Modulation of the Immune System in Down Syndrome for Improved Outcomes and Neurodevelopment - 1 (MISSION-1)

This protocol describes a phase 2, double-blind, randomized, placebo-controlled clinical trial for Janus kinase (JAK) inhibition in Down syndrome (DS). This trial will evaluate the safety and efficacy of a 6-month treatment with the JAK1/3 inhibitor tofacitinib (XELJANZ) in individuals ages 6-22 (inclusive) with DS. There will be two main arms for this study: a treatment arm and a placebo control arm. Participants will be randomized into the treatment or placebo arm. Those completing 6 months in the placebo arm may be eligible to participate in a cross-over, open-label extension arm to receive 6 months of tofacitinib treatment. Participants will be evaluated during a Screening visit to determine eligibility, complete a Baseline visit if eligible, and be monitored via safety clinical laboratories and in-person evaluations by study doctors at 1 month, 3 months (mid-point visit) and 6 months (endpoint visit). An interim analysis of safety will be completed by an independent Data and Safety Monitoring Board (DSMB) after 40 participants have completed 6 months of treatment or placebo (20 in each arm).

Study Overview

• Status: Recruiting
• Conditions: Down Syndrome
• Intervention / Treatment: Drug: Tofacitinib Oral Solution; Drug: Placebo

Detailed Description

This is a phase 2 randomized, double-blind, placebo-controlled clinical trial for Janus kinase (JAK) inhibition in Down syndrome (DS). After successful enrollment, including informed consent and assessment of inclusion and exclusion criteria, participants will be enrolled and randomized into the treatment or placebo arms and complete identical activities over the course of 6 months.

Briefly, the study recruitment goal is 80 participants (n=40 per treatment and placebo arm) with up to 92 participants enrolled. Participants enrolled in the treatment arm will receive a 6-month treatment with the JAK1/3 inhibitor tofacitinib (XELJANZ) to define the safety and efficacy of this medicine relative to placebo.

Safety monitoring will be completed over the 6-month period through a combination of self-reporting, laboratory testing, and study doctor assessment. AEs will be annotated by the study team and classified per Common Terminology Criteria for Adverse Events (CTCAE 5.0).

Diverse metrics of neurodevelopment and overall health will be obtained at the Baseline visit, 3-month visit (midpoint) and 6-month visit (endpoint). The data obtained after 6 months of treatment or placebo will be used for all endpoint analyses.

Participants enrolled in the placebo arm will be eligible to continue in the trial for an additional 6 months of tofacitinib treatment in a cross-over, open-label extension arm. Data collected during the cross-over, open-label extension arm will not contribute to any of the primary endpoint analyses. Rather, the cross-over dataset will be used to complete exploratory analyses of longitudinal intra-individual variability while on placebo and tofacitinib. Activities during 6 months of treatment in the cross-over arm will be identical to the main treatment arm. The cross-over arm will also serve to incentivize participation by ensuring that all eligible participants will be able to receive the medicine at some point during the trial.

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Constance Brecl; Phone Number: 303-724-6214; Email: constance.brecl@cuanschutz.edu
• Study Contact Backup: Name: Erika Chelales, PhD; Phone Number: 303-724-5017; Email: erika.chelales@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • CU Anschutz, Children's Hospital Colorado
      • Contact: Erika M Chelales, PhD; Phone Number: 303-724-5017; Email: DSresearch@cuanschutz.edu
      • Contact: Constance Brecl; Phone Number: 303-724-6214; Email: DSresearch@cuanschutz.edu
      • Principal Investigator: Joaquin M Espinosa, PhD
      • Principal Investigator: Jessica L Bloom, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Individuals with DS aged 6 years (inclusive) to 22 years (inclusive). All forms of DS will qualify, including complete trisomy 21, Robertsonian translocation trisomy 21, partial trisomy 21 (segmental duplication), and/or mosaic trisomy 21.
2. Available parent(s) or guardian(s) legally able to sign the consent form and who can complete study materials as appropriate.
3. Body weight is at least 10 kgs.

Exclusion Criteria:

1. Prior treatment with a JAK inhibitor or with an investigational agent, device, or procedure within 21 days of enrollment.
2. Current or planned use of a JAK inhibitor during the 6-month study period.
3. Known allergies, hypersensitivity, or intolerance to tofacitinib.
4. Active, uncontrolled, or life-threatening infection that at the determination of the treating physician would preclude safe use of tofacitinib.
5. History of gastrointestinal perforation.

