Ivarmacitinib Versus Glucocorticoids in Mild-to-Moderate Systemic Lupus Erythematosus

Safety and Efficacy of Ivarmacitinib Versus Glucocorticoids in Patients With Mild-to-Moderate Systemic Lupus Erythematosus: A Randomized, Double-Blind, Noninferiority Clinical Trial

This randomized, double-blind, parallel-group, noninferiority clinical trial will evaluate the efficacy and safety of ivarmacitinib compared with oral prednisone in participants with mild-to-moderate active systemic lupus erythematosus (SLE) without active major organ involvement. Approximately 294 participants will be randomized in a 1:1 ratio to receive either ivarmacitinib 8 mg once daily or oral prednisone starting at 30 mg/day with a prespecified tapering schedule, together with the corresponding matching placebo, for 24 weeks. The study will assess whether ivarmacitinib is noninferior to oral prednisone in achieving the primary efficacy outcome. The primary outcome is the proportion of participants achieving remission of arthritis and/or rash, as defined by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), at Week 12. Safety and secondary efficacy outcomes will be evaluated throughout the 24-week treatment period.

Inclusion Criteria:

1. Aged ≥18 years.
2. Fulfill the 2012 SLICC classification criteria or the 2019 EULAR/ACR classification criteria for SLE.
3. Have a clinical SLEDAI-2K score ≥4 and a total SLEDAI-2K score ≤12.
4. Have active musculoskeletal and/or mucocutaneous manifestations at screening, as assessed by the SLEDAI-2K.
5. Be receiving a stable dose for at least 4 weeks before screening of oral glucocorticoids (prednisone ≤10 mg/day or equivalent), and/or an antimalarial agent, and/or one immunosuppressive agent.

Exclusion Criteria:

1. Active lupus nephritis at screening, defined as 24-hour urinary protein >1 g. The 24-hour urinary protein test may be repeated once within 2 weeks; participants may be enrolled if the repeat result meets the eligibility criterion.

2. Active neuropsychiatric SLE (NPSLE) at screening, defined as new-onset seizure, psychosis, organic brain syndrome, visual disturbance, cranial neuropathy, lupus headache, or new-onset cerebrovascular accident.

3. Active hematologic involvement at screening, defined as any of the following: white blood cell count <3 × 10^9/L, platelet count <100 × 10^9/L, or hemolytic anemia.

4. Active gastrointestinal involvement at screening, defined as SLE-related acute pancreatitis or intestinal pseudo-obstruction.

5. Active cardiovascular or respiratory involvement at screening, defined as active diffuse alveolar hemorrhage, interstitial pulmonary fibrosis, pulmonary arterial hypertension, myocardial involvement, or valvular heart disease.

6. Active fibromyalgia at screening that, in the investigator's judgment, may interfere with assessment of SLE disease activity.

7. Treatment for or presence of an active systemic inflammatory disease other than SLE within 12 weeks before screening, including rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, or psoriatic arthritis. Participants with secondary Sjögren's syndrome are not excluded.

8. Major surgery within 8 weeks before screening or anticipated need for major surgery during the study.

9. Any of the following within 12 weeks before screening: venous thromboembolism (deep vein thrombosis or pulmonary embolism), myocardial infarction, unstable ischemic heart disease, or stroke; or current New York Heart Association (NYHA) class III or IV heart failure.

10. History of recurrent venous thromboembolism, defined as ≥2 episodes of deep vein thrombosis and/or pulmonary embolism.

11. History or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematologic, neurologic, or neuropsychiatric disease, or any other serious and/or unstable medical condition that, in the investigator's judgment, may pose an unacceptable risk associated with administration of the investigational product or interfere with interpretation of study data.

12. History of a lymphoproliferative disorder; active primary or recurrent malignancy; or malignancy in remission for <5 years before randomization. The following exceptions are permitted:

    1. Cervical carcinoma in situ that has been surgically resected, with no evidence of recurrence or metastatic disease for at least 3 years.
    2. Basal cell or squamous cell carcinoma of the skin that has been completely excised, with no evidence of recurrence for at least 3 years.

13. Clinically significant viral, bacterial, fungal, or parasitic infection within 4 weeks before randomization.

14. Symptomatic herpes simplex infection at the time of randomization.

15. Symptomatic herpes zoster infection within 12 weeks before randomization.

16. History of disseminated or complicated herpes zoster infection, including ophthalmic herpes zoster or central nervous system involvement.

17. Positive hepatitis B surface antigen (HBsAg), positive hepatitis C virus antibody, positive syphilis antibody, or human immunodeficiency virus (HIV) infection.

18. Active tuberculosis.

19. Receipt of any of the following treatments:

    1. Intravenous, intramuscular, or intra-articular glucocorticoids within 6 weeks before screening;
    2. Biologic therapies for immune-mediated diseases within the protocol-specified washout period before screening, including belimumab within 12 weeks, telitacicept within 12 weeks, and rituximab within 24 weeks;
    3. Cyclophosphamide (or any other cytotoxic agent) within 12 weeks before screening;
    4. Any cellular therapy within 24 weeks before screening.

20. Any prior treatment with a Janus kinase (JAK) inhibitor or tyrosine kinase 2 (TYK2) inhibitor.

21. Plasma exchange within 12 weeks before screening.

22. Receipt of a live vaccine within 12 weeks before randomization or anticipated need for a live vaccine during the study.

23. Pregnant or breastfeeding women.

24. Currently participating in, or having discontinued within 4 weeks before screening, any medical study involving an investigational product, a drug or device used for an unapproved indication, or any other medical research considered scientifically or medically incompatible with this study.

25. Unable to perform activities of daily living independently, for example, being bedridden.

26. Any other reason that, in the investigator's judgment, makes the participant unsuitable for participation in the clinical trial.