This is a long-term follow-up study of participants in the RB001-101 gene replacement therapy clinical trial for Children With SHANK3-related Phelan-McDermid Syndrome (PMS). Participants will roll over from the parent study into this long-term study for continuous safety monitoring and preliminary efficacy assessment for up to 5 years.
RB001 is an adeno-associated virus (AAV) based gene therapy product. In the preceding RB001-101 clinical study (NCT07014020), 8 participants have been dosed. To date, no serious adverse events have been observed in any participant, and preliminary improvements were noted. In accordance with guidelines for gene therapy products and pediatric rare diseases, long-term follow-up is mandatory to monitor delayed adverse events, assess durability of efficacy, and evaluate long-term developmental benefits. Therefore, we designed this long-term follow-up (LTFU) study, which will roll over participants from the parent study to continuously track the long-term risks and benefits of RB001, providing critical long-term evidence for clinical application. This is a long-term, safety and preliminary efficacy follow-up study of participants in the RB001-101 gene replacement therapy clinical trial for children with SHANK3-related Phelan-McDermid Syndrome (PMS), delivering RB001 via intracerebroventricular injection. Participants will roll over from the parent study into this long-term study for continuous safety and preliminary efficacy monitoring for a total of 5 years. The last visit of the parent study or early discontinuation from the parent study will serve as the visit at which the informed consent form process is conducted for this long-term follow-up study. Participants will return to the research center for follow-up visits every six months for 5 years (after RB001 administration). Additionally, patient record transfers from their local physician and/or neurologist will be requested in conjunction with these study visits for review by the investigator. If the patient is unable to return to the original investigative site, the sponsor will arrange with the patient's local established physician to serve as an additional investigator to conduct the required assessments.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
The study enrolled up to 2 cohorts, evaluating a higher or lower dose
Peking University First Hospital
Beijing, China, China
To evaluate the safety and tolerability of a single intracerebroventricular injection of RB001
Types, severity, and incidence of adverse events (AEs) and serious adverse events (SAEs)
Time frame: 1 to 5 years
To evaluate the changes on Clinical Global Impression Scale - Severity (CGI-S) after a single intracerebroventricular injection of RB001
Clinical Global Impression Scale (CGI) severity item provided with a seven-point scale of severity of patient's clinical condition (1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.)
Time frame: 1 to 5 years
To evaluate the changes on Clinical Global Impression Scale - Improvement (CGI-I) after a single intracerebroventricular injection of RB001
Clinical Global Impression Scale (CGI) Improvement item provided with a seven-point scale of improvement of patient's clinical condition (1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment.)
Time frame: 1 to 5 years
To evaluate the changes on Patient's Global Impressions of Improvement (PGI-I) after a single intracerebroventricular injection of RB001
The PGI-I consists of a single item in which participants or their parents rate the participant's overall health status relative to baseline using a 7 point scale, scale anchors correspond to those of the CGI-I: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse
Time frame: 1 to 5 years
To evaluate the changes on Childhood Autism Rating Scale (CARS-2) after a single intracerebroventricular injection of RB001
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Masking
NONE
Enrollment
8
The CARS2 is a clinician completed rating scale based on direct observation of the child's behavior in standardized contexts. It comprises 15 descriptive items assessing domains including relating to people, imitation, emotional response, body use, object use, and adaptation to change. Each item is scored from 0 to 4, with 0 indicating no abnormality and 4 indicating severe abnormality. The rater integrates behavioral observations with an overall clinical impression of severity to compute a total score ranging from 15 to 60, and converted into a T-score through norm-referenced comparison. Higher T-scores indicate a higher level of autism severity, and a T-score \>40 indicates the presence of moderate or above autism related symptoms.
Time frame: 1 to 5 years
To evaluate the changes on Autism Behavior Checklist (ABC) after a single intracerebroventricular injection of RB001
The ABC is a clinician rated instrument based on direct observation of the child's behavior. It includes 57 items distributed across five domains: sensory, relating, body and object use, language, and self#help behavior. Each item is rated as either "yes" (present) or "no" (absent), based on whether the behavior is observed. The total score is calculated by summing the weighted scores of items endorsed as "yes" (item weights vary from 1 to 4). Higher total scores indicate greater autism#related behavioral impairment. The score is interpreted as follows: total \< 53 = negative (low risk), 53-67 = suspicious (moderate risk), and ≥ 68 = positive (high clinical concern for autism spectrum disorder).
Time frame: 1 to 5 years
To evaluate the changes on Griffith developmental assessment scale - Chinese (GDS-C) after a single intracerebroventricular injection of RB001
the Griffiths Developmental Assessment Scale - Chinese Version (GDS-C) is accessed by certified examiners. The scale evaluates 240 age-standardized tasks across six domains (Locomotor, Personal-Social, Language, Eye-Hand Coordination, Performance, and Practical Reasoning). Tasks are scored 0 or 1 (1=pass, 0=fail), with raw scores converted to Developmental Quotients (DQ) using China-specific norms (2020 revision). DQ\<85 suggests potential mild developmental delay, while a multi-domain DQ\<70 indicates significant developmental delay.
