Clinical trial NCT01946880: Randomized MMF Withdrawal in Systemic Lupus Erythematosus (SLE)
Official title: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of Mycophenolate Mofetil (MMF) in Patients With Stable, Quiescent Systemic Lupus Erythematosus (SLE)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
SLE
Keywords: Systemic Lupus Erythematosus
Mycophenolate Mofetil (MMF)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Autoimmunity Centers of Excellence
name: Rho Federal Systems Division, Inc.
First posted: 2013-09-20
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants Experiencing Clinically Significant Disease Reactivation by Week 60
timeFrame: Baseline (Treatment Randomization) to Week 60
Secondary outcomes:
measure: Time to Clinically Significant Disease Reactivation
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Participants Experiencing a Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare by Week 60
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Participants Experiencing a 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Participants Experiencing a 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Participants Experiencing 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Participants Experiencing 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
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Time to First Mild/Moderate or Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Time to First Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Participants Experiencing Any British Isles Lupus Assessment Group (BILAG) A Flare by Week 60
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Participants in the Lupus Nephritis Subgroup Experiencing a British Isles Lupus Assessment Group (BILAG) A Renal Flare by Week 60
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Change From Baseline in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Disease Damage Index for Systemic Lupus Erythematosus (SLICC/DI): Total Score
timeFrame: Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60
measure: The Addition of Aggressive Adjunctive Therapy to Mycophenolate Mofetil (MMF) or Change in MMF Therapy to Cytotoxic Drug Due to Flare by Week 60
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Cumulative Systemic Steroid Dose by Week 60
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Change From Baseline in the Functional Assessment of Chronic Illness Therapy (FACIT-F) Fatigue Scale (FS): Total Score
timeFrame: Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60
measure: Change From Baseline in the Short Form Health Survey (SF-36) Physical Functioning (PF) Score
timeFrame: Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60
measure: Change From Baseline in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) Score
timeFrame: Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60
measure: Change From Baseline in the Lupus Quality of Life (QoL)Score
timeFrame: Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60
measure: Time From Clinically Significant Disease Reactivation to Improvement in British Isles Lupus Assessment Group (BILAG) From Maximum Level During Flare
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Time From Clinically Significant Disease Reactivation to Recovery to Baseline British Isles Lupus Assessment Group (BILAG) Score or BILAG C
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Cumulative Excess Systemic Steroid Dose From Time of Clinically Significant Disease Reactivation to Return to Pre-Flare Dose or End of Trial Participation
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Time From Clinically Significant Disease Reactivation to Return to Pre-Flare Steroid Dose
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Grade 3, 4, or 5 Adverse Events (AEs) Related to Systemic Lupus Erythematosus (SLE)
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Grade 3, 4, or 5 Adverse Events (AEs) Related to Mycophenolate Mofetil (MMF)
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Grade 3, 4, or 5 Adverse Events (AEs)
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Serious Adverse Events (SAEs).
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Infection-Related Adverse Events (AEs)
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Malignancies Reported as Adverse Events (AEs).
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Number of Grade 3, 4, or 5 Hematological Adverse Events (AEs).
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: Mortality Related to Systemic Lupus Erythematosus (SLE)
timeFrame: Baseline (Treatment Randomization) to Week 60
measure: All-Cause Mortality
timeFrame: Baseline (Treatment Randomization) to Week 60
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: San Diego
country: United States
facility: UCSD
state: California
city: San Francisco
country: United States
facility: UCSF School of Medicine
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Miami
country: United States
facility: University of Miami Hospitals and Clinics
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Manhasset
country: United States
facility: Feinstein Institute for Medical Research
state: New York
city: New York
country: United States
facility: New York University, Langone Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College: Hospital for Special Surgery - Rheumatology Division
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Medical Research Foundation
state: Oklahoma
city: Hershey
country: United States
facility: Penn State University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
affiliation: Oklahoma Medical Research Foundation
name: Eliza Chakravarty, MD
role: STUDY_CHAIR
affiliation: Oklahoma Medical Research Foundation
name: Judith A. James, MD, PhD
role: STUDY_CHAIR
References:
citation: Wenderfer SE, Eldin KW. Lupus Nephritis. Pediatr Clin North Am. 2019 Feb;66(1):87-99. doi: 10.1016/j.pcl.2018.08.007.