A Placebo-controlled Trial of Folinic Acid in Children With ASD (AFAT)
A Placebo-Controlled, Randomized, Double-Blind Study to Assess the Safety, Tolerability and Efficacy of Folinic Acid Administered to Pediatric Subjects With Autism Spectrum Disorder (ASD)
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.
調査の概要
詳細な説明
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by persistent deficits in social communication and social interaction, together with restricted, repetitive patterns of behavior, interests, or activities. In addition to these core features, many children with ASD experience associated behavioral difficulties including irritability, emotional dysregulation, hyperactivity, sleep disturbances, and gastrointestinal symptoms. ASD affects approximately 1-3% of children worldwide and is associated with substantial long-term impact on affected individuals, families, educational systems, and healthcare resources.
At present, there is no established pharmacological treatment for the core symptoms of ASD. While behavioral and educational interventions remain the foundation of treatment, access, intensity, and effectiveness vary considerably among individuals. Pharmacological treatments currently approved for ASD-related irritability may reduce disruptive behaviors in some children but are often associated with adverse effects including weight gain, metabolic abnormalities, sedation, and extrapyramidal symptoms. Consequently, there remains a significant unmet need for safe and effective interventions that address both core and associated symptoms of ASD.
Folate plays a central role in neurodevelopment and brain function. Folate-dependent pathways are involved in DNA synthesis and repair, epigenetic regulation through methylation, neurotransmitter synthesis, mitochondrial function, and cellular redox balance. Disturbances in folate transport and metabolism have been implicated in a subset of individuals with ASD.
One mechanism that has received increasing attention is dysfunction of folate transport into the central nervous system. The folate receptor alpha (FRα) is responsible for transporting 5-methyltetrahydrofolate into the brain. Autoantibodies directed against this receptor may interfere with folate transport and contribute to cerebral folate deficiency. Multiple studies have reported an increased prevalence of folate receptor alpha autoantibodies in children with ASD compared with the general population. In addition, genetic variants affecting folate metabolism and transport pathways may influence neurodevelopment and treatment response.
Folinic acid (leucovorin calcium) is a reduced form of folate that bypasses several metabolic steps required for folic acid utilization and can utilize transport mechanisms that are less dependent on folate receptor alpha function. Folinic acid has been used safely for many years in pediatric and adult medicine for a variety of indications and has a well-characterized safety profile.
Over the past decade, several randomized placebo-controlled studies have suggested that high-dose folinic acid may improve language abilities, social communication, adaptive functioning, and behavioral symptoms in some children with ASD. These findings have generated considerable interest among clinicians and families and have led to increasing off-label use of folinic acid in clinical practice. However, the currently available evidence remains limited. Previous studies were generally small, used different outcome measures, enrolled relatively heterogeneous populations, and were not designed to determine the optimal duration or dose of treatment. Furthermore, uncertainty remains regarding which biological characteristics may predict treatment response.
As a result, major clinical guidelines do not currently recommend routine treatment with folinic acid for children with ASD, and there is a need for adequately powered confirmatory trials using standardized outcome measures and rigorous methodology.
The current study was designed to address these knowledge gaps. The trial will evaluate whether folinic acid is superior to placebo in improving behavioral symptoms and adaptive functioning in young children with ASD. The study will use a randomized, double-blind, placebo-controlled design to minimize bias and provide high-quality evidence regarding efficacy, safety, and tolerability.
In addition to evaluating clinical outcomes, the study incorporates an extensive translational research program intended to improve understanding of the biological mechanisms associated with treatment response. Biological samples will be collected to assess folate-related biomarkers, folate receptor alpha autoantibodies, markers of oxidative stress, transcriptomic signatures, proteomic profiles, and gut microbiota composition. These analyses may help identify biological subgroups that are more likely to benefit from treatment and may contribute to future precision medicine approaches in ASD.
Maternal folate receptor alpha autoantibody status will also be evaluated because emerging evidence suggests that maternal folate-related factors may influence neurodevelopmental outcomes. Exploratory analyses will investigate associations among biological markers, clinical characteristics, and treatment outcomes.
The study includes an initial placebo-controlled phase followed by an active-treatment dose-comparison phase. This design allows rigorous evaluation of efficacy against placebo while also generating information regarding potential dose-related differences in response and tolerability. The study therefore aims not only to determine whether folinic acid is effective, but also to provide data that may guide future treatment strategies and trial design.
By combining a large multicenter randomized clinical trial with detailed biological characterization, this study seeks to provide definitive evidence regarding the role of folinic acid in ASD and to advance understanding of folate-related mechanisms in neurodevelopmental disorders. The findings may help identify children most likely to benefit from treatment, improve evidence-based clinical decision-making, and support the development of more individualized therapeutic approaches for ASD.
研究の種類
入学 (推定)
段階
- フェーズ2
連絡先と場所
研究連絡先
- 名前：Adi Aran, MD
- 電話番号：+97226555414
- メール：aaran@szmc.org.il
研究場所
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N/A = Not Applicable
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Jerusalem、N/A = Not Applicable、イスラエル、9103102
- 募集
- Shaare Zedek Medical Center
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主任研究者：
- Adi Aran, MD
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コンタクト：
- Shahar Feller
- 電話番号：+97226555414
- メール：folinics@gmail.com
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参加基準
適格基準
就学可能な年齢
- 子
健康ボランティアの受け入れ
説明
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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).
