Randomized MMF Withdrawal in Systemic Lupus Erythematosus (SLE)

NCT01946880 | Terminated Phase 2 Results DMC

• 2 other identifiers: DAIT ALE06NIAID CRMS ID#: 20154
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 19

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.

Conditions

Systemic Lupus Erythematosus; SLE

Keywords

Systemic Lupus Erythematosus; Mycophenolate Mofetil (MMF)

Outcome Measures

Primary Outcomes (1)

• Number of Participants Experiencing Clinically Significant Disease Reactivation by Week 60

  Disease reactivation requires:1) SELENA-SLEDAI mild/moderate or severe flare,and 2) Increased immunosuppressive therapy on a sustained basis,defined by one of the following criteria:a) Sustained activity:Significant prolonged SLE flare requiring steroid increase/burst to ≥15 mg/day prednisone (or equivalent) for \>4 weeks.b) Frequent relapsing/remitting:Participant flares requiring an increase/burst of steroids and is successfully tapered to \<15 mg/day within 4 weeks, but this occurs on \>2 occasions, or IA, IM or IV steroids on more than1 occasion.c)Clinical activity of sufficient severity to warrant resumption of/increased dose of MMF or addition of other major immunosuppressive including AZA or MTX.Regardless of steroid use, if the investigator observes disease activity of sufficient severity to warrant resumption, addition or increase in dosage of major immunosuppressant in the setting of a SELENA-SLEDAI flare, participant has met the primary endpoint.Risk difference also included

  Baseline (Treatment Randomization) to Week 60

Secondary Outcomes (35)

• Time to Clinically Significant Disease Reactivation

  Baseline (Treatment Randomization) to Week 60

• Number of Participants Experiencing a Mild/Moderate or Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare by Week 60

  Baseline (Treatment Randomization) to Week 60

• Number of Participants Experiencing a Mild/Moderate or Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare by Week 60 Within the Lupus Nephritis Subgroup

  Baseline (Treatment Randomization) to Week 60

• Number of Participants Experiencing a Mild/Moderate or Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare by Week 60 Within the Non-Lupus Nephritis Subgroup

  Baseline (Treatment Randomization) to Week 60

• Number of Participants Experiencing a Mild/Moderate or Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare by Week 60 in the Baseline MMF<2000 mg/Day Subgroup

  Baseline (Treatment Randomization) to Week 60

Study Arms (2)

Mycophenolate Mofetil Withdrawal

EXPERIMENTAL

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).

Drug: Mycophenolate Mofetil; Drug: Hydroxychloroquine or Chloroquine; Drug: Prednisone

Mycophenolate Mofetil Maintenance

ACTIVE COMPARATOR

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

Drug: Mycophenolate Mofetil; Drug: Hydroxychloroquine or Chloroquine; Drug: Prednisone

Interventions

Mycophenolate Mofetil 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.

Also known as: MMF

Mycophenolate Mofetil Maintenance; Mycophenolate Mofetil Withdrawal

Hydroxychloroquine or Chloroquine 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

Also known as: Plaquenil®, Chloroquine Phosphate®

Mycophenolate Mofetil Maintenance; Mycophenolate Mofetil Withdrawal

Prednisone 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.

Also known as: corticosteroid

Mycophenolate Mofetil Maintenance; Mycophenolate Mofetil Withdrawal

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able and willing to give written informed consent and comply with requirements of the study;
• Age 18 - 70 years, inclusive, at randomization;
• Diagnosis of SLE, per the American College of Rheumatology (ACR) criteria;
• m-SLEDAI score \< 4 at screening visit (SLEDAI score without serologies);
• Physician Global Assessment (0-3) score of 1 or less at screening visit;
• On a stable dose of MMF (1000-3000 mg/day) for at least 12 weeks prior to randomization;
• 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.
• 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).
• 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;
• On maintenance HCQ or chloroquine at a stable dose for at least 12 weeks prior to randomization.

You may not qualify if:

• A history of life-threatening neuropsychiatric SLE within 1 calendar year prior to randomization;
• 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).
• Prednisone \> 25 mg/day (or its equivalent) within 24 weeks prior to randomization for lupus activity;
• 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;
• Plasmapheresis or IV immunoglobulin within 12 weeks prior to randomization;
• Cyclophosphamide therapy within 24 weeks prior to randomization;
• Concomitant therapy with belimumab within 24 weeks prior to randomization;
• B cell depleting therapy within two calendar years of randomization;

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Autoimmunity Centers of Excellence: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (19)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

UCSD

San Diego, California, 92093-0943, United States

Location

UCSF School of Medicine

San Francisco, California, 94143-0633, United States

Location

University of Colorado

Denver, Colorado, 80204, United States

Location

University of Miami Hospitals and Clinics

Miami, Florida, 33136, United States

Location

Emory University

Atlanta, Georgia, 30303, United States

Location

University of Chicago

Chicago, Illinois, 60637-1426, United States

Location

Brigham & Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

Feinstein Institute for Medical Research

Manhasset, New York, 11025, United States

Location

New York University, Langone Medical Center

New York, New York, 10016, United States

Location

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

New York, New York, 10021, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Oklahoma Medical Research Foundation

Oklahoma City, Oklahoma, 73104, United States

Location

Penn State University

Hershey, Pennsylvania, 17033, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29412, United States

Location

Related Publications (2)

• 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.

  PMID: 38301682 DERIVED

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

  PMID: 30454753 DERIVED

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Division of Allergy, Immunology, and Transplantation (DAIT) website

MeSH Terms

Conditions

Lupus Erythematosus, Systemic

Interventions

Mycophenolic Acid; Hydroxychloroquine; Chloroquine; chloroquine diphosphate; Prednisone; Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Limitations and Caveats

Enrollment ended early with 102 participants randomized instead of the planned 120.

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Eliza Chakravarty, MD

  Oklahoma Medical Research Foundation

  STUDY CHAIR

• Judith A. James, MD, PhD

  Oklahoma Medical Research Foundation

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2013
• First Posted: September 20, 2013
• Study Start: November 20, 2013
• Primary Completion: July 3, 2019
• Study Completion: July 3, 2019
• Last Updated: August 17, 2020
• Results First Posted: August 17, 2020

Record last verified: 2020-08

Locations

US (19)