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

Primary Purpose

Autism Spectrum Disorder, Language Disorders

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Levoleucovorin Calcium

Placebo

About this trial

This is an interventional treatment trial for Autism Spectrum Disorder

Eligibility Criteria

30 Months - 60 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

1. 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

Exclusion Criteria:

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
Evaluation with the MSEL or BOSCC within 3 months of entering the study
Planned evaluation with the MSEL or BOSCC during the study
Exclusion Criteria for the MEG recording include:
1. Ferromagnetic implants, artificial joints, fixation hardware, dental work or shrapnel (additional screening will be completed to determine MRI eligibility)
2. Ferromagnetic products attached to the body (including hair extensions)
3. Head circumference greater than 60 cm
4. A weight greater than 407 lbs. (185 kg)

Sites / Locations

Southwestern Research & Resource Center
State University of New York, DownstateRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

L-leucovorin calcium

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Evaluate the safety and tolerability of L-leucovorin calcium in young children with ASD

Modified Dosage Record and Treatment Emergent Symptoms: treating clinician will perform a review of medical and behavioral history at each visit to assess incidence of treatment-emergent adverse events. The treating clinician will use the scale to record presence and intensity of adverse effects. Intensity is rated on a scale of 0 (Not present) to 3 (Severe). The treating clinician will also judge the adverse effects' relatedness to treatment. Relatedness is rated on a scale of 1 (None) to 4 (Defined). The treating clinician will denote action taken. Action taken is rated on a scale of 0 (None) to 5 (Discontinue Treatment). No total score is calculated. However, higher ratings on any individual item indicate greater severity of adverse effects.

Evaluate adverse effect symptoms in young children with ASD

Routine complete blood counts will be collected to determine whether treatment-emergent basic blood chemistry is altered. Presence of any changes during the course of study enrollment will be evaluated by the treating physician and determined clinically significant or not clinically significant. If determined by the treating physician, a change will be considered an adverse event.

Evaluate the biologic safety of L-leucovorin calcium in young children with ASD

Routine comprehensive blood panels will be collected to determine whether treatment-emergent basic blood chemistry is altered. Presence of any changes during the course of study enrollment will be evaluated by the treating physician and determined clinically significant or not clinically significant. If determined by the treating physician, a change will be considered an adverse event.

Evaluate the safety of L-leucovorin calcium in young children with ASD on antiepileptic drugs

For children using antiepileptic drugs, the level of that drug will be measured. If determined by the treating physician, a change will be considered an adverse event.

Examine the change in measures of Expressive and Receptive Language

Mullen Scales of Early Learning: a scale of cognitive abilities across core domains: visual reception, fine motor, expressive language, receptive language. Expressive language domain: 28-item scale with a raw score range of 0-50, t score range of 20-80. Receptive language domain: 33-item scale with a raw score range of 0-48, t score range of 20-80. Change in domain ability will be measured by the change in domain raw and t score. T scores are calculated from raw scores and based on age norms. A higher domain t score indicates a higher level of ability in that domain.

Evaluate the change in effects of autism symptoms on family members

Parent Target Problems: a parent-nominated list of 2 most problematic core autism symptoms. Responses are documented in a brief narrative and detail frequency, constancy, intensity, and impact of behavior on the family. Subjective reports of frequency, constancy, intensity, and impact on family will be rated by a blinded statistician at the conclusion of the study. Higher scores indicate more severe impact on family.

Evaluate the change in stereotypical autism symptoms

Aberrant Behavior Checklist-2: a 58-item parent-reported measure of stereotypical autism behaviors 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.

Evaluate change in overall autism severity

Clinical Global Impression Scale: The Clinical Global Impression Scale-Severity is a 7-point measure of overall symptom severity, ranging from 1 (Normal) to 7 (Extreme), with a raw score range of 1-7. The raw score will be reported. The Clinical Global Impression Scale-Improvement is a measure in change of symptom severity, ranging from 1 (Very Much Improved) to 7 (Very Much Worse). A Score of 4 indicates no change in symptom severity.