Time frame: 1 to 5 years
To evaluate the changes on Peabody developmental motor scales - 2nd Edition (PDMS-2) after a single intracerebroventricular injection of RB001
The PDMS-2 is a standardized, norm#referenced clinical tool used to assess gross and fine motor development in children. Certified clinicians administer age appropriate items across five domains: reflexes, stationary, locomotion, grasping, and object manipulation. each item is scored based on the child's level of performance, and raw scores are converted to standard scores, percentiles, and composite motor quotients including the gross motor quotient, fine motor quotient, and total motor quotient. Motor quotients are norm#referenced with a mean of 100 and standard deviation of 15. A motor quotient \< 85 indicates potential mild motor delay, while a quotient \< 70 suggests significant motor developmental impairment.
Time frame: 1 to 5 years
To evaluate the changes on Wechsler Preschool and Primary Scale of Intelligence (WPPSI) or Wechsler Intelligence Scale for Children (WISC) after a single intracerebroventricular injection of RB001
the certified neuropsychologist conducts assessments under standardized conditions and assigns scores based on five scales (Verbal Comprehension, Visual Spatial, Fluid/Quantitative Reasoning, Working Memory, Processing Speed) to derive a Full Scale IQ. Scores are norm-referenced (mean=100, SD=15), with higher values indicating superior cognitive ability. IQ\<85 suggests potential mild cognitive delay, while IQ\<70 indicates significant cognitive delay.
Time frame: 1 to 5 years
To evaluate the changes on Adaptive Behavior Assessment System-Second Edition (ABAS-2) after a single intracerebroventricular injection of RB001
To evaluate changes of functional adaptive behaviors from baseline at weeks 12, 26, and 52 after RB001 injection, the Adaptive Behavior Assessment System-Second Edition (ABAS-2) is administered. the rater (usually the Guardian) score the child's daily living skills across 10 domains (Communication, Self-Care, Social, etc.) using age-specific questionnaires. Items are scored 0-3 based on frequency of competent performance, and raw scores normalized to standard scores based on ages (mean=100, SD=15). The General Adaptive Composite (GAC) serves as the primary secondary endpoint. CAG \< 85 suggests potential mild delay, while CAG ≤ 70 indicates significant delay.
Time frame: 1 to 5 years
To evaluate the changes on Social Life Ability Scale For Infant-Junior Middle School Student (S-M) after a single intracerebroventricular injection of RB001
To evaluate adaptive functioning from baseline at weeks 12, 26, and 52 after RB001 injection, the Social Life Ability Scale for Infants-Junior Middle School Students (S-M Scale) is administered. Parents or primary caregivers observe the child's daily behaviors and score 132 specific items across six functional domains (Independent Living Skills, Motor Abilities, Practical Task Performance, Communication Skills, Self-Management, and Socialization). Each item is scored 0 or 1 (1 = pass, 0 = fail) based on observed capability. The total score (0-132) is calculated by summing all items, with higher scores indicating better adaptive functioning. A standard score ≤9 (equivalent to a raw score ≤70; ≥2 SD below the norm) suggests significant impairment in social adaptive abilities.
Time frame: 1 to 5 years
To evaluate the changes on Child Behavior Checklist (CBCL) after a single intracerebroventricular injection of RB001
To evaluate behavioral/emotional problems from baseline at weeks 12, 26, and 52 after RB001 injection, the Child Behavior Checklist (CBCL) is administered. Parents or caregivers rate the child's behaviors using 113+ problem items across empirically based syndromes (Anxious/Depressed, Withdrawn/Depressed, Somatic Complaints, Social Problems, Thought Problems, Attention Problems, Rule-Breaking Behavior, and Aggressive Behavior). Each item is scored 0-2 (0 = not true, 1 = sometimes true, 2 = very/often true). The total problem score (0-240) is calculated by summing all items, with higher scores indicating greater behavioral/emotional impairment. A T-score \>63 (\>90th percentile) suggests clinical concern, and \>70 (\>98th percentile) indicates. (T-scores (M = 50, SD = 10) are derived from normative samples).
Time frame: 1 to 5 years
To evaluate the changes on Children's sleep habits questionnaire(CSHQ) after a single intracerebroventricular injection of RB001
The CSHQ is a validated parent report screening tool used to assess sleep patterns and common sleep disturbances in children. Parents or primary caregivers rate their child's recent sleep behaviors across multiple domains, including bedtime resistance, sleep onset latency, sleep duration, night wakings, sleep anxiety, parasomnias, sleep disordered breathing, and daytime sleepiness. The questionnaire consists of 45 items, each scored on a frequency scale based on how often the behavior occurred during the past week: 1 = frequently (5-7 times), 2 = sometimes (2-4 times), and 3 = rarely (0-1 times). The total score is computed using the established scoring criteria; higher score indicate more severe sleep problems.
Time frame: 1 to 5 years
To evaluate AAV neutralizing antibodies after a single intracerebroventricular injection of RB001
To evaluate AAV neutralizing antibodies (Abs) titer after RB001 injection. blood samples will be collected at each time point. Antibodies will be quantified using cell-coculture method.
Time frame: 1 to 5 years