Studies
| Study First Submitted Date | 2022-12-08 |
| Study First Posted Date | 2022-12-22 |
| Last Update Posted Date | 2023-07-18 |
| Start Month Year | June 29, 2023 |
| Primary Completion Month Year | December 2026 |
| Verification Month Year | July 2023 |
| Verification Date | 2023-07-31 |
| Last Update Posted Date | 2023-07-18 |
Detailed Descriptions
| Sequence: | 20848458 |
| 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, 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. |
Facilities
| Sequence: | 201252941 | Sequence: | 201252942 |
| Status | Recruiting | Status | Recruiting |
| Name | Children's Hospital Los Angeles | Name | Children's Hospital Colorado |
| City | Los Angeles | City | Aurora |
| State | California | State | Colorado |
| Zip | 90027 | Zip | 80045 |
| Country | United States | Country | United States |
Facility Contacts
| Sequence: | 28276424 | Sequence: | 28276425 |
| Facility Id | 201252941 | Facility Id | 201252942 |
| Contact Type | primary | Contact Type | primary |
| Name | Natalie Boyd, BS | Name | Linda Roan, MS |
| [email protected] | [email protected] | ||
| Phone | 323-607-3505 | Phone | 303-724-9907 |
Browse Interventions
| Sequence: | 96578652 | Sequence: | 96578653 | Sequence: | 96578654 | Sequence: | 96578655 | Sequence: | 96578656 | Sequence: | 96578657 | Sequence: | 96578658 | Sequence: | 96578659 | Sequence: | 96578660 | Sequence: | 96578661 | Sequence: | 96578662 | Sequence: | 96578663 | Sequence: | 96578664 | Sequence: | 96578665 | Sequence: | 96578666 | Sequence: | 96578667 | Sequence: | 96578668 | Sequence: | 96578669 | Sequence: | 96578670 | Sequence: | 96578671 | Sequence: | 96578672 | Sequence: | 96578673 | Sequence: | 96578674 | Sequence: | 96578675 | Sequence: | 96578676 | Sequence: | 96578677 |
| Mesh Term | Lorazepam | Mesh Term | Immunoglobulins | Mesh Term | Immunoglobulins, Intravenous | Mesh Term | Antibodies | Mesh Term | gamma-Globulins | Mesh Term | Rho(D) Immune Globulin | Mesh Term | Tofacitinib | Mesh Term | Immunologic Factors | Mesh Term | Physiological Effects of Drugs | Mesh Term | Janus Kinase Inhibitors | Mesh Term | Protein Kinase Inhibitors | Mesh Term | Enzyme Inhibitors | Mesh Term | Molecular Mechanisms of Pharmacological Action | Mesh Term | Anticonvulsants | Mesh Term | Antiemetics | Mesh Term | Autonomic Agents | Mesh Term | Peripheral Nervous System Agents | Mesh Term | Gastrointestinal Agents | Mesh Term | Hypnotics and Sedatives | Mesh Term | Central Nervous System Depressants | Mesh Term | Anti-Anxiety Agents | Mesh Term | Tranquilizing Agents | Mesh Term | Psychotropic Drugs | Mesh Term | GABA Modulators | Mesh Term | GABA Agents | Mesh Term | Neurotransmitter Agents |
| Downcase Mesh Term | lorazepam | Downcase Mesh Term | immunoglobulins | Downcase Mesh Term | immunoglobulins, intravenous | Downcase Mesh Term | antibodies | Downcase Mesh Term | gamma-globulins | Downcase Mesh Term | rho(d) immune globulin | Downcase Mesh Term | tofacitinib | Downcase Mesh Term | immunologic factors | Downcase Mesh Term | physiological effects of drugs | Downcase Mesh Term | janus kinase inhibitors | Downcase Mesh Term | protein kinase inhibitors | Downcase Mesh Term | enzyme inhibitors | Downcase Mesh Term | molecular mechanisms of pharmacological action | Downcase Mesh Term | anticonvulsants | Downcase Mesh Term | antiemetics | Downcase Mesh Term | autonomic agents | Downcase Mesh Term | peripheral nervous system agents | Downcase Mesh Term | gastrointestinal agents | Downcase Mesh Term | hypnotics and sedatives | Downcase Mesh Term | central nervous system depressants | Downcase Mesh Term | anti-anxiety agents | Downcase Mesh Term | tranquilizing agents | Downcase Mesh Term | psychotropic drugs | Downcase Mesh Term | gaba modulators | Downcase Mesh Term | gaba agents | Downcase Mesh Term | neurotransmitter agents |
| Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor |
Conditions
| Sequence: | 52497131 | Sequence: | 52497132 |
| Name | Down Syndrome | Name | Regression |
| Downcase Name | down syndrome | Downcase Name | regression |
Id Information
| Sequence: | 40391572 |
| Id Source | org_study_id |
| Id Value | 22-1992 |
Countries
| Sequence: | 42827085 |
| Name | United States |
| Removed | False |
Design Groups
| Sequence: | 55953113 | Sequence: | 55953114 | Sequence: | 55953115 |
| Group Type | Experimental | Group Type | Experimental | Group Type | Experimental |
| Title | Lorazepam | Title | Intravenous immunoglobulin (IVIG) | Title | Tofacitinib |
| Description | Participants will receive lorazepam as an oral pill three times daily for 12 weeks as well as titration doses for an additional 4 weeks (approximately). | Description | Participants will receive 4 doses of IVIG treatment over 12 weeks. | Description | Tofacitinib will be administered as an oral pill at 5 mg twice daily over the 12-week study. |
Interventions
| Sequence: | 52805295 | Sequence: | 52805296 | Sequence: | 52805297 |
| Intervention Type | Drug | Intervention Type | Drug | Intervention Type | Drug |
| Name | Lorazepam | Name | Intravenous immunoglobulin (IVIG) | Name | Tofacitinib |
| Description | 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 over at least four weeks after completing the endpoint visit. Taper will be tailored to individuals for safety reasons with a goal of decreasing dosage by 25% weekly. Phone check ins will be conducted every three days to monitor patient. | Description | 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. | Description | Tofacitinib will be administered as an oral pill at 5 mg twice daily over the 12-week study. |
Keywords
| Sequence: | 80310349 | Sequence: | 80310350 | Sequence: | 80310351 | Sequence: | 80310352 | Sequence: | 80310353 |
| Name | Catatonia | Name | Autoimmune disorder | Name | Sleep | Name | Loss of skills | Name | Autoimmune Encephalopathy |
| Downcase Name | catatonia | Downcase Name | autoimmune disorder | Downcase Name | sleep | Downcase Name | loss of skills | Downcase Name | autoimmune encephalopathy |
Design Outcomes
| Sequence: | 178596437 | Sequence: | 178596438 | Sequence: | 178596439 | Sequence: | 178596440 | Sequence: | 178596441 | Sequence: | 178596442 | Sequence: | 178596443 | Sequence: | 178596444 | Sequence: | 178596445 | Sequence: | 178596446 | Sequence: | 178596447 | Sequence: | 178596448 | Sequence: | 178596449 |
| Outcome Type | primary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | other | Outcome Type | other | Outcome Type | other | Outcome Type | other | Outcome Type | other |
| Measure | Comparison of number and severity of all adverse events. | Measure | Change in catatonia by overall score in BFCRS. | Measure | Time to complete 25-Foot Walk assessment. | Measure | Total number of errors in visual motor assessment NEPSY-II. | Measure | Change in expressive language as measured by total number of words used. | Measure | Change in adaptive skills as measured by the VABS-3 domain level standard score. | Measure | Change in family impact score as measured by summary score on PedsQL Family Impact Score. | Measure | Change in quality of life score as measured by PedsQL summary score. | Measure | Change in minutes of total sleep and longest sleep as measured by FitBit. | Measure | Change in social interaction as measured by SRS-2 subdomain T-scores. | Measure | Change in behavior as measured by DBC-2 T-score. | Measure | Change in one or more measures of overall cognitive ability. | Measure | Change in receptive language as measured by PVT raw score. |
