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

NCT ID: NCT04060017

Last Updated: 2025-05-21

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-22
• Study Completion Date: 2026-06-30

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.

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 language impairments in very young children with ASD. Participants entered into the trial will have delayed social and communication abilities known to be associated with ASD. The investigators hypothesize that leucovorin calcium will significantly improve language as well as core and associated behavioral symptoms of ASD, and be well-tolerated with no significant adverse effects, in young children with ASD. The investigators further hypothesize that a combination of baseline cellular and genetic biomarkers will predict cognitive and behavioral response to the intervention.

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 language 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, as well as specimen biomarkers, will be measured at screening and after each treatment arm in order to determine if the supplement positively influences language ability.

Conditions

Autism Spectrum Disorder; Language Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Levoleucovorin Calcium

Intervention Type: DRUG

Liquid leucovorin calcium dosed by weight

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo

Interventions

Levoleucovorin Calcium

Liquid leucovorin calcium dosed by weight

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: OTHER

Other Intervention Names

L-leucovorin; L-leucovorin calcium; L-folinic acid, calcium salt; L-folinate, calcium salt

Eligibility Criteria

Inclusion Criteria

1. Autism Spectrum Disorder (as defined below).

2. Between 2 years 6 months and 5 years 2 months of age at baseline

3. Language impairment (Ages and Stage Questionnaire between -1 and -3 SD for Language)

4. 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.

5. English included in the languages in which the child is being raised

6. 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.

6. 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

Exclusion Criteria

1. Known FRAA status by clinically validated test performed outside of research studies.

2. Mineral or vitamin supplementation that exceeds the Tolerable Upper Daily Intake Levels set by the Institute of Medicine (See Table 5 below)

3. Significant self-abusive or violent behavior or evidence of suicidal ideation, plan or behavior

4. Severely affected as defined by CGI-Severity Standard Score = 7 (Extremely Ill)

5. Severe prematurity (<34 weeks gestation) as determined by medical history

6. Current uncontrolled gastroesophageal reflux

7. Current or history of liver or kidney disease as determined by medical history and safety labs

8. Genetic syndromes

9. Congenital brain malformations

10. Epilepsy

11. Any medical condition that the PI determines could jeopardize the safety of the study subject or compromise the integrity of the data

12. Significant negative reaction (i.e. fainting, vomiting, etc.) because of a previous blood draw.

13. 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.

14. 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).

15. Allergy or Sensitivity to ingredients in the investigational product or placebo

16. Evaluation with the MSEL or BOSCC within 3 months of entering the study

17. Planned evaluation with the MSEL or BOSCC during the study

• Minimum Eligible Age: 30 Months
• Maximum Eligible Age: 60 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

State University of New York - Downstate Medical Center

OTHER

Sponsor Role: collaborator

United States Department of Defense

FED

Sponsor Role: collaborator

Southwest Autism Research & Resource Center

OTHER

Sponsor Role: lead

Responsible Party

Richard Frye

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard E Frye, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Rossignol Medical Center

Locations

Southwestern Autism Research & Resource Center

Phoenix, Arizona, United States

Site Status: NOT_YET_RECRUITING

State University of New York, Downstate

Brooklyn, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Richard E Frye, MD, PhD

Role: CONTACT

DrFrye@RossignolMedicalCenter.com

(321) 259-7111

Facility Contacts

Christopher J Smith, PhD

Role: primary

(602) 933-2680

Sophia Crisler

Role: backup

(480) 582-9467

Harris Huberman, MD

Role: primary

harris.huberman@downstate.edu

(718) 270-2272

Daniel Mishan

Role: backup

autism.research@downstate.edu

(718) 270-2272

References

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.

Reference Type: BACKGROUND

PMID: 22230883 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32892962 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28770615 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27752075 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27013943 (View on PubMed)

Other Identifiers

DOD Leucovorin

Identifier Type: -

Identifier Source: org_study_id