Treatment of Social and Language Deficits With Leucovorin for Young Children With Autism
Overview
- Phase
- Phase 2
- Intervention
- Levoleucovorin Calcium
- Conditions
- Autism Spectrum Disorder
- Sponsor
- Southwest Autism Research & Resource Center
- Enrollment
- 80
- Locations
- 4
- Primary Endpoint
- Evaluate the change in social communication symptoms
- Status
- Recruiting
- Last Updated
- 5 days ago
Overview
Brief Summary
The primary objective of this study is to evaluate the cognitive and behavioral effects of liquid leucovorin calcium on young children with autism spectrum disorder (ASD) and determine whether it improves social communication as well as the core and associated symptoms of ASD. The investigators will enroll 80 children across two sites, between the ages of 2.5 and 5 years, with confirmed ASD and known social and communication delays. Participation will last approximately 26 weeks, from screening visit to end of treatment.
Detailed Description
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with life-long consequences that affects young children during critical times in their development. ASD is defined by impairments in social-communication as well as the presence of restricted interests and repetitive behaviors. ASD is frequently associated with co-occurring language delays. Currently the only well-accepted treatment for core ASD symptoms is behavior therapy such as Applied Behavioral Analysis and Early Intensive Behavioral Intervention. There is no US Food and Drug Administration approved medical therapy that addresses core ASD symptoms or the pathophysiological processes that underlie ASD. The primary aim of this study is to evaluate the effect of a liquid form of leucovorin calcium on social and communication impairments in very young children with ASD. Participants entered into the trial will have delayed language and moderate ASD symptoms. The investigators hypothesize that leucovorin calcium will significantly improve social communication as well as core and associated behavioral symptoms of ASD, and be well-tolerated with no significant adverse effects, in young children with ASD. To assess whether the liquid form of leucovorin calcium is superior to placebo, the investigators will study 80 children across two sites, between the ages of 2.5 and 5 years, with confirmed ASD and known social and communication delays at baseline. Participants will be randomly assigned to receive active treatment or placebo for 12 weeks under double-blind conditions. At the end of 12 weeks, all participants will receive active treatment for 12 weeks. Language skills and social communication abilities will be measured at screening and after each treatment arm in order to determine if the supplement positively influences social communication. Additionally, the investigators will measure changes in neural pathways using either magnetoencephalography at Phoenix Children's Hospital or functional Near Infrared Spectroscopy at State University of New York, Downstate. While these measures will be considered exploratory, they will be important to begin to elucidate the neuronal mechanisms underlying leucovorin's impact.
Investigators
Richard Frye
Principal Investigator
Southwest Autism Research & Resource Center
Eligibility Criteria
Inclusion Criteria
- •1\. Autism Spectrum Disorder (diagnosed as Autistic Disorder on the ADOS-2 or the ADI-R).
- •Between 2 years 6 months and 5 years 2 months of age at baseline
- •Folate Receptor Alpha Autoantibody Positive status
- •Language impairment (Ages and Stage Questionnaire between -1 and -3 SD for Language)
- •English included in the languages in which the child is being raised
- •Autism severity of moderate or higher (≥4) under the 7-item clinical global impression-severity scale. Moderate level of autism severity (4) is defined by the diagnosis of ASD with language impairment, so fulfilling #1 and #4 fulfills this requirement.
- •Ability to maintain all ongoing complementary, dietary, traditional, and behavioral treatments constant for the study period
- •Unchanged complementary, dietary, traditional, and behavioral treatments for two months prior to study entry
- •Has at least 4 month old expressive language ability as assessed by the MSEL Expressive Language Scale (i.e., Parent answers "yes" to " Voluntary babbling (such as 'bu, bu, bu")" Question #7 on the MSEL Expressive Language Scale.
- •Ability to attend to social stimulus and tolerate imaging procedures, as determined at the discretion of the investigator
Exclusion Criteria
- •Known FRAA status by clinically validated test performed outside of research studies.
- •Mineral or vitamin supplementation that exceeds the Tolerable Upper Daily Intake Levels set by the Institute of Medicine (See Table 6 below)
- •Significant self-abusive or violent behavior or evidence of suicidal ideation, plan or behavior
- •Severely affected children as defined by CGI-Severity Standard Score = 7 (Extremely Ill)
- •Severe prematurity (\<34 weeks gestation) as determined by medical history
- •Current uncontrolled gastroesophageal reflux
- •Current or history of liver or kidney disease as determined by medical history and safety labs
- •Genetic syndromes
- •Congenital brain malformations
- •Any medical condition that the PI determines could jeopardize the safety of the study subject or compromise the integrity of the data
Arms & Interventions
L-leucovorin calcium
The liquid form of leucovorin calcium will be dosed by weight, with a target dose of 1mg/kg/day, divided into two daily doses. This product may be taken alone or mixed with liquid. Participants randomized to this arm will receive active treatment for both 12-week phases of the study.
Intervention: Levoleucovorin Calcium
Placebo
The placebo will mimic the experimental treatment in flavor, odor, packaging, and dosing instructions. Participants randomized to this arm will receive placebo for the first 12 weeks of the study, then active treatment for the remaining 12 weeks.
Intervention: Placebo
Outcomes
Primary Outcomes
Evaluate the change in social communication symptoms
Time Frame: Baseline, Week 6, Week 12, Week 24
Aberrant Behavior Checklist-2, Social Withdrawal Subscale. The ABC is a 58-item parent-reported measure with ratings in the following domains: irritability, social withdrawal, stereotypic behavior, hyperactivity, and inappropriate speech. Each item is rated from 0 (Not a Problem) to 3 (Severe Problem). The raw score will be reported. The total raw score is the sum of the domain raw scores. A higher raw score in any of the domains indicates more severe problems in that domain; a higher total raw score indicates more severity of stereotypical autism symptoms overall.
Secondary Outcomes
- Evaluate change in specific autism symptom severity(Baseline, Week 6, Week 12, Week 24)
- Evaluate the change in adaptive functioning(Baseline, Week 12, Week 24)
- Evaluate the overall change in core ASD symptoms of social communication using a blind observer(Screening, Week 6, Week 12, Week 24)
- Evaluate change in overall autism severity(Baseline, Week 6, Week 12, Week 24)
- Evaluate the safety and tolerability of L-leucovorin calcium in young children with ASD(Screening, Baseline, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24)
- Evaluate adverse effect symptoms in young children with ASD(Screening, Week 12, Week 24)
- Evaluate the biologic safety of L-leucovorin calcium in young children with ASD(Screening, Week 12, Week 24)
- Evaluate the safety of L-leucovorin calcium in young children with ASD on antiepileptic drugs(Screening, Week 12, Week 24)
- Examine the change in measures of Expressive and Receptive Language(Baseline, Week 12, Week 24)
- Evaluate the change in overall cognitive ability(Baseline, Week 12, Week 24)
- Evaluate the overall change in core ASD symptoms of social communication(Screening, Week 6, Week 12, Week 24)
- Evaluate the change in effects of autism symptoms on family members(Baseline, Week 6, Week 12, Week 24)
- Evaluate the change in stereotypical autism symptoms(Baseline, Week 6, Week 12, Week 24)