A Phase 2 interventional study of Levoleucovorin Calcium and Placebo in Autism Spectrum Disorder and Language Disorders, sponsored by Southwest Autism Research & Resource Center. Recruiting at 2 sites in United States. Open to participants aged 30 Months to 60 Months. Per ClinicalTrials.gov, last updated 2026-04-27.
Sponsored by Southwest Autism Research & Resource Center · Phase 2, Interventional, and Treatment
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.
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.
1,724 studies on the registry are indexed under Autism Spectrum Disorder; 500 are open to participants now.
This study's planned enrollment of 80 is above the median of 52 across 1,368 interventional studies indexed under Autism Spectrum Disorder.
Browse Autism Spectrum Disorder studies →Southwest Autism Research & Resource Center is the lead sponsor of 8 studies on the registry; 3 are open to participants now.
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Inclusion Criteria:
Exclusion Criteria:
Exclusion Criteria for the MEG recording include:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
Liquid leucovorin calcium dosed by weight
Also known as: L-leucovorin, L-leucovorin calcium, L-folinic acid, calcium salt, L-folinate, calcium salt
Placebo
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.
Time frame: Baseline, Week 6, Week 12, Week 24
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: Screening, Week 6, Week 12, Week 24
Demonstrate changes in neuronal activation and connectivity associated with treatment response using non-invasive neuroimaging methods
Using magnetoencephalography at Phoenix Children's Hospital and functional near-infrared spectroscopy and the State University of New York, the investigators will assess whether the following pathways are altered by leucovorin calcium treatment: M100 auditory evoked gamma-band power, connectivity, and coherence. Both the magnetoencephalography and functional near-infrared spectroscopy will be able to capture these same values. Treatment-emergent change in these values will indicate that a change has occurred in the neural pathway.
Time frame: Baseline, Week 12, Week 24
Evaluate the effect of L-leucovorin on cellular regulatory pathways known to be implicated in social communication
Evaluate changes in the following cellular regulatory pathways known to be implicated in social communication: peripheral blood mononuclear cell, plasma, DNA, red blood cells, and oxidative stress rates. Treatment-emergent change in these biomarkers will indicate that a change has occurred at the cellular level.
Time frame: Screening, Week 12, Week 24
Test if biomarkers (single nucleotide polymorphisms) predict clinical response to L-leucovorin
Saliva will be collected to determine presence of the following single nucleotide polymorphisms: MTR, MTHFR6, DHFR, GCH1, MTHFR12, RFC, FOLH, COMT. Presence or absence of these genetic polymorphisms will be analyzed to assess correlation with response to L-leucovorin treatment.
Time frame: Screening, Week 12
Plan to share: No — The investigators plan to publish the results of the study in an academic journal. Results may also be shared at conferences and presentations.
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Studies of the drug tested here: Levoleucovorin calcium
Southwest Autism Research & Resource Center