Early Treatment of Language Impairment in Young Children With Autism Spectrum Disorder With Leucovorin Calcium

NCT04060017 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: DOD Leucovorin
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 2

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 language 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 language delays or impairments. Participation will last approximately 26 weeks from screening to end of treatment.

Conditions

Autism Spectrum Disorder; Language Disorders

Outcome Measures

Primary Outcomes (1)

• Evaluate the change in measures of expressive language

  Mullen Scales of Early Learning: a scale of cognitive abilities across the following domains: gross motor (not a core subscale), visual reception, fine motor, expressive language, and receptive language. Total change in expressive language ability will be measured by the change in the expressive language raw score. The expressive language domain is a 28-item scale with a raw score range of 0-50. Changes in expressive language raw scores will be reported. A higher raw score indicates a higher level of language ability.

  Screening, Week 12, Week 24

Secondary Outcomes (13)

• Evaluate the change in measures of receptive language

  Screening, 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 the 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

• Evaluate the overall change in core autism symptoms of social communication

  Screening, Week 12, Week 24

Other Outcomes (3)

• Test if biomarkers (FRAAs) predict clinical response to L-leucovorin

  Screening

• Test if biomarkers (single nucleotide polymorphisms) predict clinical response to L-leucovorin

  Screening, Week 12

• Combine presence of FRAA titers and single nucleotide polymorphisms (above) into a predicting equation that will evaluate the probability of positive response to L-leucovorin treatment.

  Up to 1 year after study completion

Study Arms (2)

L-leucovorin calcium

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Levoleucovorin Calcium DRUG

Liquid leucovorin calcium dosed by weight

Also known as: L-leucovorin, L-leucovorin calcium, L-folinic acid, calcium salt, L-folinate, calcium salt

L-leucovorin calcium

Placebo OTHER

Placebo

Placebo

Eligibility Criteria

• Age: 30 Months - 60 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Autism Spectrum Disorder (as defined below).
• Between 2 years 6 months and 5 years 2 months of age at baseline
• Language impairment (Ages and Stage Questionnaire between -1 and -3 SD for Language)
• 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.
• 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 7. Unchanged complementary, dietary, traditional, and behavioral treatments for two months prior to study entry

You may not qualify if:

• 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 5 below)
• Significant self-abusive or violent behavior or evidence of suicidal ideation, plan or behavior
• Severely affected 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.) because 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 screening.
• 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 6 below).
• Allergy or Sensitivity to ingredients in the investigational product or placebo

Sponsors & Collaborators

• Southwest Autism Research & Resource Center: lead
• State University of New York - Downstate Medical Center: collaborator
• United States Department of Defense: collaborator

Study Sites (2)

Southwestern Autism Research & Resource Center

Phoenix, Arizona, 85016, United States

Location

State University of New York, Downstate

Brooklyn, New York, 11203, United States

Location

Related Publications (5)

• Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013 Mar;18(3):369-81. doi: 10.1038/mp.2011.175. Epub 2012 Jan 10.

  PMID: 22230883 BACKGROUND

• Frye RE, Rossignol DA, Scahill L, McDougle CJ, Huberman H, Quadros EV. Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder. Semin Pediatr Neurol. 2020 Oct;35:100835. doi: 10.1016/j.spen.2020.100835. Epub 2020 Jun 25.

  PMID: 32892962 BACKGROUND

• Frye RE, Slattery JC, Quadros EV. Folate metabolism abnormalities in autism: potential biomarkers. Biomark Med. 2017 Aug;11(8):687-699. doi: 10.2217/bmm-2017-0109. Epub 2017 Aug 3.

  PMID: 28770615 BACKGROUND

• Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018 Feb;23(2):247-256. doi: 10.1038/mp.2016.168. Epub 2016 Oct 18.

  PMID: 27752075 BACKGROUND

• Frye RE, Delhey L, Slattery J, Tippett M, Wynne R, Rose S, Kahler SG, Bennuri SC, Melnyk S, Sequeira JM, Quadros E. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Front Neurosci. 2016 Mar 9;10:80. doi: 10.3389/fnins.2016.00080. eCollection 2016.

  PMID: 27013943 BACKGROUND

MeSH Terms

Conditions

Autism Spectrum Disorder; Language Disorders

Interventions

Leucovorin

Condition Hierarchy (Ancestors)

Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes

Study Officials

• Richard E Frye, MD, PhD

  Rossignol Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Quadruple masking during blinded phase, followed by unblinding during open label phase
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Prospective randomized 12-week double-blind placebo-controlled study followed by 12-week open label

Study Record Dates

• First Submitted: August 13, 2019
• First Posted: August 16, 2019
• Study Start: September 22, 2020
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2026
• Last Updated: April 27, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)