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Trial record 1 of 1 for:    ALE06
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Randomized MMF Withdrawal in Systemic Lupus Erythematosus (SLE) (ALE06)

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ClinicalTrials.gov Identifier: NCT01946880
Recruitment Status : Terminated (Slow enrollment.)
First Posted : September 20, 2013
Last Update Posted : July 25, 2019
Sponsor:
Collaborator:
Autoimmunity Centers of Excellence
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease Intervention/treatment Phase
Systemic Lupus Erythematosus SLE Drug: Mycophenolate Mofetil Drug: Hydroxychloroquine or Chloroquine Drug: Prednisone Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of Mycophenolate Mofetil (MMF) in Patients With Stable, Quiescent Systemic Lupus Erythematosus (SLE)
Actual Study Start Date : November 20, 2013
Actual Primary Completion Date : July 3, 2019
Actual Study Completion Date : July 3, 2019


Arm Intervention/treatment
Experimental: 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).
Drug: 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.
Other Name: MMF

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

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.

Active Comparator: Mycophenolate Mofetil Maintenance
These subjects will continue MMF treatment (1000-3000 mg/day) for the rest of their study participation (up to Week 60).
Drug: 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.
Other Name: MMF

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

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.




Primary Outcome Measures :
  1. The probability of experiencing clinically significant disease reactivation in each arm [ Time Frame: Week 60 ]

    Clinically significant SLE reactivation requires both:

    1. A SELENA-SLEDAI-defined mild/moderate or severe flare and
    2. Increased immunosuppressive therapy on a sustained basis


Secondary Outcome Measures :
  1. Time to clinically significant disease reactivation [ Time Frame: Up to week 60 ]
  2. probability of experiencing any SELENA-SLEDAI flare and the probability of experiencing any severe SELENA-SLEDAI flare [ Time Frame: Week 60 ]
    Defined by disease manifestation (renal disease / extra-renal disease) and by baseline MMF dosing group (≤ 2000 mg per day / > 2000 mg per day).

  3. Time from initiation of withdrawal to first SELENA-SLEDAI flare and time to first severe SELENA-SLEDAI flare [ Time Frame: Up to Week 60 ]
  4. The probability of experiencing any BILAG A flare [ Time Frame: Week 60 ]
  5. Proportion of subjects in the renal subgroup with BILAG Renal A flare [ Time Frame: Week 60 ]
  6. Change in SLICC/DI [ Time Frame: Baseline to Week 24 ]
  7. Change in SLICC/DI [ Time Frame: Baseline to Week 48 ]
  8. Change in SLICC/DI [ Time Frame: Baseline to Week 60 ]
  9. The probability of adding aggressive adjunctive therapy added to MMF (including IV immunoglobulin or rituximab) or change in MMF therapy to cytotoxic drug (e.g., cyclophosphamide) due to flare [ Time Frame: Week 60 ]
  10. Cumulative systemic steroid dose [ Time Frame: Week 60 ]
  11. Change in FACIT fatigue score [ Time Frame: Baseline to Week 24 ]
  12. Change in FACIT fatigue score [ Time Frame: Baseline to Week 48 ]
  13. Change in FACIT fatigue score [ Time Frame: Baseline to Week 60 ]
  14. Change in Lupus QoL-US [ Time Frame: Baseline to Week 24 ]
  15. Change in Lupus QoL-US [ Time Frame: Baseline to Week 48 ]
  16. Change in Lupus QoL-US [ Time Frame: Baseline to Week 60 ]
  17. Time to improvement in BILAG from maximum level during flare [ Time Frame: Maximum BILAG score during clinically significant disease reactivation to BILAG improvement up to week 60 ]
  18. Time to recovery of baseline BILAG scores [ Time Frame: Clinically significant disease reactivation to recovery of baseline BILAG scores or BILAG C, whichever is worse, up to week 60 ]
  19. Cumulative excess systemic steroid dose [ Time Frame: From time of clinically significant disease reactivation to return to pre-flare dose or week 60 ]
  20. Time to return to pre-flare steroid dose [ Time Frame: clinically significant disease reactivation (flare) to pre-flare steroid dose or week 60 ]
  21. Amount of SLE Related Grade 3-5 adverse events [ Time Frame: Up to Week 60 ]
    As defined by the National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) system, which are defined as possibly, probably, or definitely related to SLE.

  22. Amount of MMF related Grade 3-5 adverse events [ Time Frame: Up to Week 60 ]
    As defined by the NCI-CTCAE system, which are defined as possibly, probably, or definitely related to MMF.

  23. Amount of all NCI-CTCAE Grade 3-5 adverse events. [ Time Frame: Up to Week 60 ]
  24. Amount of serious adverse events. [ Time Frame: Up to Week 60 ]
  25. Frequency of malignancies [ Time Frame: Up to Week 60 ]
  26. Amount of NCI-CTCAE Grade 3-5 hematological events. [ Time Frame: Up to Week 60 ]
  27. Total incidence of mortality possibly, probably, or definitely related to SLE. [ Time Frame: Up to Week 60 ]
  28. Total incidence of all-cause mortality [ Time Frame: Up to Week 60 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01946880


Locations
Show Show 19 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Autoimmunity Centers of Excellence
Investigators
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Study Chair: Eliza Chakravarty, MD Oklahoma Medical Research Foundation
Study Chair: Judith A. James, MD, PhD Oklahoma Medical Research Foundation
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01946880    
Other Study ID Numbers: DAIT ALE06
NIAID CRMS ID#: 20154 ( Other Identifier: DAIT NIAID )
First Posted: September 20, 2013    Key Record Dates
Last Update Posted: July 25, 2019
Last Verified: July 2019
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Systemic Lupus Erythematosus
Mycophenolate Mofetil (MMF)
Additional relevant MeSH terms:
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Lupus Erythematosus, Systemic
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Mycophenolic Acid
Hydroxychloroquine
Chloroquine
Prednisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Antirheumatic Agents
Amebicides