Autism Spectrum DisorderPhase 2NCT04060030
Treatment of Social and Language Deficits With Leucovorin for Young Children With Autism
A Phase 2 study testing Levoleucovorin Calcium in people with Autism Spectrum Disorder and Language Disorders, run by Southwest Autism Research & Resource Center at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 30 to 60 months
- Conditions the study is for
- Autism Spectrum Disorder, Language Disorders
- What is being tested?
- Levoleucovorin Calcium
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 2 sitesUnited States
- Study dates
- 8 Oct 2020to 31 Jul 2026
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 to 60 months
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
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- 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
Who cannot join
- 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
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- 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)
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
State University of New York, Downstate
Brooklyn, New York, 11203
Harris Huberman, MD, (718) 270-2272, harris.huberman2@downstate.edu
Daniel Mishan, (718) 270-2272, autism.research@downstate.edu
- Not yet recruiting
Southwestern Research & Resource Center
Phoenix, Arizona, 85016
Christopher Smith, PhD, (602) 218-8192
Sophia Crisler, (480) 582-9467
About this study
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.
Read the 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.
- Conditions
- Autism Spectrum Disorder, Language Disorders
- Being tested
- Levoleucovorin Calcium, Placebo
- Medical subject headings
- Autism Spectrum Disorder, Language Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Levoleucovorin CalciumDrug
Also called L-leucovorin, L-leucovorin calcium, L-folinic acid, calcium salt, L-folinate, calcium salt
Liquid leucovorin calcium dosed by weight
PlaceboOther
Placebo
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline, Week 6, Week 12, Week 24
Secondary outcomes (13)
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.
Measured: 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
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.
Measured: Screening, Week 12, Week 24
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.
Measured: Screening, Week 12, Week 24
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.
Measured: Screening, Week 12, Week 24
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.
Measured: Baseline, Week 12, Week 24
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.
Measured: Baseline, Week 6, Week 12, Week 24
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.
Measured: Baseline, Week 6, Week 12, Week 24
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.
Measured: Baseline, Week 6, Week 12, Week 24
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.
Measured: Baseline, Week 6, Week 12, Week 24
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.
Measured: Baseline, Week 12, Week 24
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.
Measured: Baseline, Week 12, Week 24
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.
Measured: Screening, Week 6, Week 12, Week 24
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
Measured: Screening, Week 6, Week 12, Week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Aug 2019
- Study start8 Oct 2020
- Primary completion31 Jul 2026 (estimated)
- Study completion31 Jul 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Autism Spectrum DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Prospective randomized 12-week double-blind placebo-controlled study followed by 12-week open label
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Southwest Autism Research & Resource Center
- Sponsor type
- University, hospital or other
- Collaborators
- Autism Speaks, State University of New York - Downstate Medical Center
- Responsible party
- Principal investigator, Richard Frye, Southwest Autism Research & Resource Center
- Investigators
- Richard E Frye, MD, PhD, Principal investigator, Rossignol Medical Center, Phoenix AZ
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04060030
- Sponsor's protocol ID
- AS Leucovorin
- Status last verified
- Apr 2026
- First submitted
- 13 Aug 2019
- Last updated
- 27 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: The investigators plan to publish the results of the study in an academic journal. Results may also be shared at conferences and presentations.
Publications
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.
PubMed 32892962Frye 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.
PubMed 28770615Frye 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.
PubMed 27752075Frye 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.
PubMed 27013943Frye 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.
PubMed 22230883
Study at a glance
From the registry record, last updated by the sponsor on 27 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Social and Language Deficits With Leucovorin for Young Children With Autism
- ClinicalTrials.gov ID
- NCT04060030
- Acronym / sponsor ID
- AS Leucovorin
- Conditions
- Autism Spectrum Disorder, Language Disorders
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Southwest Autism Research & Resource CenterUniversity, hospital or other
- Collaborators
- Autism Speaks, State University of New York - Downstate Medical Center
- Study start
- 8 Oct 2020 (actual)
- Primary completion
- 31 Jul 2026 (estimated)
- Study completion
- 31 Jul 2026 (estimated)
- First posted
- 16 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Prospective randomized 12-week double-blind placebo-controlled study followed by 12-week open label
| Arm | Type | Receives |
|---|---|---|
| L-leucovorin calcium | Experimental | Drug: Levoleucovorin CalciumThe 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. |
| Placebo | Placebo comparator | Other: PlaceboThe 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. |
Who may qualify
- Ages
- 30 to 60 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (10 listed)
- 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
Key exclusion criteria (22 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Levoleucovorin CalciumAlso: L-leucovorin, L-leucovorin calcium, L-folinic acid, calcium salt, L-folinate, calcium saltLiquid leucovorin calcium dosed by weight | Drug | L-leucovorin calcium |
| PlaceboPlacebo | Other | Placebo |
Primary outcome
Evaluate the change in social communication symptoms
Time frame: Baseline, Week 6, Week 12, Week 24
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.
13 secondary outcomes
Evaluate the safety and tolerability of L-leucovorin calcium in young children with ASD
Time frame: 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
Time frame: Screening, Week 12, Week 24
Evaluate the biologic safety of L-leucovorin calcium in young children with ASD
Time frame: Screening, Week 12, Week 24
Evaluate the safety of L-leucovorin calcium in young children with ASD on antiepileptic drugs
Time frame: Screening, Week 12, Week 24
Examine the change in measures of Expressive and Receptive Language
Time frame: Baseline, Week 12, Week 24
Evaluate the change in effects of autism symptoms on family members
Time frame: Baseline, Week 6, Week 12, Week 24
Evaluate the change in stereotypical autism symptoms
Time frame: Baseline, Week 6, Week 12, Week 24
Evaluate change in overall autism severity
Time frame: Baseline, Week 6, Week 12, Week 24
Evaluate change in specific autism symptom severity
Time frame: Baseline, Week 6, Week 12, Week 24
Evaluate the change in overall cognitive ability
Time frame: Baseline, Week 12, Week 24
Evaluate the change in adaptive functioning
Time frame: Baseline, Week 12, Week 24
Evaluate the overall change in core ASD symptoms of social communication
Time frame: Screening, Week 6, Week 12, Week 24
Evaluate the overall change in core ASD symptoms of social communication using a blind observer
Time frame: Screening, Week 6, Week 12, Week 24
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Apr 2026.
- Background: PubMed 32892962Frye 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.
- Background: PubMed 28770615Frye 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.
- Background: PubMed 27752075Frye 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.
- Background: PubMed 27013943Frye 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.
- Background: PubMed 22230883Frye 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.
- Individual participant dataSharing planned: No. The investigators plan to publish the results of the study in an academic journal. Results may also be shared at conferences and presentations.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Richard E Frye, MD, PhD principal investigator
Rossignol Medical Center, Phoenix AZ
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Levoleucovorin Calcium in people with Autism Spectrum Disorder and Language Disorders, run by Southwest Autism Research & Resource Center at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Richard E Frye, MD, PhD ((321) 259-7111, DrFrye@RossignolMedicalCenter.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Evaluate the change in social communication symptoms (time frame: Baseline, Week 6, Week 12, Week 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04060030, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Apr 2026.