Investigating the Therapeutic Efficacy of All-trans Retinoic Acid in Autism Spectrum Disorder Patients With 15q11-13 Duplication Syndrome

NCT ID: NCT07079696

Last Updated: 2025-07-23

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-09-01
• Study Completion Date: 2027-01-31

Brief Summary

Autism spectrum disorder (ASD) , hereafter referred to as autism, is a group of neurodevelopmental disorders caused by genetic and environmental factors. Its core symptoms are social impairment, repetitive stereotyped behaviors, and restricted interests.

The 15q11-13 region of the human chromosome is a locus prone to structural abnormalities leading to neurological disorders. Maternal duplications within this region lead to Dup15q syndrome , which accounts for approximately 1% of ASD cases .

This region harbors multiple alleles, and current research indicates that the pathophysiological alterations in this syndrome primarily involve UBE3A . Among all genes in the 15q11-13 region, only UBE3A exhibits cell-type-specific maternal monoallelic expression . Consequently, duplication of the UBE3A gene is considered the primary pathogenic factor in the pathology of Dup15q syndrome.

Studies show that the metabolic conversion of retinol to retinoic acid is impaired in ASD patients with UBE3A overexpression and corresponding animal models . Notably, dietary supplementation with all-trans retinoic acid (ATRA) has been shown to significantly ameliorate autism-like behaviors caused by UBE3A overexpression in male mice .

This study aims to evaluate ATRA treatment in children with Dup15q syndrome-related autism , assessing changes in their ADOS-2 scores , to potentially provide a novel therapeutic approach for autism treatment.

Conditions

Dup15q Syndrome; Autism Spectrum Disorder; Therapy; All-trans Retinoic Acid

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group experimental

Age: 3-7 years old (stratified into Group 1: 3-5 years; Group 2: 5-7 years).

Group Type: EXPERIMENTAL

ATRA

Intervention Type: DRUG

Treatment Phase (Duration: 18 months) Intervention: ATRA oral administration using a stepwise titration protocol (detailed below). Patients may discontinue treatment if intolerable adverse events occur; post-withdrawal symptom exacerbation is monitored.

*Titration Protocol*

Treatment Cycle (C): 3 weeks per cycle. Dose escalation follows:

Cycle Dosage Duration C1.1 15 mg/m²/day 2 weeks on / 1 week off C1.2 20 mg/m²/day 2 weeks on / 1 week off C1.3 25 mg/m²/day 2 weeks on / 1 week off Blinded Assessments: primary endpoints: ADOS-2 SA score, CARS, SRS, ATEC, Gesell, and Sensory Motor (SM) scales.

Biomarker/Diagnostic tests: blood tests (CBC, liver/kidney function, vitamin panels, ATRA levels, hepatitis markers), neuroimaging (cranial fMRI), neurophysiology (EEG, audiometry), skeletal imaging (limb long-bone radiographs, growth monitoring), and biobanking: 1 blood tube for proteomics (baseline, 6/12/18 months). Repeat all assessments at 6, 12, and 18 months after ATRA treatment.

Interventions

ATRA

Treatment Phase (Duration: 18 months) Intervention: ATRA oral administration using a stepwise titration protocol (detailed below). Patients may discontinue treatment if intolerable adverse events occur; post-withdrawal symptom exacerbation is monitored.

*Titration Protocol*

Treatment Cycle (C): 3 weeks per cycle. Dose escalation follows:

Cycle Dosage Duration C1.1 15 mg/m²/day 2 weeks on / 1 week off C1.2 20 mg/m²/day 2 weeks on / 1 week off C1.3 25 mg/m²/day 2 weeks on / 1 week off Blinded Assessments: primary endpoints: ADOS-2 SA score, CARS, SRS, ATEC, Gesell, and Sensory Motor (SM) scales.

Biomarker/Diagnostic tests: blood tests (CBC, liver/kidney function, vitamin panels, ATRA levels, hepatitis markers), neuroimaging (cranial fMRI), neurophysiology (EEG, audiometry), skeletal imaging (limb long-bone radiographs, growth monitoring), and biobanking: 1 blood tube for proteomics (baseline, 6/12/18 months). Repeat all assessments at 6, 12, and 18 months after ATRA treatment.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Clinical Diagnosis Conducted by two experienced physicians based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition （DSM-V）

2. Diagnostic Scale Assessment Performed by professionally certified examiners using ADOS-2

3. Genetic Testing Diagnostic criteria via genomic analysis : detection of 15q11-13 duplication containing UBE3A

Exclusion Criteria

1. History of acute or chronic infection within the past 3 months

2. Active epileptic seizures within the past 6 months

3. Intake of nutritional supplements (e.g., vitamin A and/or minerals) within the past 1 month

4. History of chronic diseases, including abnormal liver function, abnormal renal function, or thyroid dysfunction

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 7 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Second Affiliated Hospital, School of Medicine, Zhejiang University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Department of Pediatrics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.

Hangzhou, Zhejiang, China

Countries

China

Central Contacts

Jianhua Feng

Role: CONTACT

hzhz87083886@zju.edu.cn

86+13588172577

Xueting Lin

Role: CONTACT

lin_xt@zju.edu.cn

86+19858126052

Facility Contacts

Jianhua Feng

Role: primary

hzhz87083886@zju.edu.cn

86+13588172577

Xueting Lin

Role: backup

lin_xt@zju.edu.cn

86+19858126052

Other Identifiers

2025-0465

Identifier Type: -

Identifier Source: org_study_id