Evaluate change in specific autism symptom severity

Ohio State University Clinical Impressions Scale: a clinical rating of severity and improvement of 10 autism domains: social interaction, aberrant/abnormal behavior, repetitive/ritualistic behavior, verbal communication, non-verbal communication, hyperactivity/inattention, anxiety/fears, sensory sensitivities, restricted/narrow interests, autism. Severity will be measured at baseline. Each item is rated from 1 (Normal) to 7 (Among the most severe) with a raw score range of 10-70. The raw score will be reported. Higher scores indicate more severe impairment. At the following time points, improvement will be measured. Each item is rated from 1 (Very much improved) to 7 (Very much worse) with a raw score range of 10-70. The raw score will be reported. Higher scores indicate more severe impairment.

Evaluate the change in overall cognitive ability

Mullen Scales of Early Learning: a scale of cognitive abilities across core domains: visual reception, fine motor, expressive language, receptive language. Change in cognition will be measured by change in the standard Composite Scaled Score. A higher composite score indicates higher overall cognitive ability.

Evaluate the change in adaptive functioning

Vineland Adaptive Behavior Scale-II Domain Level: a scale to assess adaptive behavior in children with developmental/intellectual disabilities. This is a 135-item parent-reported measure with ratings in the following domains: communication, daily living skills, and socialization. The frequency of each item is scaled from 0 (Never) to 2 (Usually). For each domain, there are 45 items with a maximum score of 90. Change in each domain will be measured by the change in standard score. Standard scores are calculated from the raw scores and based on age norms. A higher standard score in any domain indicates a higher level of adaptive behavior in that domain. Domain standard scores will be used to get a standard composite score. Change in adaptive behavior will be measured by the change in the standard score. A higher composite score indicates higher overall adaptive behavior ability.

Evaluate the overall change in core ASD symptoms of social communication

Brief Observation of Social Communication Change: a 16-item scale that rates social interactions between children with ASD and their interactive rater. Each item is rated on a scale of 0-5, wherein 0 indicates the least severe behavior and 5 indicates the most severe behavior. A higher score is indicative of more severe social communication deficits.

Evaluate the overall change in core ASD symptoms of social communication using a blind observer

The Social Responsiveness Scale Preschool is a quantitative scale that measures severity and type of social impairments that characterize ASD. It is a standard measure in ASD clinical trials. We will use the preschool version to match the age range of our study. T-scores are calculated with a higher T-score indicating worse symptoms

Full Information

NCT ID

NCT04060030

First Posted

August 13, 2019

Last Updated

October 23, 2023

Sponsor

Southwest Autism Research & Resource Center

Collaborators

Autism Speaks, State University of New York - Downstate Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT04060030

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

October 8, 2020 (Actual)

Primary Completion Date

January 2025 (Anticipated)

Study Completion Date

January 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Southwest Autism Research & Resource Center

Collaborators

Autism Speaks, State University of New York - Downstate Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

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 social and communication impairments in very young children with ASD. Participants entered into the trial will have delayed language and moderate ASD symptoms. The investigators hypothesize that leucovorin calcium will significantly improve social communication as well as core and associated behavioral symptoms of ASD, and be well-tolerated with no significant adverse effects, in young children with ASD. 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 social and communication 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 and social communication abilities will be measured at screening and after each treatment arm in order to determine if the supplement positively influences social communication. Additionally, the investigators will measure changes in neural pathways using either magnetoencephalography at Phoenix Children's Hospital or functional Near Infrared Spectroscopy at State University of New York, Downstate. While these measures will be considered exploratory, they will be important to begin to elucidate the neuronal mechanisms underlying leucovorin's impact.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Autism Spectrum Disorder, Language Disorders

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

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

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Quadruple masking during blinded phase, followed by unblinding during open label phase

Allocation

Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

L-leucovorin calcium

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Levoleucovorin Calcium

Other Intervention Name(s)

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

Intervention Description

Liquid leucovorin calcium dosed by weight

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Placebo

Primary Outcome Measure Information:

Title

Evaluate the change in social communication symptoms

Description

Time Frame

Baseline, Week 6, Week 12, Week 24

Secondary Outcome Measure Information:

Title

Evaluate the safety and tolerability of L-leucovorin calcium in young children with ASD

Description

Time Frame

Screening, Baseline, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24

Title

Evaluate adverse effect symptoms in young children with ASD

Description

Time Frame

Screening, Week 12, Week 24

Title

Evaluate the biologic safety of L-leucovorin calcium in young children with ASD

Description

Time Frame

Screening, Week 12, Week 24

Title

Evaluate the safety of L-leucovorin calcium in young children with ASD on antiepileptic drugs

Description

For children using antiepileptic drugs, the level of that drug will be measured. If determined by the treating physician, a change will be considered an adverse event.