6. Vaccination with live attenuated virus within six weeks of inclusion in the study or planned during the study.

   Note on vaccines: Participants not yet vaccinated for MMR-V should consider their timeline for MMR-V vaccination. Specifically, the study team recommends MMR-V vaccination as soon as possible and delay study start until 6 weeks after MMR-V vaccinations.

7. Concomitant treatment with any of the following:

   1. Concomitant treatment with other immunosuppressants (e.g., methotrexate, azathioprine, tacrolimus, cyclosporine).
   2. Strong CYP3A4 inhibitors (e.g., ketoconazole).
   3. Strong CYP3A4 Inducers (e.g., rifampin).
   4. Moderate CYP3A4 inhibitor(s) with a strong CYP2C19 inhibitor(s) (e.g., fluconazole).
   5. Other supplements or medications that at the determination of the treating physician would preclude safe use of tofacitinib.
8. Evidence of severe organ dysfunction, including severe renal impairment, that at the determination of the treating physician would preclude safe administration of tofacitinib.
9. Any history of leukemia, lymphoma, or unresolved transient myeloproliferative disorder.
10. Any current, recurrent, or metastatic forms of cancer.
11. Any cancer treatment within five years prior to study entry.
12. Known personal history of thrombosis or bleeding disorder.
13. History of tuberculosis, disseminated herpes zoster, disseminated herpes simplex, or recurrent localized herpes zoster.
14. Intravenous antimicrobial therapy within 3 months of inclusion in the study.
15. History of organ or bone marrow transplant.
16. History of myocardial infarction or stroke.
17. Evidence of lipid disorder, including but not limited to LDL > 190 mg/dL, per discretion of the treating physician.
18. Participant received blood or plasma products within 30 days of the Baseline visit.
19. Treatment with intravenous immunoglobulin (IVIG) within 8 weeks of the Baseline visit.
20. Hospitalization longer than 6 months in the last year.
21. History of neurological syndrome that in the opinion of the study doctors would inhibit successful participation in the study.
22. Less than 6 weeks post-surgery at Baseline appointment.
23. Total vision or hearing loss (with no corrective devices available).
24. Participant must be able to attempt the neurodevelopment assessment battery at Baseline and caregiver must be able to complete proxy reports for neurodevelopmental assessments.
25. Poor venous access not allowing repeated blood tests or non-compliance with venipuncture requirements.
26. Participants may be excluded for other unforeseen reasons at the study doctor's discretion.
27. Pregnancy or breastfeeding.
28. Use of estrogen-containing oral contraceptives.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm; Participants enrolled in the treatment arm will receive a 6-month treatment with the JAK1/3 inhibitor tofacitinib (XELJANZ) to define the safety and efficacy of this medicine relative to placebo.	Drug: Tofacitinib Oral Solution; JAK1/3 inhibitor; Other Names: XELJANZ
Placebo Comparator: Placebo arm; Participants in the placebo arm will complete the same study activities as the participants in the treatment arm. Placebo will be an oral solution to mimic the active product. At the end of 6 months of activities, unblinding will occur and if eligible, participants in the placebo arm may be offered to participate in the cross-over arm to undergo 6 months of treatment with tofacitinib in an open-label design.	Drug: Placebo; The placebo will be compounded by Children's Hospital of Colorado Investigational Drug Services using commercially available syrup with added flavoring to mimic the active product.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and percentage of subjects experiencing treatment-emergent adverse events.	Number, percentage, type, and severity of treatment-emergent adverse events (TEAEs) will be annotated over the 6-month period in the treatment arm and placebo arm.	From screening to 1 month after end of treatment
Change in Kaufman Brief Intelligence Test, 2nd Edition Revised (KBIT-2 Revised) - Verbal Intelligence	Raw scores for Verbal Intelligence	Baseline, 6 months
Change in Kaufman Brief Intelligence Test, 2nd Edition Revised (KBIT-2 Revised) - Nonverbal Intelligence	Raw scores for Nonverbal Intelligence	Baseline, 6 months
Change in Leiter 3 - Attention Sustained subtest	The raw score is the correct number of targets minus errors made across four trials.	Baseline, 6 months
Change in Vineland Adaptive Behavior Scales 3 (VABS-3) - Sum of Domain Raw Scores	The sum of raw scores will be calculated as the applicable domain-level raw scores.	Baseline, 6 months
Change in Clinical Global Impressions (CGI) Scale - Improvement in Health (CGI-I-H)	The CGI-I scale, which ranges from 1 to 7, with 1 being "very much improved" and 7 being "very much worse" to assess changes in global health during the 6-month intervention period. Noteworthy, we will also collect the CGI-S score (severity) at each time point (baseline, 3 months - midpoint visit, and 6 months - endpoint visit). The CGI-I will be collected at 3 months and 6 months.	Baseline, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Peabody Picture Vocabulary Test, Fifth Edition (PPVT-5)	The PPVT-5 is a standardized measure of receptive vocabulary skills. We will analyze change in of growth scale value scores (GSVs), allowing measurement of an individual's change in performance over time.	Baseline, 6 months
