Down Syndrome Regression Disorder (DSRD), Down Syndrome (Trisomy 21), Neuroinflammatory / Neuropsychiatric Disorder
Conditions
Keywords
Ublituximab, Down Syndrome Regression Disorder (DSRD), B-cell depletion
Brief summary
The goal of this clinical trial is to evaluate whether the monoclonal antibody ublituximab can treat Down Syndrome Regression Disorder (DSRD) by assessing its safety, tolerability, and preliminary efficacy in affected individuals. This study is conducted in adults aged 18-40 years with Down syndrome who have DSRD and have had an inadequate or partial response to first-line therapies. The main questions it aims to answer are: * Does ublituximab demonstrate acceptable safety and tolerability, as measured by treatment-emergent adverse events from baseline through Week 24? * Does ublituximab lead to improvement in cognitive, neuropsychiatric, motor, and functional outcomes from baseline to Weeks 12 and 24? This is a single-arm study, so there is no comparison group. Participants will: * Receive two intravenous infusions of ublituximab (150 mg on Day 1 and 450 mg on Day 15) * Attend study visits at Screening, Baseline (Day 1) , Week 2 (Day 15), Week 3, Week 6, Week 12, and Week 24 * Undergo clinical assessments, including neurological and physical exams and safety monitoring labs throughout the study * Complete cognitive, behavioral, and functional evaluations at Baseline, Week 12, and Week 24 * Provide blood samples for safety monitoring and research biomarker analyses
Interventions
DRUGUblituximab
Participants assigned to the Ublituximab arm will receive a fixed two-dose intravenous regimen consisting of 150 mg on Day 1 and 450 mg on Day 15. All participants will be followed for 24 weeks with regular safety monitoring, clinical assessments, and evaluation of cognitive, neuropsychiatric, and functional outcomes.
Sponsors
Jonathan Santoro
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants are assigned to a single treatment arm and receive ublituximab. There is no comparator or control group, and outcomes are assessed longitudinally over 24 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 40 years, inclusive at time of consent * Diagnosis of Down syndrome (trisomy 21 or translocation type) * Diagnosis of possible or probable Down Syndrome Regression Disorder (DSRD) based on 2022 International Consensus Criteria * History of partial response or non-response to first-line treatment (e.g., lorazepam, SSRIs, corticosteroids, and/or IVIg). Partial response = 10-50% improvement, Non-response = \<10% improvement, Based on BFCRS or NPI-Q after 3 months of treatment. * Ability to attend all study visits with a study partner or legally authorized representative * Study partner willing to comply with all study procedures * Willingness to complete required washout periods for medications that may interfere with the study * Highly effective contraception for reproductive participants and partners of childbearing potential. * Study partner/LAR sufficiently proficient in English to complete assessments.
Exclusion criteria
* Mosaic Down syndrome * Weight \< 40 kg at screening * Pregnancy or breastfeeding * Current or past tobacco smoking * Poor venous access or inability to comply with IV procedures * Use of IVIg within 8 weeks prior to baseline * Use of immunosuppressive drugs within 12 weeks prior to baseline * Prior treatment with anti-CD20 or B-cell therapies within required washout unless B-cell recovery criteria are met * Other immunosuppressive biologics within 24 months. * Any prior use of chemotherapeutic agents (e.g., methotrexate, cyclophosphamide) * History of solid organ transplant * Recent receipt of blood or plasma products (≤30 days) * Clinically significant cardiac disease, clotting disorder, or other serious medical condition * Active or chronic infection of clinical significance (including HBV, HCV, TB, HIV per protocol criteria) * History of malignancy * Abnormal screening labs indicating unacceptable risk * Receipt of live or live-attenuated vaccines within 4 weeks prior to treatment * Untreated thyroid disease (hypo- or hyperthyroidism) * History of moyamoya syndrome or stroke * Wards of the state * Employees or students of Children's Hospital Los Angeles (CHLA) * Prior neurosurgical intervention (exceptions for longstanding shunts) * Current investigational therapy/prohibited medications * Detailed HBV, HCV, and TB criteria * Requirement for B-cell recovery \>50 cells/μL after prior anti-CD20 therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total AEs on Ublituximab | Baseline through Week 24 | Safety will be evaluated by the incidence, type, severity (graded per CTCAE v5.0), and relationship of treatment-emergent adverse events (AEs) occurring after the first dose of ublituximab. Tolerability will be assessed by the proportion of participants completing both doses and follow-up without dose modifications, interruptions, or discontinuation due to AEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Scores for Adaptive Behavior using VABS-3 Composite and Domain Survey | Baseline, Week 12, and Week 24 | Change from baseline in adaptive functioning measured by the Vineland Adaptive Behavior Scales, Third Edition (VABS-3), including communication, daily living skills, socialization, and maladaptive behavior domains as reported by caregivers. |