| Time Frame | Baseline to 14 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks | Time Frame | Baseline to 12 weeks |
| Description | 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. | Description | Change in overall score in the Bush-Francis Catatonia Rating Scale (BFCRS) between baseline and 12 weeks within or between treatment arms. A decrease in score indicates an improved performance. | Description | Change in the time it takes to complete walking 25 feet between baseline to 12 weeks. A decrease in score indicates an improved performance. | Description | Using NEPSY-II to measure change in total number of errors between both car and motorcycle trials. A decrease in score indicates an improved performance. | Description | Change in total number or words used in a guided language sample. An increase in score indicates improvement. | Description | Change in standard scores for at least one domain in the Vineland Adaptive Behavior Scales-3 (VABS-3) between baseline and 12 weeks within or between treatment arms. An increase in standard score by domain indicates improvement. | Description | Change in the Pediatric Quality of Life Inventory (PedsQL) within or between treatment arms. An increase in summary score indicates improvement. | Description | Change in the Pediatric Quality of Life Inventory (PedsQL) summary score within or between treatment arms. An increase in summary score indicates improvement. | Description | Change in the sleep as monitored by FitBit watch recordings within or between treatment arms. To include total amount of minutes of sleep in a 24-hour period over an average of seven days, longest block of sleep in a 24-hour period over an average of seven days, and total sleep minutes between 8 pm and 8 am. | Description | Change in Social Responsiveness Scale-2 (SRS-2) subdomain treatment T-scores within or between treatment arms. A decrease in score indicates improvement. | Description | A statistically significant change in Developmental Behavioral Checklist-2 (DBC-2) T-scores within or between treatment arms. A decrease in score indicates improvement. | Description | A statistically significant change in one or more measures of overall cognitive ability within or between treatment arms. Measures include: Behavior Rating Inventory of Executive Function, 2nd Edition (BRIEF-2): Change in T-scores. Down Syndrome Mental Status Exam (DSMSE): Change in Total Memory and Non-Memory Composite score. . Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associate Learning (PAL) subdomain will be used to measure episodic learning. CANTAB Spatial Span (SS) will be used to measure spatial processing. CANTAB Reaction Time Interval (RTI) subdomain will be used to measure processing speed. Kaufman Brief Intelligence Test-2 Revised (KBIT-2 Revised): Change in Standard Score. Neuropsychiatric Inventory (NPI): Change in total score. | Description | Change in the raw score of the NIH Toolbox Picture Vocabulary Test (PVT). An increase in score indicates an improved performance. |
Browse Conditions
| Sequence: | 194729838 | Sequence: | 194729839 | Sequence: | 194729840 | Sequence: | 194729841 | Sequence: | 194729842 | Sequence: | 194729843 | Sequence: | 194729844 | Sequence: | 194729845 | Sequence: | 194729846 | Sequence: | 194729847 | Sequence: | 194729848 | Sequence: | 194729849 |
| Mesh Term | Down Syndrome | Mesh Term | Syndrome | Mesh Term | Disease | Mesh Term | Pathologic Processes | Mesh Term | Intellectual Disability | Mesh Term | Neurobehavioral Manifestations | Mesh Term | Neurologic Manifestations | Mesh Term | Nervous System Diseases | Mesh Term | Abnormalities, Multiple | Mesh Term | Congenital Abnormalities | Mesh Term | Chromosome Disorders | Mesh Term | Genetic Diseases, Inborn |
