Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder

NCT02839915 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: FAS-NIHR01HD088528
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 4

Brief Summary

The purpose of this study is to determine the effectiveness of folinic acid in the treatment of language problems in children with autism spectrum disorder. Folinic acid, also known as leucovorin, is approved by the U.S. Food and Drug Administration (FDA) to decrease side effects during cancer chemotherapy. Folinic acid may be helpful in treating language problems in children with autism spectrum disorder, but this is not known. Therefore, folinic acid is an investigational new drug for this study. Investigators will enroll a total of 134 participants across all three centers, over a 5 year period and participation will last between 12 and 24 weeks.

Conditions

Autism Spectrum Disorder

Keywords

Language Impairment

Outcome Measures

Primary Outcomes (2)

• Change in Clinical Evaluation of Language Fundamentals 4 (CELF-4) Score.

  The Scale title is the "Clinical Evaluation of Language Fundamentals 4" which is abbreviated as CELF-4 as indicated in the title above. Higher Scores indicate better performance. The Minimum Scaled Score is 40 and the Maximum Scaled Score is 160. The CELF-4 will be administered for participants between \> 6.6 and \< 12.5 years of age. The CELF-4 is comprised of 4 subtests intended to identify language problems and can be used to track progress over time. Administration of the CELF takes 30-45 minutes. The Core-CELF score is a composite that includes receptive and expressive language. Using the tables in the manual, raw scores from the four subtests are compared to normative data by age. The population mean = 100 + 15.

  Screening, Week 12

• Change in Clinical Evaluation of Language Fundamentals Preschool (CELF-P) score

  The Scale title is the "Clinical Evaluation of Language Fundamentals Preschool" which is abbreviated as CELF-P as indicated in the title above. Higher Scores indicate better performance. The Minimum Scaled Score is 40 and the Maximum Scaled Score is 160. The CELF-P will be administered for participants between \> 5.0 and \< 6.5 years of age to obtain an estimate of expressive and receptive language skills (based on population mean of 100 +15). Administration of the Core CELF-P takes 20-30 minutes. To make the CELF-P match the CELF-4, one additional subtest on CELF-P called the Concepts and Following Directions was added (this subtest is included in the Core of the CELF-4, but not included in the Core CELF-P).

  Screening, Week 12

Secondary Outcomes (1)

• Change in Clinician Global Impression for Improvement (CGI-I) Score

  Up to 12 Weeks

Other Outcomes (6)

• Change in the age appropriate version of the CELF compared to the pre-treatment level in the open-label extension phase

  Pre-treatment, and 24weeks (or early termination)

• Change in folate gene expression

  Pre-treatment, 12 weeks(optional), and 24weeks (or early termination)

• Change in in methylation

  Pre-treatment, 12 weeks (optional), and 24weeks (or early termination)

Study Arms (2)

Folinic Acid

EXPERIMENTAL

Subjects randomized to receive Folinic Acid will take Liquid levo-leucovorin via oral route. The target dose is 1 mg/kg/day with a maximum of 25 mg/day, divided in two daily doses. A two- to four-week supply of 15 ml vials will be dispensed in line with the visit schedule. With the exception of children in the lowest weight group (≥ 15 - \< 20 kg) from days 1-14, parents will administer the prescribed dose twice a day at the same time each day.

Drug: Folinic Acid

Placebo Control

PLACEBO COMPARATOR

Subjects randomized to receive placebo will take placebo twice a day (Exception: children in the lowest weight group ( ≥ 15 - \< 20 kg) will start once a day for Days1-13). The pattern of dose escalation will be the same as the active compound. After 12 weeks, the blind will not be broken and subjects will be offered treatment for a 12-week open-label extension phase.

Other: Placebo

Interventions

Folinic Acid DRUG

Liquid levo-leucovorin via oral route. L-leucovorin is the active isomer.

Also known as: Liquid levo-leucovorin

Folinic Acid

Placebo OTHER

Inactive placebo comparator

Placebo Control

Eligibility Criteria

• Age: 5 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Boys and girls ≥ 5 years and \< 17 years 5 months of age;
• Weight ≥ 15 kg;
• DSM-5 diagnosis of Autism Spectrum Disorder as established by clinical assessment, corroborated by the Social Communication Questionnaire and the Autism Diagnostic Observational Schedule.
• A score \< 80 on the Core Language score of the Clinical Evaluation of Language Fundamentals -4 (CELF)- 4 or the Second Edition of the CELF-Preschool test (CELF-P).
• Current Clinical Global Impression Severity score ≥ 4 on ASD + communication delay.
• IQ at least 40 as measured by the Leiter-3 or mental age at least 18 months as measured on the Receptive Language Scale of the Mullen.
• Stable educational plan (one month) with no planned changes in the intensity of treatment for 12 weeks. (Otherwise eligible subjects with anticipated changes in their school program in the near term will be invited to return when the transition has been accomplished.
• Stable speech therapy program in the community (one month) with no planned changes for 12 weeks.
• English is spoken in the home and at least one parent is able to read, write and speak English.
• Stable medication (no changes in past 6 weeks and no planned changes for the next 6 months (duration of the study).

You may not qualify if:

• IQ below 40 as measured by the Leiter-3 or below a mental age of 18 months on the Receptive Language Scale of Mullen. (N.B. subjects who test below 18 months of age, but are otherwise eligible, may be enrolled following a case review by the Steering Committee - e.g., child's uncooperative behavior resulted in a likely underestimate of intellectual ability);
• Is within the scorable range of the CELF-4 or CELF-P as detailed in the Language Algorithm;
• Current DSM-IV diagnosis requiring alternative pharmacotherapy, e.g., Major Depression, Bipolar Disorder, a psychotic disorder (based on clinical assessment assisted by the Child and Adolescent Symptom Inventory);
• Presence of serious behavioral problems (tantrums, aggression, self-injury) for which another treatment is warranted.
• Significant medical condition by history or by physical examination or lab tests that would be incompatible with the study drug.
• Children taking anticonvulsant medication for seizures.
• Children taking Bactrim (trimethoprim + sulfamethoxazole) because Bactrim can interfere with folate metabolism. Children who discontinue use of Bactrim for 2 months may be re-evaluated for the study. Caregivers will be advised not to use any of these medications during the trial.
• Children taking valproic acid or derivatives or lamotrigine for any purpose will be excluded because these drugs can interfere with folate metabolism. Caregivers will be advised not to use any of these medications during the trial.
• Children on mineral or vitamin supplements that exceed the Recommended Daily Allowance set by the IOM.

Sponsors & Collaborators

• Southwest Autism Research & Resource Center: lead
• Emory University: collaborator
• Harvard University: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• State University of New York - Downstate Medical Center: collaborator

Study Sites (4)

Southwestern Research and Resource Center

Phoenix, Arizona, 85016, United States

Location

Children's Healtcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Harvard University

Lexington, Massachusetts, 02421, United States

Location

State University of New York, Downstate

Brooklyn, New York, 11203, United States

Location

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator and Sponsor

Study Record Dates

• First Submitted: July 19, 2016
• First Posted: July 21, 2016
• Study Start: August 13, 2020
• Primary Completion: April 15, 2024
• Study Completion: December 1, 2025
• Last Updated: May 21, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Time Frame: Biyearly NDAR is updated
• Access Criteria: Registered for NDAR Access

Locations

US (4)