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Minocycline to Treat Childhood Regressive Autism

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00409747
Recruitment Status : Completed
First Posted : December 11, 2006
Results First Posted : December 11, 2015
Last Update Posted : December 11, 2015
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Brief Summary:

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 or disease Intervention/treatment Phase
Autism Minocycline Regressive Autism Drug: Minocycline Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Childhood Regressive Autism With Minocycline: an Anti-Inflammatory Agent Active Within the CNS
Study Start Date : November 2006
Actual Primary Completion Date : June 2010
Actual Study Completion Date : April 2011

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Minocycline Drug: Minocycline

Primary Outcome Measures :
  1. z Score [ Time Frame: Pre and post treatment with minocyline at 6 months for 10 subjects ]

    The Mann-Whitney U-test was used to compare pre-/post-treatment differences in analyte concentrations in serum, plasma and CSF. The Mann-Whitney U test generates a z-score test statistic with an associated p value. A negative z-statistic reflects a decrease in analyte level from pre- to post-treatment. Statistical significance level was set at 0.05. There is one test statistic (z-score) per analyte, reflecting the pre-post comparison across all subjects.

    Pre and post treatment measurements of csf analytes: TNF alpha, Il-6, CCL-2(MCP-1), CCL3 (MIP-1alpha), CCL5(RANTES), CXCL(IL-8), BDNF, CD40L, GDNF, HGF, Leptin

Secondary Outcome Measures :
  1. Clinical Global Impressions Scale-Severity (CGI). (Connors & Barkley, 1985) [ Time Frame: Baseline and 6 months ]
    This instrument has two scales - Severity (CGI-S). The CGI-S is a seven point scale with a minimum score of 1 and a maximum score as 7 as follows: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   3 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.


  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00409747

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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
National Institute of Mental Health (NIMH)
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: National Institute of Mental Health (NIMH) Identifier: NCT00409747    
Other Study ID Numbers: 070024
07-M-0024 ( Other Identifier: NIH Protocol number )
First Posted: December 11, 2006    Key Record Dates
Results First Posted: December 11, 2015
Last Update Posted: December 11, 2015
Last Verified: November 2015
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Regressive Autism
Additional relevant MeSH terms:
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Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Anti-Bacterial Agents
Anti-Infective Agents