Treatments for Down Syndrome Regression Disorder

Mechanistic Investigation of Therapies for Down Syndrome Regression Disorder

This study is testing three different treatments for Down Syndrome Regression Disorder to see which one is safe and works best for people aged 8 to 30.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 66 (estimated)
• Ages: 8 Years to 30 Years
• Sex: All
• Sponsor: University of Colorado, Denver (Academic / other)
• Drugs / interventions: rituximab, adalimumab, tofacitinib, methotrexate, cyclophosphamide, prednisone
• Locations: 2 sites (Los Angeles, California and 1 other locations)
• Trial ID: NCT05662228 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety and efficacy of three therapies for Down Syndrome Regression Disorder (DSRD), a neuropsychiatric condition affecting individuals with Down syndrome. Participants aged 8 to 30 will be randomized to receive either lorazepam, intravenous immunoglobulin (IVIG), or tofacitinib over a 12-week period. The study aims to define the safety profiles of these treatments, compare their effectiveness, and explore the underlying mechanisms of DSRD. A subset of participants will also undergo an initial observational period to gather additional data.

Who should consider this trial

Good fit: Ideal candidates include individuals with Down syndrome aged 8 to 30 who have been diagnosed with possible or probable DSRD.

Not a fit: Patients who are pregnant, breastfeeding, or have known allergies to the study medications may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide effective treatment options for individuals suffering from DSRD, improving their quality of life.

How similar studies have performed: While there have been case reports suggesting immune-modulating therapies may help DSRD, this approach is relatively novel and not extensively tested in clinical trials.

Eligibility criteria

Inclusion Criteria:

* Individuals with DS between the ages of 8 and 30 years, inclusive. DS is broadly defined to include complete trisomy 21, Robertsonian translocation trisomy 21, partial trisomy 21 (segmental duplication), and mosaic trisomy 21.
* Diagnosis of possible or probable DSRD per 2022 consensus guidelines.
* Must agree to random treatment assignment.
* Must agree to complete a washout of any medications intended to treat symptoms of DSRD or that may interfere with study interventions.
* Must be able to present with a study partner or legal guardian at all study visits.

Exclusion Criteria:

General

* Weight less than 40 kg.
* Pregnant or breast feeding.
* Past or current tobacco smoking.
* Poor venous access not allowing repeated blood tests or non-compliance with venipuncture requirements.
* Known allergies, hypersensitivity, or intolerance to lorazepam, IVIG, or tofacitinib.
* Participants may be excluded for other unforeseen reasons or confounding reasons for DSRD symptoms at the study doctor's discretion.

Co-occurring Conditions

* Any co-occurring genetic disorder.
* Active symptomatic cardiac disease.
* Clinically significant chronic or active viral infection, including but not limited to HIV, hepatitis, CMV, EBV, HSV or untreated tuberculosis.
* Untreated chronic or active bacterial infection.
* Untreated hypothyroidism or hyperthyroidism.
* History of disseminated herpes zoster, disseminated herpes simplex, or recurrent localized dermatomal herpes zoster.
* History of malignancy (solid tumor or leukemia).
* Moyamoya syndrome or stroke (active or prior).
* Baseline abnormal renal function indicative of moderate or severe renal disease by eGFR \<=45.
* History of acute narrow-angle glaucoma.
* History of venous or arterial thrombosis.
* IgA deficiency with antibodies against IgA.
* Pathogenic neuronal autoantibody positivity against established causes of autoimmune encephalopathy in CSF.
* Any subject with a history of anaphylaxis or a severe systemic response to blood or plasma-derived products.

Medications or Interventions

* Any vaccination planned during the study or within the last 6 weeks.
* Use of electroconvulsive therapy, lorazepam, or a JAK inhibitor within the last 4 weeks.
* Use of IVIG within the last 8 weeks.
* Use of immunosuppressant drugs (e.g., prednisone, mycophenolate mofetil, azathioprine) within the last 8 weeks.
* Use of rituximab within the past 6 months, unless B cell levels have recovered and are above 50 cells/uL.
* Use of other immunosuppressant biologics (e.g., adalimumab, etanercept) within the past 6 months.
* Use of strong CP3A4 inhibitors or inducers (e.g., ketoconazole, rifampin) within the last 4 weeks.
* Use of moderate CP3A4 inhibitors with a strong CYP2C19 inhibitor (e.g., fluconazole) within the last 4 weeks.
* Use of moderate CYP2C9 inhibitors (e.g., valproic acid) within the last 4 weeks.
* Use of strong CYP1A2 inducers (e.g., phenobarbital) or moderate CYP1A2 inhibitors (e.g., fluvoxamine) within the last 4 weeks.
* Use of certain mood stabilizers or anticonvulsants (e.g., clonazepam, lithium, oxcarbazepine) within the last 4 weeks.
* Any prior use of methotrexate, cyclophosphamide, or other chemotherapeutics.
* Any prior solid organ transplant.
* Any prior neurosurgical intervention.
* Any subject who has received blood or plasma products ≤ 30 days prior to first Baseline visit.

Where this trial is running

Los Angeles, California and 1 other locations

• Children's Hospital Los Angeles — Los Angeles, California, United States (Recruiting)
• Children's Hospital Colorado — Aurora, Colorado, United States (Recruiting)

Study contacts

• Principal investigator: Joaquin Espinosa, PhD — Linda Crnic Institute for Down Syndrome
• Study coordinator: Angela Rachubinski, PhD

Conditions Down Syndrome; Regression; Catatonia; Autoimmune disorder; Sleep; Loss of skills; Autoimmune Encephalopathy