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
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アクティブコンパレータ：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.
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Calcium folinate hydrate oral solution administered at a target dose of 2 mg/kg/day (maximum 50 mg/day) in two divided doses.
他の名前：
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プラセボコンパレーター：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.
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Matching oral placebo solution containing inactive aqueous excipients and matched in appearance, taste, and smell to the folinic acid formulation
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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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
時間枠：Baseline to Week 9
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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).
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Baseline to Week 9
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Change From Baseline to Week 9 in Vineland Adaptive Behavior Scales, Third Edition (VABS-3) Communication Domain Standard Score
時間枠：Baseline to Week 9
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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.
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Baseline to Week 9
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Change From Baseline to Week 9 in VABS-3 Socialization Domain Standard Score
時間枠：Baseline to Week 9
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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.
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Baseline to Week 9
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Change From Baseline to Week 9 in Clinical Global Impression-Improvement (CGI-I)
時間枠：Week 9
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Clinician-rated global improvement since baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse)
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Week 9
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Change From Baseline to Week 9 in MacArthur-Bates Communicative Development Inventories (MB-CDI)
時間枠：Baseline to Week 9
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Parent-reported measure of expressive vocabulary and communication skills.
Higher scores indicate better communication abilities
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Baseline to Week 9
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その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Change From Baseline to Week 9 in Caregiver Global Impression of Change (CGIC)
時間枠：Week 9
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Caregiver-rated global improvement since baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse)
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Week 9
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Number of Participants With Treatment-Emergent Adverse Events
時間枠：Baseline to Week 9
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Number of participants experiencing mild, moderate, severe, or serious adverse events during the placebo-controlled phase
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Baseline to Week 9
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Number of Participants With Clinically Significant Laboratory or Physical Examination Abnormalities
時間枠：Week 9
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Number of participants with clinically significant abnormalities in complete blood count, liver function tests, bilirubin, vital signs, or physical examination findings
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Week 9
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Change From Baseline to Week 9 in Body Mass Index (BMI)
時間枠：Baseline to Week 9
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Change in body mass index measured during study visits
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Baseline to Week 9
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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
時間枠：Baseline to Week 9
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Caregiver-reported measure of autism-related social impairment.
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Baseline to Week 9
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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
時間枠：Baseline to Week 9
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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.
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Baseline to Week 9
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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
時間枠：Baseline to Week 9
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Caregiver interview assessing maladaptive behaviors.
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Baseline to Week 9
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Change From Baseline to Week 9 in Emotion Dysregulation Inventory (EDI) Score. Scores are reported as standardized T-scores, with a mean of 50 and standard deviation of 10. Higher scores indicate greater emotion dysregulation.
時間枠：Baseline to Week 9
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Caregiver-reported assessment of emotional dysregulation.
The EDI includes scales assessing Reactivity and Dysphoria.
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Baseline to Week 9
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Change From Baseline to Week 9 in Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB) Total Score
時間枠：Baseline to Week 9
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The questionnaire includes 40 items divided into four domains: Temper Loss, Noncompliance, Aggression, and Low Concern for Others.
Each item is rated on a 6-point scale ranging from 0 (Never) to 5 (Many times in the same day).
Total scores range from 0 to 200, with higher scores indicating more frequent and severe disruptive behaviors
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Baseline to Week 9
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Change From Baseline to Week 9 in Autism Impact Measure (AIM) Total Score
時間枠：Baseline to Week 9
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This is a caregiver-reported questionnaire designed to assess the frequency and impact of core autism spectrum disorder symptoms.
The instrument consists of 41 items covering social reciprocity, communication, and restricted and repetitive behaviors.
Each item is rated for both frequency and impact, and scores are summed to generate a total score ranging from 82 to 410.
Higher scores indicate greater autism symptom severity and impairment.
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Baseline to Week 9
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Change From Baseline to Week 9 in Quality of Life in Autism Questionnaire (QOLA) Parent Version total score
時間枠：Baseline to Week 9
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The QOLA Parent version includes Part A, parents' overall perception of their quality of life, and Part B, the impact of ASD symptoms on parents' quality of life; higher scores indicate better quality of life.
Total scores: Part A ranges from 28 to 140, with higher scores reflecting better perceived parental quality of life; Part B ranges from 20 to 100, with higher scores indicating that the child's autism-related difficulties are perceived as less problematic for the parent
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Baseline to Week 9
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Change From Baseline to Week 9 in Children's Sleep Habits Questionnaire (CSHQ) Total Score
時間枠：Baseline to Week 9
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The CSHQ assesses common sleep problems in children across multiple domains; scores range from 33 to 99, with higher scores indicating a greater likelihood of sleep problems.
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Baseline to Week 9
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Change From Baseline to Week 9 in Gastrointestinal Signs and Symptoms Inventory (GISSI) Score
時間枠：Baseline to Week 9
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The GISSI is a caregiver-reported measure assessing the presence and severity of gastrointestinal symptoms, including constipation, diarrhea, abdominal pain, and bloating.
The inventory consists of 15 items, each scored as 0 (problem does not exist), 1 (problem may exist), or 2 (problem exists).
Total scores range from 0 to 30, with higher scores indicating a greater burden of gastrointestinal symptoms.
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Baseline to Week 9
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協力者と研究者
スポンサー
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- 0038-26-SZMC
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IPD プランの説明
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IPD 共有サポート情報タイプ
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