Therapies for Down Syndrome Regression Disorder

Sponsor

University of Colorado, Denver (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05662228

Collaborator

Children's Hospital Los Angeles (Other)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Individuals with Down syndrome (DS) have an increased risk of numerous co-occurring conditions, including the neuropsychiatric condition known as Down Syndrome Regression Disorder (DSRD). A DSRD diagnosis often includes a sub-acute onset of catatonia, mutism, depersonalization, loss of ability to perform activities of daily living, hallucinations, delusions, and aggression and is most commonly observed in adolescents and young adults.

The study evaluates the safety and efficacy of three currently prescribed therapies:

lorazepam, intravenous immunoglobulin (IVIG) and tofacitinib.

Condition or Disease	Intervention/Treatment	Phase
Down Syndrome Regression	Drug: Lorazepam Drug: Intravenous immunoglobulin (IVIG) Drug: Tofacitinib	Phase 2

Detailed Description

Recent published case reports and clinical experience of the investigators indicate Down Syndrome Regression Disorder (DSRD) may be successfully treated with immune-modulating therapies. 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

66 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

We will use covariate-adaptive randomization to assign participants to one of three treatment arms while accounting for sex, age, and race/ethnicity.We will use covariate-adaptive randomization to assign participants to one of three treatment arms while accounting for sex, age, and race/ethnicity.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Mechanistic Investigation of Therapies for Down Syndrome Regression Disorder

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2027

Anticipated Study Completion Date :

Dec 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lorazepam Participants will receive lorazepam as an oral pill three times daily for 12 weeks	Drug: Lorazepam Lorazepam will be administered as an oral pill over the first 15 days of study in a daily titration, starting at 0.5 mg BID and increasing to up to 2 mg three times daily, as tolerated. Dosing will continue at the maximum tolerated dose through the 12-week endpoint. Participants will be titrated off lorazepam in the reverse schedule after completing the endpoint visit. Other Names: Ativan
Experimental: Intravenous immunoglobulin (IVIG) Participants will receive 4 doses of IVIG treatment over 12 weeks	Drug: Intravenous immunoglobulin (IVIG) IVIG will be administered as a series of four intravenous infusions at a dose of 1 mg/kg with pre-infusion medications of 1 mg/kg diphenhydramine and 15 mg/kg acetaminophen. The first two infusions occur at baseline and one day after (induction dosing), followed by one infusion at 4 weeks and one infusion at 8 weeks. Other Names: Gammagard Liquid (immune globulin infusion [human] 10%)
Experimental: Tofacitinib Tofacitinib will be administered as an oral pill at 5 mg twice daily over the 12-week study.	Drug: Tofacitinib Tofacitinib will be administered as an oral pill at 5 mg twice daily over the 12-week study. Other Names: Xeljanz

Arm

Intervention/Treatment

Experimental: Lorazepam

Participants will receive lorazepam as an oral pill three times daily for 12 weeks

Drug: Lorazepam

Lorazepam will be administered as an oral pill over the first 15 days of study in a daily titration, starting at 0.5 mg BID and increasing to up to 2 mg three times daily, as tolerated. Dosing will continue at the maximum tolerated dose through the 12-week endpoint. Participants will be titrated off lorazepam in the reverse schedule after completing the endpoint visit.

Other Names:

Ativan

Experimental: Intravenous immunoglobulin (IVIG)

Participants will receive 4 doses of IVIG treatment over 12 weeks

Drug: Intravenous immunoglobulin (IVIG)

IVIG will be administered as a series of four intravenous infusions at a dose of 1 mg/kg with pre-infusion medications of 1 mg/kg diphenhydramine and 15 mg/kg acetaminophen. The first two infusions occur at baseline and one day after (induction dosing), followed by one infusion at 4 weeks and one infusion at 8 weeks.

Other Names:

Gammagard Liquid (immune globulin infusion [human] 10%)

Experimental: Tofacitinib

Tofacitinib will be administered as an oral pill at 5 mg twice daily over the 12-week study.

Drug: Tofacitinib

Tofacitinib will be administered as an oral pill at 5 mg twice daily over the 12-week study.

Other Names:

Xeljanz

Outcome Measures

Primary Outcome Measures

Determine relative safety and tolerability of lorazepam, IVIG, and tofacitinib in individuals with DSRD. [Baseline to 14 weeks]
A summary of adverse events (AEs) by type and organ system will be reported for the entire study period, along with any statistically significant differences observed in rates of AEs across treatment arms.

Secondary Outcome Measures

Change in catatonia. [Baseline to 12 weeks]
A statistically significant change in the Bush-Francis Catatonia Rating Scale (BFCRS) within or between treatment arms.
Change in movement and visuomotor function. [Baseline to 12 weeks]
A statistically significant change in one or more measures of movement and visuomotor function within or between treatment arms. Measures used include the Timed 25-Foot Walk and the NEPSY-II Visuomotor domain test.
Change in language. [Baseline to 12 weeks]
A statistically significant change in one or more measures of language within or between treatment arms. Measures used include a guided language sample analysis and the Peabody Picture Vocabulary Test, 5th Edition (PPVT-5).
Change in adaptive skills. [Baseline to 12 weeks]
A statistically significant change in one or more measures of adaptive skills within or between treatment arms as measured using the Vineland Adaptive Behavior Scales-3 (VABS-3).
Change in quality of life. [Baseline to 12 weeks]
A statistically significant change in the Pediatric Quality of Life Inventory (PedsQL) and Kingston Caregiver Stress Scale (KCSS) within or between treatment arms.

Other Outcome Measures

Change in sleep habits. [Baseline to 12 weeks]
A statistically significant change in the sleep as monitored by FitBit watch recordings within or between treatment arms.
Change in behavior and social interaction. [Baseline to 12 weeks]
A statistically significant change in one or more measures of behavior and social interaction within or between treatment arms. Measures used include the Developmental Behavior Checklist-2 (DBC-2) and Social Responsiveness Scale-2 (SRS-2).
Change in overall cognitive ability. [Baseline to 12 weeks]
A statistically significant change in one or more measures of overall cognitive ability within or between treatment arms. Measures used include the Behavior Rating Inventory of Executive Function, 2nd Edition (BRIEF-2); Neuropsychiatric Inventory (NPI); Down Syndrome Mental Status Exam (DSMSE); Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Span, Paired Associates Learning (PAL) and Reaction Time Interval (RTI) domains; and Kaufman Brief Intelligence Test, 2nd Ed (KBIT-2).

Eligibility Criteria

Criteria

Ages Eligible for Study:

8 Years to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 (19).
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 fully vaccinated for COVID-19, as defined by current CDC guidance and definitions.
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).
History of severe renal disease as defined by eGFR <= 29.
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.

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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

University of Colorado, Denver
Children's Hospital Los Angeles

Investigators

Principal Investigator: Joaquin Espinosa, PhD, Linda Crnic Institute for Down Syndrome
Principal Investigator: Elise Sannar, MD, Children's Hospital Colorado
Principal Investigator: Jonathon Santoro, MD, Children's Hospital Los Angeles