A Placebo-controlled Trial of Folinic Acid in Children With ASD
ConditionAutism Spectrum Disorder
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age3-6
SponsorProf. Adi Aran
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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.
Trial design
Design model
Parallel
Treatments tested in this trial
Folinic Acid
DrugCalcium folinate hydrate oral solution administered at a target dose of 2 mg/kg/day (maximum 50 mg/day) in two divided doses.
Placebo
DrugMatching oral placebo solution containing inactive aqueous excipients and matched in appearance, taste, and smell to the folinic acid formulation
Treatment groups
150 Participants
are divided into 2 treatment groupsGroup A: Folinic AcidActive comparator 1 intervention
Group B: PlaceboPlacebo comparator 1 intervention
Trial outcomes
Primary outcomes
1
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
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).
Time frame
Baseline to Week 9Secondary outcomes
1
Change From Baseline to Week 9 in Vineland Adaptive Behavior Scales, Third Edition (VABS-3) Communication Domain Standard Score
The VABS-3 Communication Domain assesses receptive, expressive, and written communication skills through a structured caregiver interview. Standard scores have a mean of 100 and a standard deviation of 15, with higher scores indicating better adaptive functioning.
Time frame
Baseline to Week 92
Change From Baseline to Week 9 in VABS-3 Socialization Domain Standard Score
The VABS-3 Socialization Domain assesses interpersonal relationships, play and leisure skills, and coping skills through a structured caregiver interview. Standard scores have a mean of 100 and a standard deviation of 15, with higher scores indicating better adaptive functioning.
Time frame
Baseline to Week 93
Change From Baseline to Week 9 in Clinical Global Impression-Improvement (CGI-I)
Clinician-rated global improvement since baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse)
Time frame
Week 94
Change From Baseline to Week 9 in MacArthur-Bates Communicative Development Inventories (MB-CDI)
Parent-reported measure of expressive vocabulary and communication skills. Higher scores indicate better communication abilities
Time frame
Baseline to Week 9Other outcomes
1
Change From Baseline to Week 9 in Caregiver Global Impression of Change (CGIC)
Caregiver-rated global improvement since baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse)
Time frame
Week 92
Change in Social Responsiveness Scale, Second Edition (SRS-2) Total Score from baseline to Week 9. The total score ranges from 0 to 195, with higher scores indicating greater autism-related social impairment
Caregiver-reported measure of autism-related social impairment.
Time frame
Baseline to Week 93
Change From Baseline to Week 9 in Aberrant Behavior Checklist-Community (ABC-C) - Total Score. The total score ranges from 0 to 174, with higher scores indicating greater behavioral impairment
The ABC-C is a 58-item caregiver-rated measure of behavioral symptoms. Items are grouped into five subscales: Irritability, Lethargy/Social Withdrawal, Stereotypic Behavior, Hyperactivity/Noncompliance, and Inappropriate Speech.
Time frame
Baseline to Week 94
Change From Baseline to Week 9 in Vineland Adaptive Behavior Scales, Third Edition (VABS-3) Maladaptive Behavior Domain Score. Scores range from 0 to 72, Higher scores indicate greater maladaptive behavior
Caregiver interview assessing maladaptive behaviors.
Time frame
Baseline to Week 9Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Prof. Adi Aran
Lead sponsor
Shaare Zedek Medical Center
Sponsor institution
Source ClinicalTrials.gov