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

NCT04060030 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: AS 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 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.

Conditions

Autism Spectrum Disorder; Language Disorders

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• 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

Other Outcomes (3)

• Demonstrate changes in neuronal activation and connectivity associated with treatment response using non-invasive neuroimaging methods

  Baseline, Week 12, Week 24

• Evaluate the effect of L-leucovorin on cellular regulatory pathways known to be implicated in social communication

  Screening, Week 12, Week 24

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

  Screening, Week 12

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 (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

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 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

Sponsors & Collaborators

• Southwest Autism Research & Resource Center: lead
• Autism Speaks: collaborator
• State University of New York - Downstate Medical Center: collaborator

Study Sites (2)

Southwestern Research & Resource Center

Phoenix, Arizona, 85016, United States

NOT YET RECRUITING

State University of New York, Downstate

Brooklyn, New York, 11203, United States

RECRUITING

Related Publications (5)

• 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

• 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

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, Phoenix AZ

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Richard E Frye, MD, PhD

CONTACT

(321) 259-7111; DrFrye@RossignolMedicalCenter.com

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: October 8, 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)