| Change in Scores for Catatonia Severity using Bush-Francis Catatonia Rating Scale | Baseline, Week 12, and Week 24 | Change from baseline in catatonia symptoms measured by the Bush-Francis Catatonia Rating Scale (BFCRS), with decreases in total score indicating improvement in symptom severity. 0 (no catatonia) - 45 (Severe Catatonia) |
| Change in Score for Neuropsychiatric Symptoms using Neuropsychiatric Inventory Questionnaire (NPI-Q) | Baseline, Week 12, and Week 24 | Change from baseline in neuropsychiatric symptom burden as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q), a caregiver-reported assessment of symptom frequency and severity across behavioral domains. |
| Change in Motor Function (Timed 25-Foot Walk) | Baseline, Week 12, and Week 24 | Change from baseline in time (seconds) required to complete the Timed 25-Foot Walk (T25-FW), reflecting gait speed and motor function, with decreased time indicating improvement. |
| Change in Global Clinical Status Using Clinician Global Impression of Change-Down Syndrome (CGIC-DS) | Baseline, Week 12, and Week 24 | Change from baseline in global clinical status assessed using the Clinician Global Impression of Change-Down Syndrome (CGIC-DS), a Down syndrome-adapted clinician-rated instrument. The Baseline version generates a Clinical Global Impression-Severity (CGI-S) rating to assess overall illness severity, and the Follow-up version generates a Clinical Global Impression-Improvement (CGI-I) rating to assess clinical change relative to baseline. CGI-S scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill), while CGI-I scores range from 1 (very much improved) to 7 (very much worse). Assessments will be conducted at Baseline, Week 12, and Week 24. |
| Change in Global Clinical Status Using Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) Scores Derived from the Clinician Global Impression of Change-Down Syndrome (CGIC-DS) | Baseline, Week 12, and Week 24 | Change from baseline in global clinical status measured using CGI-S and CGI-I ratings derived from the Clinician Global Impression of Change-Down Syndrome (CGIC-DS). CGI-S assesses overall illness severity, and CGI-I assesses improvement or worsening relative to baseline. Assessments will be conducted at Baseline, Week 12, and Week 24. Lower CGI-S scores indicate reduced illness severity, and lower CGI-I scores indicate greater clinical improvement. |
| Change in Participant Quality of Life Using Pediatric Quality of Life Inventory (PedsQL) Parent Report | Baseline, Week 12, and Week 24 | Change from baseline in participant quality of life measured by the Pediatric Quality of Life Inventory (PedsQL) Parent Report. This caregiver-reported assessment evaluates health-related quality of life across physical functioning, emotional functioning, social functioning, and work/studies functioning domains. Higher scores indicate better quality of life and functional status. Assessments will be conducted at Baseline, Week 12, and Week 24. |
| Change in Caregiver and Family Functioning Using Pediatric Quality of Life Inventory Family Impact Module (PedsQL-FIM) | Baseline to Week 24 | Change from baseline in caregiver and family functioning measured by the Pediatric Quality of Life Inventory Family Impact Module (PedsQL-FIM). This caregiver-reported assessment evaluates the impact of the participant's condition on caregiver well-being and family functioning across physical, emotional, social, cognitive, communication, daily activities, and family relationship domains. Higher scores indicate better caregiver quality of life, improved family functioning, and less negative impact on the family. Assessments will be conducted at Baseline, Week 12, and Week 24. |
| Change in Communication Ability Using Observer-Reported Communication Ability (ORCA) Measure | Baseline, Week 12, and Week 24 | Change from baseline in communication abilities measured by the Observer-Reported Communication Ability (ORCA) Measure, a caregiver-reported assessment of expressive and receptive communication skills. The ORCA evaluates verbal communication, use of gestures, social communication, requesting, conversation, comprehension, and functional communication abilities in everyday settings. Higher scores indicate greater communication ability and improved functional communication. |
| Change in Obsessive-Compulsive Symptom Severity Using Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) | Baseline, Week 12, and Week 24 | Change from baseline in obsessive-compulsive symptom severity measured by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), a clinician-administered assessment of obsessions and compulsions. The CY-BOCS evaluates symptom severity across domains including time occupied, interference, distress, resistance, and degree of control. Higher scores indicate greater obsessive-compulsive symptom severity, and decreases in total score indicate improvement. |
Countries
United States
Contacts
CONTACTMariam Yousuf
CONTACTSamuel Otey
PRINCIPAL_INVESTIGATORJonathan Santoro, MD
Children's Hospital Los Angeles
Outcome results
None listed