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

Modulation of the Immune System in Down Syndrome for Improved Outcomes and Neurodevelopment - 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 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).

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 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 6.0).

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.

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 significantly abnormal laboratory values or 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.