Folinic Acid as a Treatment for Autism Spectrum Disorder in Children (FOLIN-A)

Folinic Acid as a Treatment for Autism Spectrum Disorder in Children: A Double-blind Randomised Placebo-controlled Trial With Open Label Extension (FOLIN-A Trial)

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects communication, behavior, and social interaction in children. Current treatments are limited and mainly focus on managing symptoms. This study aims to evaluate whether folinic acid is safe and effective in improving symptoms of autism spectrum disorder in children. Participants will be randomly assigned to receive either folinic acid or a placebo during the double-blind treatment phase. After this phase, all participants will have the option to receive folinic acid in an open-label extension. The results of this study may help determine whether folinic acid could be a potential treatment option for children with autism spectrum disorder.

Study Overview

• Status: Recruiting
• Conditions: Autism Spectrum Disorder
• Intervention / Treatment: Drug: Folinic Acid; Drug: Placebo

Detailed Description

This study is a double-blind, randomised, placebo-controlled clinical trial designed to evaluate the safety and effectiveness of folinic acid in children with autism spectrum disorder (ASD). Eligible participants will be randomly assigned to receive either 2 mg/kg/day of folinic acid or a matching placebo during a 12-week double-blind randomised controlled trial (RCT) treatment phase. Neither the participants, caregivers, nor study staff will know which treatment is assigned during this period. The primary aim is to assess whether folinic acid improves symptoms of autism spectrum disorder. Following completion of the double-blind phase, participants will enter a 12-week open-label extension, during which all participants will receive 2 mg/kg/day of folinic acid. This extension phase will allow for further evaluation of longer-term safety and potential benefits. The findings from this study may contribute to a better understanding of the role of folinic acid as a potential treatment option for children with autism spectrum disorder.

• Study Type: Interventional
• Enrollment (Estimated): 184
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Study Coordinator; Phone Number: 6563947201; Email: folin-a@kkh.com.sg

Study Locations

• Singapore
  • Singapore
    • Singapore, Singapore, Singapore
      • Recruiting
      • KK Women's and Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Children aged 3 years 0 months to 10 years 11 months at the time of enrolment
• Weight ≥ 10 kg and ≤ 30 kg at the time of enrolment
• Confirmed diagnosis of Autism Spectrum Disorder (ASD) based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) or Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, supported by standardized diagnostic assessments
• Stable on regular behavioral interventions and any medications for at least 6 months prior to enrolment
• At least one parent or legal guardian able to understand and complete study questionnaires in English
• Written informed consent obtained from a parent or legal guardian

Exclusion Criteria:

• Known allergy or intolerance to folinic acid
• Current or prior supplementation with folinic acid or other folate preparations (folic acid supplementation permitted)
• Vitamin B12 (cobalamin) deficiency or pernicious anemia
• Concurrent use of medications known to interfere with folate metabolism (e.g., methotrexate, trimethoprim, fluorouracil, capecitabine, glucarpidase)
• Known genetic, metabolic, or chromosomal disorder, or structural brain abnormalities
• History of epilepsy or seizures (except simple febrile seizures) or current use of antiepileptic or antipsychotic medication
• Significant sensory (hearing or visual) or motor impairment
• Participation in another interventional clinical trial for autism within the past 6 months
• Unable or unwilling to comply with study visits and procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Folinic Acid; Participants in this arm will receive folinic acid during the double-blind randomised controlled trial (RCT) phase of the study. After completion of the double-blind phase, participants will continue into an open-label extension in which folinic acid is provided.	Drug: Folinic Acid; Oral folinic acid administered during the double-blind randomised controlled trial (RCT) phase, followed by open-label folinic acid treatment.
Placebo Comparator: Placebo; Participants in this arm will receive a matching placebo during the double-blind randomised controlled trial (RCT) phase of the study. After completion of the double-blind phase, participants will continue into an open-label extension in which folinic acid is provided.	Drug: Placebo; Matching oral placebo administered during the double-blind randomised controlled trial (RCT) phase.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pervasive Developmental Disorder-Behavior Inventory (PDDBI) Autism Composite T-Score	The Pervasive Developmental Disorder-Behavior Inventory (PDDBI) is a validated caregiver-completed instrument used to assess adaptive and maladaptive behaviors in individuals with autism spectrum disorder (ASD). The Autism Composite T-score is a standardized score (mean = 50, standard deviation = 10) that summarizes overall autism symptom severity, with higher scores indicating greater symptom severity. This outcome measure evaluates the change from baseline to Week 12 in PDDBI Autism Composite T-score. Lower T-scores indicate improvement in autism-related symptoms. Changes in scores will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in language function as measured by the Clinical Evaluation of Language Fundamentals (CELF)	Change from baseline to Week 12 in standardized language function scores as assessed using the Clinical Evaluation of Language Fundamentals (CELF), a standardized individually administered assessment of receptive and expressive language skills in children. CELF standardized scores have a mean of 100 and a standard deviation of 15, with higher scores indicating better language performance. Changes in scores will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12
Change from baseline in receptive vocabulary score as measured by the Receptive One-Word Picture Vocabulary Test (ROWPVT)	Change from baseline to Week 12 in standardized receptive vocabulary scores as assessed using the Receptive One-Word Picture Vocabulary Test (ROWPVT), a standardized individually administered assessment of a child's ability to understand spoken words. Scores are standardized with a mean of 100 and a standard deviation of 15, where higher scores indicate better receptive vocabulary ability. Changes in scores will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12
Change from baseline in expressive vocabulary score as measured by the Expressive One-Word Picture Vocabulary Test (EOWPVT)	Change from baseline to Week 12 in standardized expressive vocabulary scores as assessed using the Expressive One-Word Picture Vocabulary Test (EOWPVT), a standardized individually administered assessment of a child's ability to produce spoken words. Scores are standardized with a mean of 100 and a standard deviation of 15, where higher scores indicate better expressive vocabulary ability. Changes in scores will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12
Change from baseline in Clinical Global Impression-Severity and Improvement scores as measured by the Clinical Global Impression Scale (CGI-S and CGI-I)	Change from baseline to Week 12 in Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scores, assessed using the Clinical Global Impression Scale, a standardized assessor-rated measure of illness severity and overall clinical improvement. CGI-S scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill), where lower scores indicate better outcomes, and CGI-I scores range from 1 (very much improved) to 7 (very much worse), where lower scores indicate greater improvement. Changes in scores will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12
Change from baseline in Aberrant Behavior Checklist total score as measured by the Aberrant Behavior Checklist (ABC)	Change from baseline to Week 12 in total scores on the Aberrant Behavior Checklist (ABC), a standardized caregiver-completed questionnaire that assesses behavioural symptoms in children across domains such as irritability, lethargy, stereotypy, hyperactivity, and inappropriate speech. Total scores range from 0 to 174, with higher scores indicating greater severity of behavioural problems (worse outcomes). Changes in scores will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12
