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Effects of the Anti-inflammatory Flavonoid Luteolin on Behavior in Children With Autism Spectrum Disorders

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: NCT01847521
Recruitment Status : Completed
First Posted : May 7, 2013
Last Update Posted : May 7, 2013
Information provided by (Responsible Party):
Dr Konstantinos Francis, Attikon Hospital

Brief Summary:

Background. Increasing evidence indicates that brain inflammation is important in the pathogenesis of neuropsychiatric disorders, including at least a significant proportion of subjects with Autism spectrum disorder (ASD). Natural flavonoids, such as luteolin and quercetin, exhibit potent antioxidant and anti-inflammatory activities, inhibit the release of inflammatory mediators from human mast cells, and reduce maternal interleukin 6-induced autism-like behavioral deficits related to social interactions in mice. In a case series of 37 children with ASD who took a dietary supplement containing luteolin and quercetin for 4 months reported gains in eye contact, attention and social interaction according to parental reports.

Aim. The purpose of this study was to assess the effectiveness and tolerability in white children with ASD of a dietary supplement containing 2 flavonoids, luteolin and quercetin, and the quercetin glycoside rutin.

Methods. Fifty children (42 boys and 8 girls) divided into 2 equal age groups (4-6 years old, and 7-10 years) with ASD were enrolled in a 26-week, prospective, open-label trial at the 2nd University Department of Psychiatry at "Attikon" General Hospital, Athens, Greece, the Ethics Committee of which approved the study. The parents of all subjects were informed of the study's aims, including risks versus benefits of participating and not participating as well as the inclusion and exclusion criteria, and they written consent for participation in the study.

Participants had already been diagnosed with ASD based on clinical assessments, and this diagnosis was corroborated at the 'Attikon' clinic by meeting the cutoff scores on both the DSM-IV-TR, symptom list and the ADOS algorithm. All children were medication naive. Apart from the diagnostic evaluation, the assessment also included a thorough medical evaluation comprising a physical examination and health history (including a review of allergic and gastrointestinal symptoms, as well as any food allergies or food intolerance). All concurrent interventions were thoroughly noted (type and hours), and the same was done at all visits. After meeting screening criteria, subjects were evaluated at the baseline visit, mid-trial visit at 18 weeks, and final visit at 26 weeks.

Children were administered a dietary formulation containing 2 flavonoids, luteolin (100 mg/capsule) and quercetin (70 mg/capsule), and the quercetin glycoside rutin (30 mg/capsule). The dose used was 1 softgel capsule per 10 kg (22 lb) weight per day with food for 26 weeks.

The primary outcomes were the age-equivalent scores in the 3 domains of the Vineland Adaptive Behavior Scales (VABS), communication, daily living skills, and socialization. The VABS was chosen because the impact of an agent on adaptive functioning in real life is even more important for obtaining a better quality of life than just alleviation of some symptoms. The raw scores from the interview can be also expressed as an age-equivalent score and a standard score compared with those of the subject's peers. There are also supplementary special norms for individuals with autism. Although standard scores could be more useful in subject characterization, their use as an outcome measure has been proven to be less sensitive due to floor effects and reduced variability, especially in short time periods, and thus these scores underestimate change. Conversely, scores of special norms tend to overestimate change, as a small increase in a raw score can produce a big improvement in special norm percentile rank. Thus, raw scores and age-equivalent scores seem to be the most appropriate for use as outcome measures, with the latter being more easily interpreted as change over time.

Secondary outcomes included the Aberrant Behavior Checklist (ABC), the Autism Treatment Evaluation Checklist (ATEC), and the Clinical Global Impression-Improvement score (CGI-I). To explore other possible effects of the formulation not captured from the aforementioned instruments, we chose to record any other benefits observed and reported by the parents during its use. For this, the primary clinician (K.F.) conducted telephone or in-person interviews of the parents, independently of the assessing clinician (A.T.), to discuss the possible gains of the child. CGI-I was also independently coded by the primary clinician with personal assessments as well as with information gathered by parents and, in the majority of cases, by the subjects' trainers.

Compliance was monitored by softgel capsule count and the parents' assurance that the capsules had actually been taken at each visit; in case of a capsule count <85% of the prescribed dosage at midterm and at the end of the study, the subject was excluded from the final analysis.

Adverse events were systematically recorded on an adverse event form by using scales indicating severity, relationship to the study procedures, action taken, and any therapy required.

Condition or disease Intervention/treatment Phase
Autism Spectrum Disorders Dietary Supplement: Luteolin, Quercetin and Rutin combined in a capsule Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Study Start Date : December 2011
Actual Primary Completion Date : February 2013
Actual Study Completion Date : March 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Capsule containing Luteolin, Quercetin, and Rutin
One capsule containing Luteolin (100 mg/capsule), Quercetin (70 mg/capsule), and Rutin (30 mg/capsule). 1 capsule per 10 kg weight per day with food
Dietary Supplement: Luteolin, Quercetin and Rutin combined in a capsule
Other Name: Neuroprotek

Primary Outcome Measures :
  1. Change in Age-Equivalent scores of the Vineland Adaptive Behavior Scales domains from baseline at 26 weeks [ Time Frame: Change from baseline at 26 weeks ]

Secondary Outcome Measures :
  1. Change in Aberrant Behavior Checklist subscales from baseline at 18th week and at 26th week [ Time Frame: From baseline at 18th week and at 26th week ]
  2. Change in Autism Treatment Evaluation Checklist from baseline at 18th week and at 26th week [ Time Frame: From baseline at 18th week and at 26th week ]
  3. Clinical Global Impression-Improvement score at 18th week and at 26th week [ Time Frame: At 18th week and 26th week ]

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:   4 Years to 10 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • ASD clinical diagnosis
  • Meeting the cutoff score on the DSM-IV-TR symptom list
  • Meeting the cutoff score on the Autism Diagnostic Observation Schedule algorithm, at least for ASD

Exclusion Criteria:

  • any medical condition likely to be etiological for ASD [eg, Fragile X syndrome, tuberous sclerosis],
  • any neurologic disorder involving pathology above the brain stem [other than uncomplicated nonfocal epilepsy],
  • any evidence of probable neonatal brain damage,
  • mastocytosis [including urticaria pigmentosa]
  • a history of systemic inflammatory diseases

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): NCT01847521

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Attikon Hospital
Chaidari, Athens, Greece, 124 62
Sponsors and Collaborators
Attikon Hospital

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Dr Konstantinos Francis, Lecturer of Child Psychiatry, Athens University, Attikon Hospital Identifier: NCT01847521    
Other Study ID Numbers: NeuroproteckOpenLabel
First Posted: May 7, 2013    Key Record Dates
Last Update Posted: May 7, 2013
Last Verified: May 2013
Additional relevant MeSH terms:
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Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs