Randomized MMF Withdrawal in Systemic Lupus Erythematosus (SLE)

An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of Mycophenolate Mofetil (MMF) in Patients With Stable, Quiescent Systemic Lupus Erythematosus (SLE)

This trial seeks to describe the effect of withdrawal from mycophenolate mofetil (MMF) on risk of clinically significant disease reactivation in quiescent SLE patients who have been on long-term MMF therapy.

Participants who have had inactive disease for at least 24 weeks will be enrolled. Half the subjects will continue on MMF and half the subjects will be tapered off their MMF within 12 weeks. All subjects will continue hydroxychloroquine and small doses of prednisone as needed. Subject visits to assess endpoints will occur every 4 weeks from Day 0 through Week 24 and then at Weeks 32, 40, 48, and 60.

Inclusion Criteria:

1. Able and willing to give written informed consent and comply with requirements of the study;

2. Age 18 - 70 years, inclusive, at randomization;

3. Diagnosis of SLE, per the American College of Rheumatology (ACR) criteria;

4. m-SLEDAI score < 4 at screening visit (SLEDAI score without serologies);

5. Physician Global Assessment (0-3) score of 1 or less at screening visit;

6. On a stable dose of MMF (1000-3000 mg/day) for at least 12 weeks prior to randomization;

7. Total duration of stable or decreasing MMF therapy must be at least:

   • two years for subjects initiating MMF for renal indications (with or without concurrent extra-renal manifestations), or
   • one year for subjects initiating MMF for extra-renal indications.

8. If the subject is on prednisone or other corticosteroid, the following criteria must be met:

   • the dose may not exceed 10 mg/day (or its equivalent) for the 12 weeks prior to randomization; however, temporary (up to 4 total days) increases, not to exceed 20mg/day, are permitted;
   • the dose must be held stable for the four weeks prior to randomization (no temporary increases within 4 weeks of randomization are permitted).

9. If the subject has a history of B cell depleting therapy within the past 3 years, presence of CD19 positive cells must be documented within 12 weeks prior to screening;

10. On maintenance HCQ or chloroquine at a stable dose for at least 12 weeks prior to randomization.

Exclusion Criteria:

1. A history of life-threatening neuropsychiatric SLE within 1 calendar year prior to randomization;

2. Any of the following laboratory abnormalities at the screening visit:

   • Proteinuria as defined by a spot protein/creatinine ratio > 1.0 mg/mg;
   • Serum creatinine > 2.0 mg/dL;
   • Transaminases > 2.5x the upper limit of normal (ULN);
   • Hemoglobin < 9 g/dL, unless the subject has documented hemoglobinopathy;
   • White blood count (WBC) < 2000/mm^3 (equivalent to < 2 x10^9/L);
   • Neutrophils < 1000/mm^3 (equivalent to < 1 x10^9/L); or
   • Platelet count < 75,000/mm^3 (equivalent to < 75 x 10^9/L).

3. Prednisone > 25 mg/day (or its equivalent) within 24 weeks prior to randomization for lupus activity;

4. Concomitant immunosuppressants including but not limited to azathioprine, methotrexate, 6-mercaptopurine, leflunomide, calcineurin inhibitors, anti-tumor necrosis factor agents within 12 weeks prior to randomization;

5. Plasmapheresis or IV immunoglobulin within 12 weeks prior to randomization;

6. Cyclophosphamide therapy within 24 weeks prior to randomization;

7. Concomitant therapy with belimumab within 24 weeks prior to randomization;

8. B cell depleting therapy within two calendar years of randomization;

9. Experimental therapy within the 24 weeks, or five half-lives of the agent, whichever is longer, prior to randomization;

10. Solid organ or stem cell transplantation;

11. Identified definitive diagnosis of another autoimmune disease that may require immunosuppression for treatment, including but not limited to: rheumatoid arthritis, scleroderma, primary Sjogren's syndrome, primary vasculitis, psoriasis, multiple sclerosis, ankylosing spondylitis, and inflammatory bowel disease.

12. Chronic infections including, but not limited to, human immunodeficiency virus (HIV), active tuberculosis (TB), currently receiving therapy)), hepatitis B or hepatitis C, or latent systemic fungal infection;

13. At or within 12 weeks of screening:

    • a history of or current positive purified protein derivative (PPD) (> 5 mm induration regardless of prior Bacillus Calmette-Guérin (BCG) vaccine administration) or positive QuantiFERON unless documentation exists of completion of at least one month of prophylaxis for latent TB or completed treatment for active TB; or
    • an indeterminate QuantiFERON® unless followed by a subsequent negative PPD or negative QuantiFERON.

14. History of malignancy within the last five years, except for resected basal or squamous cell carcinoma, treated cervical dysplasia, or treated in situ cervical cancer Grade I;

15. Pregnant or lactating, or intention to pursue pregnancy within three months after the completion of the study;

16. Unable or unwilling to use reliable methods of contraception, as outlined in the Mycophenolate REMS (e.g., Risk Evaluation and Mitigation Strategy), from four weeks prior to randomization to 6 weeks after completion of the study. This criterion applies to females of reproductive potential. (Reference: Mycophenolate REMS, Program Resources and Educational Materials, Information for Patients, What are my birth control options? Access the link at: (https://www.mycophenolaterems.com/PatientOverview.aspx).

17. Drug or alcohol abuse within one calendar year of randomization;

18. Other medical or psychiatric conditions that the investigator feels would place the subject at special risk by participation in this protocol.