveness of minocycline, an antibiotic with
anti-inflammatory properties, in treating regressive autism. Although behavioral therapies
have improved some symptoms of autism, there are no medical treatments for the disorder, and
many children have ongoing behavioral difficulties. A medicine with anti-inflammatory
properties may be beneficial for children with regressive autism.
This will be an open-label trial, meaning all children in this study will receive
minocycline. They will also receive vitamin B6 to reduce the possible chance of side effects
of the minocycline.
Children ages 3 to 12 with regressive autism may be eligible for this study. The children
will take minocycline and vitamin B6 daily for 6 months. Prior to starting the medication
and vitamin B6, children will receive a comprehensive diagnostic assessment for autism as
well as a physical examination, medical history, and laboratory tests. Children will then
receive ongoing assessments to monitor their behavior, communication, language skills, and
medical issues at 2 weeks, and at 1, 2, 4, 6, and 12 months. Children who respond to the
treatment will receive an additional 3 months of minocycline and vitamin B6.
Autism is a neurodevelopmental disorder that results in abnormalities of social and language
development and is associated with rigid and repetitive behaviors. Although there is strong
evidence of heritability, the involved genes have not been identified. The prevalence of
autism spectrum disorders may be as common as 1 in 166. The average concordance rate in
monozygotic twins is 70% suggesting that environmental factors play a role in the disease.
Subgroups of autistic children seem unusually sensitive to infections, immunizations and
dietary factors, but none of these factors has been causally identified with the disease.
Nevertheless, autoimmunity has been considered to play a role on the basis of indirect
evidence. There is no evidence-based efficacious treatment for autism.
There is a subgroup of children with autism that appear to develop typically for a period of
time, and then lose skills, or regress. A recent study by Vargas and co-workers at Johns
Hopkins has demonstrated that the regressive subtype of autism is associated with chronic
brain neuroinflammation as exemplified by activation of microglia and astroglia and the
abnormal production of inflammatory cytokines and growth factors assayed in both tissue
samples (brain banks) and CS. The authors remarked that these responses were similar to
those seen in some neurodegenerative disorders such as amyotrophic lateral sclerosis, and
that chronic microglia activation appears to be responsible for a sustained
neuroinflammatory response that facilitates the production of multiple neurotoxic mediators.
Chronic neuroglial activation could be the result of an abnormal persistence of a fetal
development pattern. In this scenario neuroglial activation could play a role in initiating
and in maintaining the pathology. Alternatively, neuroglial activation may only be a
secondary response to the initiating causal factor(s) and not a direct effector of injury.
Since neuroglial activation requires the nuclear translocation of the pro-inflammatory
transcription factor NF-kappa B, and since inhibitors of NF-kappa-B with good CNS penetrance
are available, the role of neuroinflammation in initiating and sustaining the autistic
condition can be probed.
The antibiotic minocycline is a powerful inhibitor of microglial activation, apparently
through blockade of NF-kappa-B nuclear translocation. Minocycline is neuroprotective in
mouse models of amyotrophic lateral sclerosis (ALS) and Huntington's disease and has been
recently shown to stabilize the course of Huntington's disease in humans over a 2-year
period.
To evaluate the possibility of benefit in autistic children, we propose to conduct an
open-label trial of the anti-inflammatory antibiotic minocycline, an agent that reduces
inflammation by blocking the nuclear translocation of the proinflammatory transcription
factor NF-kappa-B. Minocycline is Food and Drug Administration (FDA)-approved for treatment
of a variety of infections and has been widely used for the treatment of adolescent acne.
Minocycline is currently in phase III trials for the treatment of Huntington's disease and
amyotrophic lateral sclerosis.
This proposal is for an initial 6-month, single-arm, off label, open-label study (with a 3
month extension phase offered to responders) that will evaluate dose safety and efficacy of
minocycline in 10 children, ages 3 to 12 years, with a primary diagnosis of autism and a
history of developmental regression. The subjects will be evaluated by a
diagnostic/behavioral assessment, and the extent of neuroinflammation judged by CSF
cytokine/chemokine profiles before and after the 6-month treatment. Subjects will also be
given 0.6 mg/kg vitamin B6 twice a day as a prophylactic for possible minocycline induced
nausea and vomiting. If the results of this feasibility study are encouraging, we expect to
conduct a double-blind, placebo-controlled trial of minocycline therapy.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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