Randomized MMF Withdrawal in Systemic Lupus Erythematosus (SLE)

NCT ID: NCT01946880

Last Updated: 2020-08-17

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 102 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-20
• Study Completion Date: 2019-07-03

Brief Summary

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.

Detailed Description

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.

Conditions

Systemic Lupus Erythematosus; SLE

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Mycophenolate Mofetil Withdrawal

These subjects will taper off MMF per the protocol-specified schedule over 12 weeks and remain off MMF for the rest of their study participation (up to Week 60 or until the primary endpoint of disease reactivation is met, whichever comes first).

Group Type: EXPERIMENTAL

Mycophenolate Mofetil

Intervention Type: DRUG

Subjects will enter the trial on 1000-3000 mg/day of MMF and will be randomized to remain on MMF treatment or to be tapered off MMF within 12 weeks.

Hydroxychloroquine or Chloroquine

Intervention Type: DRUG

Subjects will be on concurrent anti-malarial agents (hydroxychloroquine or chloroquine). Hydroxychloroquine is approved by the FDA for the treatment of SLE. Hydroxychloroquine has been shown to help prevent flare in SLE, and to improve skin and musculoskeletal activity in particular.Even lupus nephritis outcomes appear improved on a background of hydroxychloroquine therapy

Prednisone

Intervention Type: DRUG

Once the subject is randomized into the trial, the prednisone (or other corticosteroid) dose must be stable through Week 36 (24 weeks following protocol taper of MMF), in the absence of flares as described in Section 3.2 of the study protocol, Description of Primary Endpoint. Further taper of prednisone after that point is by the investigator's discretion based on the subject's clinical status.

Mycophenolate Mofetil Maintenance

These subjects will continue MMF treatment (1000-3000 mg/day) for the rest of their study participation (up to Week 60).

Group Type: ACTIVE_COMPARATOR

Mycophenolate Mofetil

Intervention Type: DRUG

Subjects will enter the trial on 1000-3000 mg/day of MMF and will be randomized to remain on MMF treatment or to be tapered off MMF within 12 weeks.

Hydroxychloroquine or Chloroquine

Intervention Type: DRUG

Subjects will be on concurrent anti-malarial agents (hydroxychloroquine or chloroquine). Hydroxychloroquine is approved by the FDA for the treatment of SLE. Hydroxychloroquine has been shown to help prevent flare in SLE, and to improve skin and musculoskeletal activity in particular.Even lupus nephritis outcomes appear improved on a background of hydroxychloroquine therapy

Prednisone

Intervention Type: DRUG

Once the subject is randomized into the trial, the prednisone (or other corticosteroid) dose must be stable through Week 36 (24 weeks following protocol taper of MMF), in the absence of flares as described in Section 3.2 of the study protocol, Description of Primary Endpoint. Further taper of prednisone after that point is by the investigator's discretion based on the subject's clinical status.

Interventions

Mycophenolate Mofetil

Subjects will enter the trial on 1000-3000 mg/day of MMF and will be randomized to remain on MMF treatment or to be tapered off MMF within 12 weeks.

Intervention Type: DRUG

Hydroxychloroquine or Chloroquine

Subjects will be on concurrent anti-malarial agents (hydroxychloroquine or chloroquine). Hydroxychloroquine is approved by the FDA for the treatment of SLE. Hydroxychloroquine has been shown to help prevent flare in SLE, and to improve skin and musculoskeletal activity in particular.Even lupus nephritis outcomes appear improved on a background of hydroxychloroquine therapy

Intervention Type: DRUG

Prednisone

Once the subject is randomized into the trial, the prednisone (or other corticosteroid) dose must be stable through Week 36 (24 weeks following protocol taper of MMF), in the absence of flares as described in Section 3.2 of the study protocol, Description of Primary Endpoint. Further taper of prednisone after that point is by the investigator's discretion based on the subject's clinical status.

Intervention Type: DRUG

Other Intervention Names

MMF; Plaquenil®; Chloroquine Phosphate®; corticosteroid

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Autoimmunity Centers of Excellence

OTHER

Sponsor Role: collaborator

Rho Federal Systems Division, Inc.

INDUSTRY

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eliza Chakravarty, MD

Role: STUDY_CHAIR

Oklahoma Medical Research Foundation

Judith A. James, MD, PhD

Role: STUDY_CHAIR

Oklahoma Medical Research Foundation

Locations

Cedars-Sinai Medical Center

Los Angeles, California, United States

UCSD

San Diego, California, United States

UCSF School of Medicine

San Francisco, California, United States

University of Colorado

Denver, Colorado, United States

University of Miami Hospitals and Clinics

Miami, Florida, United States

Emory University

Atlanta, Georgia, United States

University of Chicago

Chicago, Illinois, United States

Brigham & Women's Hospital

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

Feinstein Institute for Medical Research

Manhasset, New York, United States

New York University, Langone Medical Center

New York, New York, United States

Weill Cornell Medical College: Hospital for Special Surgery - Rheumatology Division

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Oklahoma Medical Research Foundation

Oklahoma City, Oklahoma, United States

Penn State University

Hershey, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Countries

United States

References

Chakravarty EF, Utset T, Kamen DL, Contreras G, McCune WJ, Aranow C, Kalunian K, Massarotti E, Clowse MEB, Rovin BH, Lim SS, Majithia V, Dall'Era M, Looney RJ, Erkan D, Saxena A, Olsen NJ, Ko K, Guthridge JM, Goldmuntz E, Springer J, D'Aveta C, Keyes-Elstein L, Barry B, Pinckney A, McNamara J, James JA. Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial. Lancet Rheumatol. 2024 Mar;6(3):e168-e177. doi: 10.1016/S2665-9913(23)00320-X. Epub 2024 Jan 29.

Reference Type: DERIVED

PMID: 38301682 (View on PubMed)

Wenderfer SE, Eldin KW. Lupus Nephritis. Pediatr Clin North Am. 2019 Feb;66(1):87-99. doi: 10.1016/j.pcl.2018.08.007.

Reference Type: DERIVED

PMID: 30454753 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Related Links

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID) website

https://www.niaid.nih.gov/about/dait

Division of Allergy, Immunology, and Transplantation (DAIT) website

Other Identifiers

NIAID CRMS ID#: 20154

Identifier Type: OTHER

Identifier Source: secondary_id

DAIT ALE06

Identifier Type: -

Identifier Source: org_study_id