Minocycline to Treat Childhood Regressive Autism

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00409747
First received: December 8, 2006
Last updated: June 2, 2011
Last verified: April 2011
  Purpose

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.


Condition Intervention Phase
Autism
Minocycline
Regressive Autism
Drug: Minocycline Capsule
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Primary Purpose: Treatment
Official Title: Treatment of Childhood Regressive Autism With Minocycline: an Anti-Inflammatory Agent Active Within the CNS

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Change in CSF cytokine concentrations [ Time Frame: 6 months (LP's done pre-/post 6-months of tx with minocycline) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in autistic symptoms (social and communication deficits and/or restricted and repetitive behaviors) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 14
Study Start Date: November 2006
Study Completion Date: April 2011
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Minocycline Capsule
    N/A
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   3 Years to 12 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

The sample will be children with:

  • Diagnosis of idiopathic autism and regression
  • Age between 3 and 12 years
  • Willingness to undergo lumbar puncture for evaluation of proinflammatory CSF cytokines
  • Stable behavioral plus or minus medication therapies.

EXCLUSION CRITERIA:

  • Significant prematurity at birth (less than 32 weeks gestation); or birthweight significantly below normal for gestational age (SGA--small for gestational age).
  • Neurologic disorders including cerebral palsy, uncontrolled epilepsy, and Landau-Kleffner syndrome.
  • Evidence of renal insufficiency or hepatic disease (to reduce the incidence of side-effects, since minocycline is excreted by the kidneys following hepatic metabolism)
  • Increased risk of developing lupus-like syndrome with minocycline administration (positive anti-double stranded DNA or anti-nucleosome antibody tests at baseline, or presence of a first degree relative with S.L.E.)
  • Recent (less than two months prior to study entry) initiation of a behavioral therapy program or new psychotropic medication trial.
  • Subjects on one of the medications/supplements listed as those with possible interactions or those on high dose B6 supplementation. For those families who are interested in the study but are on any of these medications/supplements at the time of intake, they will be instructed to wean the medication as appropriate (working with the prescribing MD), and they will be enrolled after a 6-week wash-out period.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00409747

Locations
United States, District of Columbia
Childrens National Medical Center
Washington, District of Columbia, United States
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
Responsible Party: Susan E. Swedo, M.D./National Institute of Mental Health, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00409747     History of Changes
Other Study ID Numbers: 070024, 07-M-0024
Study First Received: December 8, 2006
Last Updated: June 2, 2011
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Immunology
Microglia
NF-Kappa-B
Antibiotic
Autism
Minocycline
Regressive Autism

Additional relevant MeSH terms:
Autistic Disorder
Child Development Disorders, Pervasive
Mental Disorders Diagnosed in Childhood
Mental Disorders
Anti-Inflammatory Agents
Minocycline
Therapeutic Uses
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 14, 2014