A Placebo-controlled Trial of Folinic Acid in Children With ASD

Sponsor
Prof. Adi Aran
Study ID
NCT07642661
Phase
PHASE2
Status
Recruiting
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Conditions

Eligibility Criteria

Sex
ALL
Age
3 Years - 6 Years
Healthy Volunteers
Not accepted

Interventions

  • Folinic Acid — DRUG
    Calcium folinate hydrate oral solution administered at a target dose of 2 mg/kg/day (maximum 50 mg/day) in two divided doses.
  • Placebo — DRUG
    Matching oral placebo solution containing inactive aqueous excipients and matched in appearance, taste, and smell to the folinic acid formulation

Study Details

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication and the presence of restricted or repetitive behaviors. Although behavioral and educational interventions can be helpful, there is currently no established medication for the core symptoms of ASD. Medications approved for associated irritability may be effective in some children but are often associated with significant adverse effects. Folinic acid (also known as leucovorin) is a reduced form of folate that plays an important role in brain development, neurotransmitter production, DNA methylation, and cellular metabolism. Previous clinical studies have suggested that folinic acid may improve communication, social functioning, and behavioral symptoms in some children with ASD. However, existing studies have generally been small and have used different outcome measures, and the current evidence is insufficient to establish the efficacy and optimal dosing of folinic acid in ASD. This multicenter, randomized, double-blind, placebo-controlled clinical trial is designed to evaluate the safety, tolerability, and efficacy of folinic acid in children with ASD. A total of 150 children aged 3 to 6 years with ASD and clinically significant behavioral symptoms will be enrolled at multiple sites in Israel. Participants will be randomly assigned in a 1:1 ratio to receive either folinic acid or matching placebo for 9 weeks in addition to their existing treatments. The primary objective of the study is to determine whether folinic acid improves behavioral symptoms compared with placebo, as measured by the Aberrant Behavior Checklist Irritability Subscale (ABC-I). Secondary objectives include evaluating the effects of folinic acid on communication, socialization, adaptive functioning, autism symptoms, emotional regulation, disruptive behavior, sleep, gastrointestinal symptoms, caregiver quality of life, and overall clinical improvement. Following completion of the initial 9-week placebo-controlled phase, participants will enter a second 8-week double-blind treatment phase in which they will be randomly assigned to receive one of two folinic acid dose regimens. This phase is intended to explore whether different maintenance doses are associated with differences in clinical outcomes. The study will also investigate potential biological markers associated with treatment response. Blood and stool samples will be collected to assess folate-related biomarkers, folate receptor alpha autoantibodies, oxidative stress markers, transcriptomic profiles, proteomic signatures, and gut microbiota composition. The study will also examine whether these biological measures are associated with symptom severity or response to treatment. The results of this study are expected to provide important information regarding the efficacy, safety, and optimal use of folinic acid in children with ASD and may help identify biological factors associated with treatment response.

Key Dates

First listed
Jun 11, 2026
Start date
Jun 23, 2026
Status verified
Jun 2026
Primary completion
Dec 31, 2027
Completion
Dec 31, 2027

Study Design

Enrollment
150 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Active Comparator: Folinic Acid
    Participants receive oral folinic acid (calcium folinate hydrate) oral solution as an add-on to their existing treatments. During the initial 9-week double-blind phase, participants receive folinic acid at a target dose of 2 mg/kg/day (maximum 50 mg/day) administered in two divided doses following a brief dose-titration period. After completion of the first phase, participants are independently randomized to receive folinic acid at either 1 mg/kg/day or 2 mg/kg/day for an additional 8 weeks while remaining blinded to dose assignment.
  • Placebo Comparator: Placebo
    Participants receive a matching placebo oral solution as an add-on to their existing treatments during the initial 9-week double-blind phase. After completion of the placebo-controlled phase, participants are independently randomized to receive folinic acid at either 1 mg/kg/day or 2 mg/kg/day for an additional 8 weeks while remaining blinded to dose assignment.

Primary Outcome Measure

Change From Baseline to Week 9 in Aberrant Behavior Checklist-Irritability Subscale (ABC-I) Score. Scores range from 0 to 45, with higher scores indicating greater irritability and behavioral problems [ Time Frame: Baseline to Week 9 ]

Central Contacts

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