Treatment of Social and Language Deficits With Leucovorin for Young Children With Autism

Study 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.

Official Title
-----------------
Treatment of Social and Language Deficits With Leucovorin for Young Children With Autism

Conditions
-----------------
Autism Spectrum Disorder, Language Disorders

Intervention / Treatment
-----------------
* Drug: Levoleucovorin Calcium
* Other: Placebo


Participation Criteria
=================
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 Epilepsy Any medical condition that the PI determines could jeopardize the safety of the study subject or compromise the integrity of the data Significant negative reaction (i.e. fainting, vomiting, etc.) as a result of a previous blood draw. Failure to thrive or Body Mass Index < 5%ile or <5%ile for weight (male <11.2kg; female <10.8kg by CDC 2000 growth charts) at the time of the study. Concurrent treatment with drug that would significantly interact with l-leucovorin such as specific chemotherapy agents, antimalarial and immune suppressive agents and select antibiotics (See Table 7 below). Allergy or Sensitivity to ingredients in the investigational product or placebo Evaluation with the MSEL or BOSCC within 3 months of entering the study Planned evaluation with the MSEL or BOSCC during the study Exclusion Criteria for the MEG recording include: Ferromagnetic implants, artificial joints, fixation hardware, dental work or shrapnel (additional screening will be completed to determine MRI eligibility) Ferromagnetic products attached to the body (including hair extensions) Head circumference greater than 60 cm A weight greater than 407 lbs. (185 kg)

