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| Name | Class |
|---|---|
| State University of New York - Downstate Medical Center | OTHER |
| United States Department of Defense | FED |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Levoleucovorin Calcium | Drug | Liquid leucovorin calcium dosed by weight |
|
| Measure | Description | Time Frame |
|---|---|---|
| Evaluate the change in measures of expressive language | Mullen Scales of Early Learning: a scale of cognitive abilities across the following domains: gross motor (not a core subscale), visual reception, fine motor, expressive language, and receptive language. Total change in expressive language ability will be measured by the change in the expressive language raw score. The expressive language domain is a 28-item scale with a raw score range of 0-50. Changes in expressive language raw scores will be reported. A higher raw score indicates a higher level of language ability. | Screening, Week 12, Week 24 |
| Measure | Description | Time Frame |
|---|---|---|
| Evaluate the change in measures of receptive language | Mullen Scales of Early Learning: a scale of cognitive abilities across the following domains: gross motor (not a core subscale), visual reception, fine motor, expressive language, and receptive language. Total change in receptive language ability will be measured by the change in the receptive language raw and t score. The receptive language domain is a 33-item scale with a raw score range of 0-48 and a t score range of 20-80. T scores are calculated from the raw score and based on age norms. Changes in receptive language raw and t scores will be reported. A higher raw and t score indicates a higher level of language ability. In addition, we will analyze change in expressive language t-score. |
| Measure | Description | Time Frame |
|---|---|---|
| Test if biomarkers (FRAAs) predict clinical response to L-leucovorin | FRAA titers (described above) will be measured and analyzed as a predictive variable in treatment outcomes. | Screening |
| Test if biomarkers (single nucleotide polymorphisms) predict clinical response to L-leucovorin |
Inclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Richard E Frye, MD, PhD | Rossignol Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Southwestern Autism Research & Resource Center | Phoenix | Arizona | 85016 | United States | ||
| State University of New York, Downstate |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22230883 | 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. | |
| 32892962 | Background | 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. |
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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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Prospective randomized 12-week double-blind placebo-controlled study followed by 12-week open label
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Quadruple masking during blinded phase, followed by unblinding during open label phase
| Placebo | Other | Placebo |
|
| Screening, Week 12, Week 24 |
| 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. | Screening, Baseline, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24 |
| Evaluate the 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. | 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. | Screening, Week 12, Week 24 |
| Evaluate the overall change in core autism 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. Because this evaluation is not valid with PPE it will not be performed during evaluation when PPE is required | Screening, 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. | Screening, Week 6, Week 12, Week 24 |
| Evaluate the change in social withdrawal 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. | Screening, Week 6, Week 12, Week 24 |
| Evaluate the change in effects of autism symptoms most problematic to 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. | Screening, 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. | Baseline, Week 6, Week 12, Week 24 |
| Evaluate change in autism severity of specific symptoms | 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. | 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. 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. Visual reception domain: 33-item scale with a raw score range of 0-50, t score range of 20-80. Fine motor domain: 33-item scale with a raw score range of 0-50, t score range of 20-80. Change in domain ability will be measured by the change in domain 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. Domain t scores will be used to get a standard composite score. Change in cognition will be measured by change in the Early Learning Composite standardized Scaled score. A higher composite score indicates higher overall cognitive ability. | Baseline, Week 12, Week 24 |
| Evaluate the change in adaptive functioning | Vineland Adaptive Behavior Scale-II Domain LevelI: 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. | Baseline, Week 12, Week 24 |
| Evaluate the change in social withdrawal autism symptoms | Social Responsiveness Scale Preschool Version. The Social Responsiveness Scale 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. | Baseline, Week 6, Week 12, Week 24 |
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. |
| Screening, Week 12 |
| 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. | A combination of FRAA titers and single nucleotide polymorphisms will be analyzed along with outcome data to predict response to L-leucovorin. Presence or absence of one or both of these biomarkers will be analyzed to assess how these biomarkers correlate with treatment outcome (i.e. whether the treatment was effective). | Up to 1 year after study completion |
| Brooklyn |
| New York |
| 11203 |
| United States |
| 28770615 | 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. |
| 27752075 | 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. |
| 27013943 | 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. |
| ID | Term |
|---|---|
| D000067877 | Autism Spectrum Disorder |
| D007806 | Language Disorders |
| ID | Term |
|---|---|
| D002659 | Child Development Disorders, Pervasive |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
| D003147 | Communication Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D002955 | Leucovorin |
| ID | Term |
|---|---|
| D005575 | Formyltetrahydrofolates |
| D013763 | Tetrahydrofolates |
| D005492 | Folic Acid |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D003067 | Coenzymes |
| D045762 | Enzymes and Coenzymes |
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