Change in Naturalistic Language Sample	This measure evaluates spontaneous expressive language narration. We will analyze total utterances and mean length of utterance.	Baseline, 6 months
Change in Achenbach Child (or Adult) Behavior Checklist	This is a caregiver-report measure of maladaptive behavior. This is a standardized questionnaire with available score norms by chronological age resulting in T-scores. We will analyze change in the internalizing and externalizing T-scores.	Baseline, 6 months
Change in Social Responsiveness Scale 2 (SRS-2), School Age and Adult	The SRS is a standardized proxy-report questionnaire for assessment of the presence and degree of autism symptomatology. We will analyze change in the social communication T-scores and the total T-scores.	Baseline, 6 months
Change in Modified Corsi Span test	This is a measure of working memory. Scores are summed based on total performance across all trials.	Baseline, 6 months
Change in Dimensional Change Card Sort test	This measure assesses cognitive flexibility. Total number of correct post-switch responses will be calculated across the last two trials.	Baseline, 6 months
Change in Beery Visual Motor Integration Scales (Beery VMI)	Screener for visual-motor deficits that can lead to learning, behavior and neuropsychological problems. We will analyze raw scores from this measure.	Baseline, 6 months
Change in Vineland Adaptive Behavior Scales 3 (VABS-3) Communication Total Raw Score	The VABS-3 Communication Total Raw Score (the sum of raw scores for Receptive, Expressive, and Written subdomains). The VABS-3 provides a measure of adaptive behavior developed for use with individuals with intellectual and developmental disabilities.	Baseline, 6 months
Change in Vineland Adaptive Behavior Scales 3 (VABS-3) Daily Living Skills Total Raw Score	The VABS-3 Daily Living Skills Total Raw Score (the sum of raw scores for Personal, Domestic, and Community subdomains). The VABS-3 provides a measure of adaptive behavior developed for use with individuals with intellectual and developmental disabilities.	Baseline, 6 months
Change in Vineland Adaptive Behavior Scales 3 (VABS-3) Socialization Total Raw Score	The VABS-3 Socialization Total Raw Score (the sum of raw scores for Interpersonal Relationships, Play and Leisure, and Coping Skills subdomains). The VABS-3 provides a measure of adaptive behavior developed for use with individuals with intellectual and developmental disabilities.	Baseline, 6 months
Change in Vineland Adaptive Behavior Scales 3 (VABS-3) Motor Skills Total Raw Score	The VABS-3 Motor Skills Total Raw Score (the sum of raw scores for Gross Motor and Fine Motor subdomains).	Baseline, 6 months
Change in Composite Neurodevelopmental Improvement Scores	A composite improvement score to aggregate information from multiple tests. This composite improvement score is calculated from scaled differences considering the directionality of improvement for each test (including both direct and indirect assessments). Scaled differences are first calculated for each individual measurement as standard deviations over the mean, and then the composite mean of all tests are calculated for each participant.	Baseline, 6 months
Change in Clinical Global Impression - Improvement in Neurodevelopment (CGI-I-ND)	CGI-I-ND is a scale focused on neurodevelopment. Clinicians rate improvement on a scale of 1 to 7, with 1 being "very much improved" and 7 being "very much worse".	Baseline, 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PedsQL	Summary Score, which is a mean score across multiple dimensions (e.g., social functioning, emotional functioning).	Baseline, 6 months

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: GLOBAL Down Syndrome Foundation; Anschutz Acceleration Initiative
• Investigators: Principal Investigator: Joaquin Espinosa, PhD, Linda Crnic Institute for Down Syndrome, CU Anschutz

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): August 1, 2030

Study Registration Dates

• First Submitted: May 13, 2026
• First Submitted That Met QC Criteria: May 13, 2026
• First Posted (Actual): May 20, 2026

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Down syndrome; Tofacitinib; JAK inhibition
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Congenital Abnormalities; Abnormalities, Multiple; Intellectual Disability; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Down Syndrome; tofacitinib
• Other Study ID Numbers: 24-0432

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified participant data will be made available for all primary outcome measures.
• IPD Sharing Time Frame: Data will be made available upon publication in a peer-reviewed journal.
• IPD Sharing Access Criteria: Data access requests will be reviewed by the sponsor-investigator and collaborators.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No