A randomized, parallel-group, open-label, Phase IIb pilot trial to evaluate the effectiveness in reducing systemic disease activity with methotrexate compared with hydroxychloroquine in adult male and female participants with moderate-to-severe primary Sjögren’s disease (MOSAIC STUDY)

Prior treatment

• Have received live attenuated vaccines within 4 weeks prior to screening or are expected to receive them during the study
• Have participated in another interventional clinical trial within 30 days prior to screening
• Are receiving prohibited immunosuppressive or biologic therapies or have received high-dose corticosteroids (≥ 15 mg/day prednisone equivalent) within 6 weeks prior to randomization

Other illness

• Have a diagnosis of other systemic autoimmune diseases that may interfere with the assessment of primary Sjögren’s disease
• Clinically significant pre-existing interstitial lung disease (ILD) or active pulmonary fibrosis of any etiology, including Sjögren-associated ILD requiring ongoing immunosuppressive or antifibrotic therapy, as determined by clinical history, chest imaging, or pulmonary function testing.
• History of methotrexate-induced pneumonitis or other drug-induced hypersensitivity pneumonitis attributed to methotrexate.
• Hepatitis B virus (HBV) infection, defined as a positive Hepatitis B surface antigen (HBsAg) result. Participants who are HBsAg-negative but Hepatitis B core antibody (HBcAb)-positive are eligible only if HBV DNA by quantitative PCR is undetectable at screening, subject to HBV DNA monitoring every 12 weeks during the treatment period.
• Have any condition that, in the opinion of the Investigator, would compromise participant safety or interfere with study assessments
• Have a history of lymphoproliferative disease or active malignancy (with the exception of adequately treated non-invasive malignancies).
• Have clinically significant cardiovascular, pulmonary, renal, or neurological disease that may interfere with study participation or outcome assessment.
• Have active or severe infection, including chronic or recurrent infections, or positive screening for HIV, hepatitis B or C, or tuberculosis.
• Have known hypersensitivity or contraindications to methotrexate or hydroxychloroquine

Lab values

• Active hepatitis C virus (HCV) infection, defined as a positive HCV antibody result with detectable HCV RNA by quantitative PCR. Participants with a documented Sustained Virological Response (SVR) following antiviral treatment, or spontaneous viral clearance, confirmed by undetectable HCV RNA at screening, are eligible
• Have clinically significant laboratory abnormalities at screening (including but not limited to liver dysfunction, cytopenias, or impaired renal function).

Age

• Presence or history of clinically significant maculopathy, retinopathy of any etiology (e.g., age-related macular degeneration, diabetic retinopathy, hereditary retinal dystrophies), or other clinically significant retinal disorder that could either confound the assessment of hydroxychloroquine-associated ocular toxicity or increase the participant’s baseline risk of visual impairment, as determined at the baseline ophthalmological examination described in Section 8.4.7.

Other

• Are pregnant or breastfeeding, or planning pregnancy during the study period

• Age ≥ 18 and < 75 years of age at the time of signing the informed consent form (ICF)
• Have a diagnosis of primary Sjögren’s disease and fulfill the 2016 ACR/EULAR Classification Criteria at the time of screening. Note: Classification may be confirmed using both historical documentation and assessments performed during the Screening Period.
• Have moderate to severe systemic disease activity as defined by an ESSDAI score ≥ 5 at screening
  • Are seropositive for anti-SSA/Ro antibodies at screening or documented in previous medical records.
  • Have evidence of residual salivary gland function, defined as stimulated whole salivary flow > 0.1 mL/min
  • If receiving treatment for primary Sjögren’s disease, are on a stable therapeutic regimen prior to screening and are expected to remain on a stable dose during the study, unless modification is required for safety reasons.
  • Are able and willing to provide written informed consent and comply with study procedures
  • Female participants of childbearing potential agree to use highly effective contraception during the study and for an appropriate period after the last dose of study treatment