Ages Eligible for Study
-----------------
Minimum Age: 30 Months
Maximum Age: 60 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective randomized 12-week double-blind placebo-controlled study followed by 12-week open label
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-leucovorin calcium<br>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. | Drug: Levoleucovorin Calcium<br>* Liquid leucovorin calcium dosed by weight<br>* Other names: L-folinate, calcium salt;|
| Placebo Comparator: Placebo<br>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. | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the change in social communication symptoms | 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. | Baseline, Week 6, Week 12, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of L-leucovorin calcium in young children with ASD | Modified Dosage Record and Treatment Emergent Symptoms: treating clinician will perform a review of medical and behavioral history at each visit to assess incidence of treatment-emergent adverse events. The treating clinician will use the scale to record presence and intensity of adverse effects. Intensity is rated on a scale of 0 (Not present) to 3 (Severe). The treating clinician will also judge the adverse effects' relatedness to treatment. Relatedness is rated on a scale of 1 (None) to 4 (Defined). The treating clinician will denote action taken. Action taken is rated on a scale of 0 (None) to 5 (Discontinue Treatment). No total score is calculated. However, higher ratings on any individual item indicate greater severity of adverse effects. | 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 | Routine complete blood counts will be collected to determine whether treatment-emergent basic blood chemistry is altered. Presence of any changes during the course of study enrollment will be evaluated by the treating physician and determined clinically significant or not clinically significant. If determined by the treating physician, a change will be considered an adverse event. | Screening, Week 12, Week 24 | 
| Evaluate the biologic safety of L-leucovorin calcium in young children with ASD | Routine comprehensive blood panels will be collected to determine whether treatment-emergent basic blood chemistry is altered. Presence of any changes during the course of study enrollment will be evaluated by the treating physician and determined clinically significant or not clinically significant. If determined by the treating physician, a change will be considered an adverse event. | Screening, Week 12, Week 24 | 
| Evaluate the safety of L-leucovorin calcium in young children with ASD on antiepileptic drugs | For children using antiepileptic drugs, the level of that drug will be measured. If determined by the treating physician, a change will be considered an adverse event. | Screening, Week 12, Week 24 | 
| Examine the change in measures of Expressive and Receptive Language | Mullen Scales of Early Learning: a scale of cognitive abilities across core domains: visual reception, fine motor, expressive language, receptive language. Expressive language domain: 28-item scale with a raw score range of 0-50, t score range of 20-80. Receptive language domain: 33-item scale with a raw score range of 0-48, t score range of 20-80. Change in domain ability will be measured by the change in domain raw and t score. T scores are calculated from raw scores and based on age norms. A higher domain t score indicates a higher level of ability in that domain. | Baseline, Week 12, Week 24 | 
| Evaluate the change in effects of autism symptoms on family members | Parent Target Problems: a parent-nominated list of 2 most problematic core autism symptoms. Responses are documented in a brief narrative and detail frequency, constancy, intensity, and impact of behavior on the family. Subjective reports of frequency, constancy, intensity, and impact on family will be rated by a blinded statistician at the conclusion of the study. Higher scores indicate more severe impact on family. | Baseline, Week 6, Week 12, Week 24 | 
| Evaluate the change in stereotypical autism symptoms | Aberrant Behavior Checklist-2: a 58-item parent-reported measure of stereotypical autism behaviors 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. | Baseline, Week 6, Week 12, Week 24 | 
| Evaluate change in overall autism severity | Clinical Global Impression Scale: The Clinical Global Impression Scale-Severity is a 7-point measure of overall symptom severity, ranging from 1 (Normal) to 7 (Extreme), with a raw score range of 1-7. The raw score will be reported. The Clinical Global Impression Scale-Improvement is a measure in change of symptom severity, ranging from 1 (Very Much Improved) to 7 (Very Much Worse). A Score of 4 indicates no change in symptom severity. | Baseline, Week 6, Week 12, Week 24 | 
| Evaluate change in specific autism symptom severity | Ohio State University Clinical Impressions Scale: a clinical rating of severity and improvement of 10 autism domains: social interaction, aberrant/abnormal behavior, repetitive/ritualistic behavior, verbal communication, non-verbal communication, hyperactivity/inattention, anxiety/fears, sensory sensitivities, restricted/narrow interests, autism. Severity will be measured at baseline. Each item is rated from 1 (Normal) to 7 (Among the most severe) with a raw score range of 10-70. The raw score will be reported. Higher scores indicate more severe impairment. At the following time points, improvement will be measured. Each item is rated from 1 (Very much improved) to 7 (Very much worse) with a raw score range of 10-70. The raw score will be reported. Higher scores indicate more severe impairment. | Baseline, Week 6, Week 12, Week 24 | 
| Evaluate the change in overall cognitive ability | Mullen Scales of Early Learning: a scale of cognitive abilities across core domains: visual reception, fine motor, expressive language, receptive language. Change in cognition will be measured by change in the standard Composite Scaled Score. A higher composite score indicates higher overall cognitive ability. | Baseline, Week 12, Week 24 | 
| Evaluate the change in adaptive functioning | Vineland Adaptive Behavior Scale-II Domain Level: a scale to assess adaptive behavior in children with developmental/intellectual disabilities. This is a 135-item parent-reported measure with ratings in the following domains: communication, daily living skills, and socialization. The frequency of each item is scaled from 0 (Never) to 2 (Usually). For each domain, there are 45 items with a maximum score of 90. Change in each domain will be measured by the change in standard score. Standard scores are calculated from the raw scores and based on age norms. A higher standard score in any domain indicates a higher level of adaptive behavior in that domain. Domain standard scores will be used to get a standard composite score. Change in adaptive behavior will be measured by the change in the standard score. A higher composite score indicates higher overall adaptive behavior ability. | Baseline, Week 12, Week 24 | 
| Evaluate the overall change in core ASD symptoms of social communication | Brief Observation of Social Communication Change: a 16-item scale that rates social interactions between children with ASD and their interactive rater. Each item is rated on a scale of 0-5, wherein 0 indicates the least severe behavior and 5 indicates the most severe behavior. A higher score is indicative of more severe social communication deficits. | Screening, Week 6, Week 12, Week 24 | 
| Evaluate the overall change in core ASD symptoms of social communication using a blind observer | The Social Responsiveness Scale Preschool is a quantitative scale that measures severity and type of social impairments that characterize ASD. It is a standard measure in ASD clinical trials. We will use the preschool version to match the age range of our study. T-scores are calculated with a higher T-score indicating worse symptoms | Screening, Week 6, Week 12, Week 24 |