Folinic Acid as a Treatment for Autism Spectrum Disorder in Children

ConditionAutism Spectrum Disorder

Trial statusRecruiting

Trial phasePhase 2

Trial typeInterventional

Biological sexAll

Age3-10

SponsorKK Women's and Children's Hospital

About this 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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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)

Trial design

Design model

Parallel

Treatments tested in this trial

Folinic Acid
Drug
Oral folinic acid administered during the double-blind randomised controlled trial (RCT) phase, followed by open-label folinic acid treatment.
Placebo
Drug
Matching oral placebo administered during the double-blind randomised controlled trial (RCT) phase.

Treatment groups

184 Participants

are divided into 2 treatment groups

Group A: Folinic AcidExperimental treatment 1 intervention

Group B: PlaceboPlacebo comparator 1 intervention

Trial outcomes

Primary outcomes

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

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

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

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

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

Other outcomes

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

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

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

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