Clinical trial NCT04060017: Early Treatment of Language Impairment in Young Children With Autism Spectrum Disorder With Leucovorin Calcium
Official title: Early Treatment of Language Impairment in Young Children With Autism Spectrum Disorder With Leucovorin Calcium
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Autism Spectrum Disorder
Language Disorders
Lead sponsor: Southwest Autism Research & Resource Center
Sponsor class: OTHER
Collaborators: name: State University of New York - Downstate Medical Center
name: United States Department of Defense
First posted: 2019-08-16
Enrollment: 80
Sex: ALL
Minimum age (years): 30
Maximum age (years): 60
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective randomized 12-week double-blind placebo-controlled study followed by 12-week open label
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Evaluate the change in measures of expressive language
timeFrame: Screening, Week 12, Week 24
Secondary outcomes:
measure: Evaluate the change in measures of receptive language
timeFrame: Screening, Week 12, Week 24
measure: Evaluate the safety and tolerability of L-leucovorin calcium in young children with ASD
timeFrame: Screening, Baseline, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24
measure: Evaluate the safety of L-leucovorin calcium in young children with ASD
timeFrame: Screening, Week 12, Week 24
measure: Evaluate the safety of L-leucovorin calcium in young children with ASD on antiepileptic drugs
timeFrame: Screening, Week 12, Week 24
measure: Evaluate the overall change in core autism symptoms of social communication
timeFrame: Screening, Week 12, Week 24
measure: Evaluate the change in stereotypical autism symptoms
timeFrame: Screening, Week 6, Week 12, Week 24
measure: Evaluate the change in social withdrawal autism symptoms
timeFrame: Screening, Week 6, Week 12, Week 24
measure: Evaluate the change in effects of autism symptoms most problematic to family members
timeFrame: Screening, Week 6, Week 12, Week 24
measure: Evaluate change in overall autism severity
timeFrame: Baseline, Week 6, Week 12, Week 24
measure: Evaluate change in autism severity of specific symptoms
timeFrame: Baseline, Week 6, Week 12, Week 24
measure: Evaluate the change in overall cognitive ability
timeFrame: Baseline, Week 12, Week 24
measure: Evaluate the change in adaptive functioning
timeFrame: Baseline, Week 12, Week 24
measure: Evaluate the change in social withdrawal autism symptoms
timeFrame: Baseline, Week 6, Week 12, Week 24
Other outcomes:
measure: Test if biomarkers (FRAAs) predict clinical response to L-leucovorin
timeFrame: Screening
measure: Test if biomarkers (single nucleotide polymorphisms) predict clinical response to L-leucovorin
timeFrame: Screening, Week 12
measure: 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.
timeFrame: Up to 1 year after study completion
Locations:
city: Phoenix
country: United States
facility: Southwestern Autism Research & Resource Center
state: Arizona
city: Brooklyn
country: United States
facility: State University of New York, Downstate
state: New York
Study officials:
affiliation: Rossignol Medical Center
name: Richard E Frye, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.