Folinic Acid as a Treatment for Autism Spectrum Disorder in Children

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• Autism Spectrum Disorder 1,727

Keywords

• Autism Spectrum Disorder
• ASD
• Folinic Acid
• Leucovorin
• Children
• Pediatric
• Randomized Controlled Trial
• Placebo-Controlled
• Open-Label Extension

Autism Spectrum Disorder

1,727 studies on the registry are indexed under Autism Spectrum Disorder; 504 are open to participants now.

This study's planned enrollment of 184 is above the median of 52 across 1,371 interventional studies indexed under Autism Spectrum Disorder.

Lead sponsor

KK Women's and Children's Hospital is the lead sponsor of 136 studies on the registry; 33 are open to participants now.

Study arms

• 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

• 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

Interventions

• DrugFolinic Acid

  Oral folinic acid administered during the double-blind randomised controlled trial (RCT) phase, followed by open-label folinic acid treatment.

• DrugPlacebo

  Matching oral placebo administered during the double-blind randomised controlled trial (RCT) phase.

Primary outcomes

1. 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.

   Time frame: Baseline to Week 12

Secondary outcomes

1. 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.

   Time frame: Baseline to Week 12

2. 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.

   Time frame: Baseline to Week 12

3. 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.

   Time frame: Baseline to Week 12

4. 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.

   Time frame: Baseline to Week 12

5. 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.

   Time frame: Baseline to Week 12

6. 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.

   Time frame: Baseline to Week 12

7. 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.

   Time frame: Baseline to Week 12

8. 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.

   Time frame: Baseline to Week 12

9. 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.

   Time frame: Baseline to Week 24

Other outcomes

1. 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).

   Time frame: Baseline to Week 12

2. 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.

   Time frame: Baseline to Week 12

3. 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).

   Time frame: Baseline to Week 12

4. 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.

   Time frame: Baseline to Week 12

5. 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).

   Time frame: Baseline to Week 12

6. Sustained Effects of Folinic Acid on Autism Symptoms

   Change from baseline in autism outcome measures following 24 weeks of folinic acid treatment.

   Time frame: Baseline to Week 24

Individual participant data

Plan to share: Undecided — 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.