Time Frame

Screening, Week 12, Week 24

Title

Examine the change in measures of Expressive and Receptive Language

Description

Time Frame

Baseline, Week 12, Week 24

Title

Evaluate the change in effects of autism symptoms on family members

Description

Time Frame

Baseline, Week 6, Week 12, Week 24

Title

Evaluate the change in stereotypical autism symptoms

Description

Time Frame

Baseline, Week 6, Week 12, Week 24

Title

Evaluate change in overall autism severity

Description

Time Frame

Baseline, Week 6, Week 12, Week 24

Title

Evaluate change in specific autism symptom severity

Description

Time Frame

Baseline, Week 6, Week 12, Week 24

Title

Evaluate the change in overall cognitive ability

Description

Time Frame

Baseline, Week 12, Week 24

Title

Evaluate the change in adaptive functioning

Description

Time Frame

Baseline, Week 12, Week 24

Title

Evaluate the overall change in core ASD symptoms of social communication

Description

Time Frame

Screening, Week 6, Week 12, Week 24

Title

Evaluate the overall change in core ASD symptoms of social communication using a blind observer

Description

Time Frame

Screening, Week 6, Week 12, Week 24

Other Pre-specified Outcome Measures:

Title

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

Description

Using magnetoencephalography at Phoenix Children's Hospital and functional near-infrared spectroscopy and the State University of New York, the investigators will assess whether the following pathways are altered by leucovorin calcium treatment: M100 auditory evoked gamma-band power, connectivity, and coherence. Both the magnetoencephalography and functional near-infrared spectroscopy will be able to capture these same values. Treatment-emergent change in these values will indicate that a change has occurred in the neural pathway.

Time Frame

Baseline, Week 12, Week 24

Title

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

Description

Evaluate changes in the following cellular regulatory pathways known to be implicated in social communication: peripheral blood mononuclear cell, plasma, DNA, red blood cells, and oxidative stress rates. Treatment-emergent change in these biomarkers will indicate that a change has occurred at the cellular level.

Time Frame

Screening, Week 12, Week 24

Title

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

Description

Saliva will be collected to determine presence of the following single nucleotide polymorphisms: MTR, MTHFR6, DHFR, GCH1, MTHFR12, RFC, FOLH, COMT. Presence or absence of these genetic polymorphisms will be analyzed to assess correlation with response to L-leucovorin treatment.

Time Frame

Screening, Week 12

10. Eligibility

Sex

All

Minimum Age & Unit of Time

30 Months

Maximum Age & Unit of Time

60 Months

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 1. 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 Exclusion Criteria: 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 Evaluation with the MSEL or BOSCC within 3 months of entering the study Planned evaluation with the MSEL or BOSCC during the study Exclusion Criteria for the MEG recording include: Ferromagnetic implants, artificial joints, fixation hardware, dental work or shrapnel (additional screening will be completed to determine MRI eligibility) Ferromagnetic products attached to the body (including hair extensions) Head circumference greater than 60 cm A weight greater than 407 lbs. (185 kg)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Richard E Frye, MD, PhD

Phone

(321) 259-7111

DrFrye@RossignolMedicalCenter.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Richard E Frye, MD, PhD

Organizational Affiliation

Rossignol Medical Center, Phoenix AZ

Official's Role

Principal Investigator

Facility Information:

Facility Name

Southwestern Research & Resource Center

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

85016

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Christopher Smith, PhD

Phone

602-218-8192

First Name & Middle Initial & Last Name & Degree

Sophia Crisler

Phone

(480) 582-9467

Facility Name

State University of New York, Downstate

City

Brooklyn

State/Province

New York

ZIP/Postal Code

11203

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Harris Huberman, MD

Phone

718-270-2272

harris.huberman2@downstate.edu

First Name & Middle Initial & Last Name & Degree

Daniel Mishan

Phone

(718) 270-2272

autism.research@downstate.edu

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

The investigators plan to publish the results of the study in an academic journal. Results may also be shared at conferences and presentations.

Citations:

PubMed Identifier

32892962

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.

Results Reference

background

PubMed Identifier

28770615

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.

Results Reference

background

PubMed Identifier

27752075

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.

Results Reference

background

PubMed Identifier

27013943

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.

Results Reference

background

PubMed Identifier

22230883

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.

Results Reference

background

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

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