Examining Distinct Immunophenotypes to Validate and Enhance Rational Treatment in Systemic Lupus

• Status: Not yet recruiting
• Trial end date: 2026-04-18
• Target enrollment: 0
• Participant gender: All

Summary

The primary purpose of this study is to evaluate the potential effectiveness of 24 weeks of MMF within previously discovered immunologically defined subsets of SLE patients. Treatment effects will be evaluated within the individual immunologically-homogenous subsets defined at screening. This study will also explore and compare pre-randomization gene expression patterns among responders and non-responders to MMF and MMF plus voclosporin, use comprehensive immunophenotyping to study the immunologic changes that accompany treatment- induced disease improvement and to better understand immunologic changes associated with the loss of clinical response.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Cyclosporine; Mycophenolic Acid

Criteria

Inclusion Criteria:

1. Meets European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2019 criteria for Systemic Lupus Erythematosus (SLE)

2. Moderately severe, active, but non-organ threatening disease. Specifically, signs or symptoms meeting criteria for a minimum of 2 British Isles Lupus Assessment Group B (BILAG B moderate) activity scores in any organ systems or 1 BILAG A (severe) score in the constitutional, musculoskeletal or mucocutaneous system at the time of screening

3. Approval, by an adjudication committee of a brief entry packet describing the type, severity and duration of symptoms meeting the minimal criteria for entry. The participant will meet this criterion if the committee is confident of all of the following:

1. Convincing diagnosis of SLE

2. Active disease, due to SLE, warranting the potential of dual therapy with potent immune modulators

3. No medical or other condition to contraindicate participation in a placebo-controlled, outpatient study of this design

4. Women of childbearing potential must have a negative serum pregnancy test at screening

5. Completion of primary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination series according to current Food and Drug Administration (FDA) Approval or Emergency Use Authorization (EUA) at least 14 days prior to the initiation of screening

6. Able or willing to use reliable methods of contraception, as outlined in the Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) brochure for health care providers, from 4 weeks prior to first randomization to 6 weeks after completion of the study. This criterion applies to females of reproductive potential

Participants who meet the following criterion at the Stage 2 Randomization Visit may proceed to randomization in Stage 2:

7. After methylprednisolone acetate shots and prior to randomization in Stage 2, the participant and his/her physician must agree that disease activity has improved sufficiently from screening such that randomization is acceptable.

a. The physician must score the Clinician's Global Impression of Change C (CGI-C) as "moderately better" or "much better" prior to randomization

i. The reference value for the CGI-C should be the investigator's determination of the participant's condition at the Screening Visit

b. The participant must agree that his/her symptoms have improved (yes/no)

Exclusion Criteria:

1. Inability or unwillingness of a participant to understand and provide written informed consent or comply with the study protocol

2. British Isles Lupus Assessment Group A (BILAG A severe) disease in the Cardiorespiratory, Neuropsychiatric, Gastrointestinal, Ophthalmic, Renal, or Haematological Systems

3. Severe or unstable nephritis defined as any of the following:

1. History of confirmed Class 3-5 nephritis within the last 2 years

2. History of confirmed Class 3-5 nephritis > 2 years ago in the absence of documented treatment including both induction and maintenance therapy

3. Urine protein: creatinine ratio (UPCR) > 1 g/g at screening

4. Evidence of chronic kidney disease defined as estimated glomerular filtration rate (eGFR) < 45 mL/min per 1.73 m2 at screening

5. History of cirrhosis or chronic liver disease unrelated to Systemic Lupus Erythematosus (SLE) other than fatty liver disease

6. History, within 1 year of the Screening Visit, of uncontrolled SLE that would have warranted a BILAG A (except mucocutaneous, constitutional, musculoskeletal) including, but not limited to, hemolytic anemia, neuropsychiatric lupus, or interstitial lung disease

7. Uncontrolled hypertension (HTN) at the Screening or Randomization Visits defined as a blood pressure > 150/100 with or without treatment, not to exceed 3 complementary antihypertensive treatments

8. Any of the following laboratory values during screening:

1. Hemoglobulin (Hg) < 8.0 g/dL

2. White blood cell count (WBC) < 2.0 x 10^9 cells/L

3. Absolute neutrophil count (ANC) < 1.0 x 10^9 cells/L

4. Platelets < 60 x 10^9 cells/L at screening

5. Aspartate Aminotransferase (AST) or Alanine Aminotransferase ALT > 2.5 times the upper limit of normal (ULN)

6. Serum IgG levels < 5 g/L

9. Use of => 40 mg/day of prednisone within 4 weeks prior to the Screening Visit or use of > 20 mg/day of prednisone at screening

10. Unwilling or unable to taper to <= 10 mg/day of prednisone or equivalent by the day of randomization

11. Use of hydroxychloroquine, chloroquine, or quinacrine, if taking, at a prescribed dose that has not been stable for at least 2 months prior to randomization

12. Use of Mycophenolate Mofetil (MMF) within 1 year of randomization

13. Use of MMF 1-3 years prior if it was ineffective at controlling general lupus symptoms

14. Use of calcineurin inhibitors within 1 year of randomization

15. Use of rituximab, obinutuzumab, ocrelizumab, or long-acting cellular depletion agents within 1 year of randomization

16. History of intolerance or allergy to MMF, voclosporin, or methylprednisolone acetate

17. Individuals with known hypersensitivity to Polysorbate 80 (Tween)

18. A woman who is pregnant, breastfeeding, or planning pregnancy from the time of consent until 6 weeks after completion of the study

19. Any participant with plans for major surgery during the time of the trial

20. Active infections requiring hospitalization or intravenous antibiotics within 1 month prior to the Screening Visit

21. Any grade 2 infection within 2 weeks of the Screening Visit

22. Acute herpes zoster within 4 months of the Screening Visit

23. Positive results from a SARS-CoV-2 molecular test administered within 7 days prior to randomization

24. Positive Quantiferon Gold (or equivalent) assay. Indeterminate Quantiferon Gold(or equivalent) assays must be repeated (with same or other interferon gamma release assay per local policy) and shown to be negative. Alternatively, if the Quantiferon Gold (or equivalent) assay remains indeterminate, a participant must have a negative purified protein derivative (PPD). Finally, if the participant has had the Bacille Calmette-Guerin (BCG) vaccine or has some other condition complicating the interpretation of TB testing, consultation with infection disease specialist must be obtained

25. Serologic evidence at screening of chronic infections including:

1. Human immunodeficiency virus (HIV) infection

2. Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity; if a participant has an isolated positive hepatitis B core antibody, they will be eligible to participate in the study if they are negative for reflex viral load at Screening

3. Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody positive, they will be eligible to participate in the study if they are negative for viral load at Screening

26. Current, diagnosed, or self-reported drug or alcohol abuse within the last 6 months that, in the opinion of the investigator, would interfere with the ability to comply with study protocol

27. Recipient of live attenuated vaccine(s) within 8 weeks of the Screening Visit

28. Use of investigational drugs (excluding SARS-CoV-2 vaccinations or SARS-CoV2 therapeutics) within 8 weeks of the Screening Visit or 5 half-lives, whichever is longer

29. Past or current mental or physical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or may impact the quality or interpretation of the data obtained from the study