Change from baseline in total problem score as measured by the Child Behavior Checklist (CBCL)	Change from baseline to Week 12 in total problem scores on the Child Behavior Checklist (CBCL), a standardized caregiver-reported questionnaire that assesses a broad range of emotional and behavioural problems in children. Total scores are standardised T-scores (typically ranging from approximately 30 to 100, with a mean of 50 and standard deviation of 10), where higher scores indicate greater behavioural and emotional problems (worse outcomes). Changes in scores will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12
Change from baseline in adaptive behavior composite score as measured by the Vineland Adaptive Behavior Scales (VABS)	Change from baseline to Week 12 in standardised adaptive behavior scores as assessed using the Vineland Adaptive Behavior Scales (VABS), a standardized caregiver-reported assessment of a child's adaptive functioning across domains such as communication, daily living skills, socialization, and motor skills. Adaptive behavior composite scores are standardised (typically ranging from approximately 20 to 160, with a mean of 100 and standard deviation of 15), where higher scores indicate better adaptive functioning (better outcomes). Changes in scores will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12
Change from baseline in proportion of gaze duration to social stimuli as measured by eye-tracking assessment	Change from baseline to Week 12 in eye-tracking measures of visual attention, specifically the proportion of total gaze duration directed toward social stimuli (e.g., faces or biological motion) compared with non-social stimuli, assessed using a standardized eye-tracking paradigm. Higher proportions indicate greater relative attention to social stimuli. Changes in proportions will be compared between participants receiving folinic acid and those receiving placebo.	Baseline to Week 12
Incidence of adverse events and serious adverse events as measures of safety and tolerability of folinic acid	Change from baseline to Week 24 in the incidence of adverse events (AEs) and serious adverse events (SAEs), monitored throughout the study period to assess the safety and tolerability of folinic acid treatment.	Baseline to Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in plasma glutathione redox ratio (GSH:GSSG)	Change from baseline to Week 12 in plasma glutathione redox ratio (reduced glutathione:oxidized glutathione; GSH:GSSG), a biomarker of oxidative stress balance. Higher ratios indicate a more reduced (favorable) redox state. Plasma reduced glutathione (GSH, µM) and oxidized glutathione (GSSG, µM) will be measured at baseline (T1) and Week 12 (T2).	Baseline to Week 12
Change from baseline in plasma methylation ratio (S-adenosylmethionine:S-adenosylhomocysteine; SAM:SAH)	Change from baseline to Week 12 in plasma methylation ratio (S-adenosylmethionine:S-adenosylhomocysteine; SAM:SAH), a biomarker of methylation capacity. Higher ratios indicate greater methylation potential (better outcomes). Additional biomarkers related to one-carbon metabolism, including plasma homocysteine (µmol/L), will measured where available.	Baseline to Week 12
Change in Plasma Ergothioneine Levels	Change from baseline to Week 12 in plasma ergothioneine concentration (ET, nM). Plasma ergothioneine (ET, nM), hercynine (nM), and ophthalmic acid will be measured at baseline (T1) and Week 12 (T2).	Baseline to Week 12
Change in Folate Status Biomarkers	Change from baseline in serum and plasma folate status biomarkers. Folate status biomarkers include measures related to one-carbon metabolism and amino acid pathways. Plasma amino acid concentrations (µmol/L) will be interpreted with reference to established age-specific clinical ranges.	Baseline to Week 12
Association of FRAA Status With Treatment Response	Association between folate receptor autoantibody (FRAA) status and change in autism outcome measures. FRAA status will be classified as positive or negative based on the assay-specific cutoff defined by the testing laboratory: Blocking FRAA (pmol blocked per mL) and binding FRAA (optical density [OD] units per µL).	Baseline to Week 12
Sustained Effects of Folinic Acid on Autism Symptoms	Change from baseline in autism outcome measures following 24 weeks of folinic acid treatment.	Baseline to Week 24

Collaborators and Investigators

• Sponsor: KK Women's and Children's Hospital
• Collaborators: Nanyang Technological University; Singapore Health Services; National University of Singapore

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: May 8, 2026
• First Submitted That Met QC Criteria: June 1, 2026
• First Posted (Actual): June 5, 2026

Study Record Updates

• Last Update Posted (Actual): June 5, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Children; Pediatric; ASD; Randomized Controlled Trial; Autism Spectrum Disorder; Leucovorin; Placebo-Controlled; Folinic Acid; Open-Label Extension
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Enzymes and Coenzymes; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Coenzymes; Leucovorin
• Other Study ID Numbers: FOLIN-A-01; MOH-CIRG24jan-0004 (Other Grant/Funding Number: National Medical Research Council (NMRC), Singapore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: At this time, there is no confirmed plan to share individual participant data (IPD) collected in this study. The study team will consider requests for access to de-identified individual participant data, including the analyzable dataset and relevant supporting documentation, on a case-by-case basis following completion of the study. Any data sharing will be subject to applicable institutional review board (IRB) requirements, data protection regulations, and data sharing agreements to ensure participant confidentiality and appropriate use.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No