Therapies for Down Syndrome Regression Disorder

Recent published case reports and clinical experience of the investigators indicate Down Syndrome Regression Disorder (DSRD) may be successfully treated with immune-modulating therapies, in addition to current pharmacologic options. This study is a multidimensional clinical trial designed to advance the understanding of the etiology of DSRD and to evaluate the safety and efficacy of three distinct therapeutic approaches to treating DSRD: (1) the benzodiazepine lorazepam (Ativan™) (2) intravenous immunoglobulin (IVIG, Gammagard™) or (3) the JAK inhibitor tofacitinib (Xeljanz™). Participants will be randomized into one of the three treatment arms above for the 12-week study period, with a subset of participants undergoing an initial 12-week observational period.

Specific Aims:

• To define the relative safety profile of lorazepam, IVIG, and tofacitinib in DSRD.
• To compare the efficacy of lorazepam, IVIG, and tofacitinib in DSRD.
• To investigate potential mechanisms underlying DSRD and its response to therapies.

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.