| Downcase Mesh Term | down syndrome | Downcase Mesh Term | syndrome | Downcase Mesh Term | disease | Downcase Mesh Term | pathologic processes | Downcase Mesh Term | intellectual disability | Downcase Mesh Term | neurobehavioral manifestations | Downcase Mesh Term | neurologic manifestations | Downcase Mesh Term | nervous system diseases | Downcase Mesh Term | abnormalities, multiple | Downcase Mesh Term | congenital abnormalities | Downcase Mesh Term | chromosome disorders | Downcase Mesh Term | genetic diseases, inborn |
| Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor |
Sponsors
| Sequence: | 48621480 | Sequence: | 48621481 |
| Agency Class | OTHER | Agency Class | OTHER |
| Lead Or Collaborator | lead | Lead Or Collaborator | collaborator |
| Name | University of Colorado, Denver | Name | Children's Hospital Los Angeles |
Overall Officials
| Sequence: | 29455500 | Sequence: | 29455501 | Sequence: | 29455502 |
| Role | Principal Investigator | Role | Principal Investigator | Role | Principal Investigator |
| Name | Joaquin Espinosa, PhD | Name | Elise Sannar, MD | Name | Jonathon Santoro, MD |
| Affiliation | Linda Crnic Institute for Down Syndrome | Affiliation | Children's Hospital Colorado | Affiliation | Children's Hospital Los Angeles |
Central Contacts
| Sequence: | 12092893 | Sequence: | 12092894 |
| Contact Type | primary | Contact Type | backup |
| Name | Angela Rachubinski, PhD | Name | Belinda Enriquez Estrada, MS |
| Phone | 303-724-7366 | Phone | 303-724-0491 |
| [email protected] | [email protected] | ||
| Role | Contact | Role | Contact |
Design Group Interventions
| Sequence: | 68593162 | Sequence: | 68593163 | Sequence: | 68593164 |
| Design Group Id | 55953113 | Design Group Id | 55953114 | Design Group Id | 55953115 |
| Intervention Id | 52805295 | Intervention Id | 52805296 | Intervention Id | 52805297 |
Eligibilities
| Sequence: | 30951483 |
| Gender | All |
| Minimum Age | 8 Years |
| Maximum Age | 30 Years |
| Healthy Volunteers | No |
| 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 (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. |
| Adult | True |
| Child | True |
| Older Adult | False |
Calculated Values
| Sequence: | 253859114 |
| Number Of Facilities | 2 |
| Registered In Calendar Year | 2022 |
| Were Results Reported | False |
| Has Us Facility | True |
| Has Single Facility | False |
| Minimum Age Num | 8 |
| Maximum Age Num | 30 |
| Minimum Age Unit | Years |
| Maximum Age Unit | Years |
| Number Of Primary Outcomes To Measure | 1 |
| Number Of Secondary Outcomes To Measure | 7 |
| Number Of Other Outcomes To Measure | 5 |
Designs
| Sequence: | 30697071 |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Observational Model | |
| Primary Purpose | Treatment |
| Time Perspective | |
| Masking | None (Open Label) |
| Intervention Model Description | We will use covariate-adaptive randomization to assign participants to one of three treatment arms while accounting for sex, age, race/ethnicity and other medical history. |
Intervention Other Names
| Sequence: | 26835570 | Sequence: | 26835571 | Sequence: | 26835572 |
| Intervention Id | 52805295 | Intervention Id | 52805296 | Intervention Id | 52805297 |
| Name | Ativan | Name | Gammagard Liquid (immune globulin infusion [human] 10%) | Name | Xeljanz |
Responsible Parties
| Sequence: | 29063828 |
| Responsible Party Type | Sponsor |
Ipd Information Types
| Sequence: | 3360834 | Sequence: | 3360835 | Sequence: | 3360836 | Sequence: | 3360837 |
| Name | Study Protocol | Name | Statistical Analysis Plan (SAP) | Name | Informed Consent Form (ICF) | Name | Analytic Code |