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

NCT07642661 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: 0038-26-SZMC
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Autism Spectrum Disorder

Keywords

ASD; Autism; Folinic Acid; Leucovorin; Calcium Folinate; placebo; Folate Receptor Alpha Autoantibodies

Outcome Measures

Primary Outcomes (1)

• Change From Baseline to Week 9 in Aberrant Behavior Checklist-Irritability Subscale (ABC-I) Score

  The ABC-I is a caregiver-completed measure of irritability and behavioral symptoms in children with autism spectrum disorder. The ABC-I consists of 15 items assessing behaviors such as aggression, self-injury, temper tantrums, depressed mood, and rapidly changing mood. Individual items are scored from 0 (not a problem) to 3 (severe problem), with higher scores indicating greater symptom severity. The outcome measure is the change in total ABC-I score from baseline to Week 9. Negative values indicate improvement.

  Baseline to Week 9

Secondary Outcomes (4)

• Change From Baseline to Week 9 in Vineland Adaptive Behavior Scales, Third Edition (VABS-3) Communication Domain Standard Score

  Baseline to Week 9

• Change From Baseline to Week 9 in VABS-3 Socialization Domain Standard Score

  Baseline to Week 9

• Change From Baseline to Week 9 in Clinical Global Impression-Improvement (CGI-I)

  Week 9

• Change From Baseline to Week 9 in MacArthur-Bates Communicative Development Inventories (MB-CDI)

  Baseline to Week 9

Other Outcomes (13)

• Change From Baseline to Week 9 in Caregiver Global Impression of Change (CGIC)

  Week 9

• Change From Baseline to Week 9 in Social Responsiveness Scale, Second Edition (SRS-2) Total Score

  Baseline to Week 9

• Change From Baseline to Week 9 in Aberrant Behavior Checklist-Community (ABC-C) Subscale Scores

  Baseline to Week 9

Study Arms (2)

Folinic Acid

ACTIVE COMPARATOR

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.

Drug: Folinic Acid

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

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.

Also known as: Leucovorin, Calcium Folinate, Leucovorin Calcium

Folinic Acid

Placebo DRUG

Matching oral placebo solution containing inactive aqueous excipients and matched in appearance, taste, and smell to the folinic acid formulation

Placebo

Eligibility Criteria

• Age: 3 Years - 6 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Children aged 3 to 6 years.
• Diagnosis of autism spectrum disorder (ASD) according to DSM-5 criteria.
• ASD diagnosis confirmed by Autism Diagnostic Observation Schedule, Second Edition (ADOS-2).
• ASD diagnosis made at least 6 months before screening.
• Non-syndromic ASD, defined as ASD occurring in the absence of a known genetic syndrome, chromosomal abnormality, major congenital anomaly, or identifiable metabolic or neurological disorder.
• CGI-S score ≥ 4.
• ABC-I score ≥ 12.
• SRS-2 total T-score ≥ 66.
• Body weight between 11.45 kg and \<27 kg.

You may not qualify if:

• A seizure or a change in antiepileptic medication within 8 weeks prior to randomization.
• Clinically significant abnormalities on physical examination or laboratory testing, including significant impairment of cardiac, hepatic, or renal function.
• Treatment with folinic acid within 3 months prior to randomization.
• Any change in pharmacological treatment, behavioral treatment, home environment, or school setting (other than school holidays) within 4 weeks prior to randomization, or planned changes during study participation.
• Predicted inability or unwillingness to comply with study procedures.
• Use of antifolate medications or other agents known to interfere with folate metabolism (e.g., methotrexate, trimethoprim).

Sponsors & Collaborators

• Prof. Adi Aran: lead

Study Sites (1)

Shaare Zedek Medical Center

Jerusalem, N/A = Not Applicable, 9103102, Israel

Location

Related Links

• The study protocol, Statistical Analysis Plan (SAP), and informed consent form are available through the Open Science Framework (OSF). The link provides view-only access to these study documents

MeSH Terms

Conditions

Autism Spectrum Disorder; Autistic Disorder

Interventions

Leucovorin

Condition Hierarchy (Ancestors)

Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes

Central Study Contacts

Adi Aran, MD

CONTACT

+97226555414; aaran@szmc.org.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants, parents/caregivers, investigators, study coordinators, treating physicians, outcome assessors, and study personnel involved in study conduct and data collection will remain blinded to treatment assignment. Folinic acid and placebo will be supplied in identical bottles and packaging and will be matched in appearance, taste, and smell. Randomization lists and treatment codes will be generated and maintained by an independent unblinded biostatistician and will not be accessible to blinded study personnel until study completion and database lock. During the second treatment phase, participants and study personnel will also remain blinded to the assigned folinic acid dose.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director neuropediatric unit

Study Record Dates

• First Submitted: June 7, 2026
• First Posted: June 11, 2026
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: June 11, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: The study protocol, Statistical Analysis Plan (SAP), and Informed Consent Form (ICF) will be made publicly available prior to study initiation. De-identified individual participant data (IPD) underlying the published results will become available 12 months after publication of the primary study results and will remain available for 5 years thereafter

Locations

IL (1)