NCT01946880终止2 期
An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of Mycophenolate Mofetil (MMF) in Patients With Stable, Quiescent Systemic Lupus Erythematosus (SLE)
National Institute of Allergy and Infectious Diseases (NIAID)19 个研究点 分布在 1 个国家目标入组 102 人开始时间: 2013年11月20日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 102
- 试验地点
- 19
- 主要终点
- Number of Participants Experiencing Clinically Significant Disease Reactivation by Week 60
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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;
- •Experimental therapy within the 24 weeks, or five half-lives of the agent, whichever is longer, prior to randomization;
- •Solid organ or stem cell transplantation;
- •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.
- •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;
- •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.
- •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;
- •Pregnant or lactating, or intention to pursue pregnancy within three months after the completion of the study;
- •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).
- •Drug or alcohol abuse within one calendar year of randomization;
- •Other medical or psychiatric conditions that the investigator feels would place the subject at special risk by participation in this protocol.
研究组 & 干预措施
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).
干预措施: Mycophenolate Mofetil (Drug)
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).
干预措施: Hydroxychloroquine or Chloroquine (Drug)
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).
干预措施: Prednisone (Drug)
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).
干预措施: Mycophenolate Mofetil (Drug)
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).
干预措施: Hydroxychloroquine or Chloroquine (Drug)
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).
干预措施: Prednisone (Drug)
结局指标
主要结局
Number of Participants Experiencing Clinically Significant Disease Reactivation by Week 60
时间窗: Baseline (Treatment Randomization) to 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
次要结局
- 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(Baseline (Treatment Randomization) to Week 60)
- 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(Baseline (Treatment Randomization) to Week 60)
- 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(Baseline (Treatment Randomization) to Week 24, Week 48, and 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)
- Time to First Mild/Moderate or Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare(Baseline (Treatment Randomization) to Week 60)
- Time to First Severe Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus-Disease Activity Index (SELENA-SLEDAI) Flare(Baseline (Treatment Randomization) to Week 60)
- 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 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)
- 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)
- 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(Baseline (Treatment Randomization) to Week 60)
- Number of Participants Experiencing Any British Isles Lupus Assessment Group (BILAG) A Flare by Week 60(Baseline (Treatment Randomization) to Week 60)
- Cumulative Systemic Steroid Dose by Week 60(Baseline (Treatment Randomization) to Week 60)
- 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(Baseline (Treatment Randomization) to Week 60)
- 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(Baseline (Treatment Randomization) to Week 60)
- Change From Baseline in the Short Form Health Survey (SF-36) Physical Functioning (PF) Score(Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60)
- Number of Grade 3, 4, or 5 Adverse Events (AEs)(Baseline (Treatment Randomization) to Week 60)
- Number of Participants in the Lupus Nephritis Subgroup Experiencing a British Isles Lupus Assessment Group (BILAG) A Renal Flare by Week 60(Baseline (Treatment Randomization) to Week 60)
- The Addition of Aggressive Adjunctive Therapy to Mycophenolate Mofetil (MMF) or Change in MMF Therapy to Cytotoxic Drug Due to Flare by Week 60(Baseline (Treatment Randomization) to Week 60)
- Change From Baseline in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) Score(Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60)
- Time From Clinically Significant Disease Reactivation to Return to Pre-Flare Steroid Dose(Baseline (Treatment Randomization) to Week 60)
- Number of Grade 3, 4, or 5 Adverse Events (AEs) Related to Mycophenolate Mofetil (MMF)(Baseline (Treatment Randomization) to Week 60)
- Number of Malignancies Reported as Adverse Events (AEs).(Baseline (Treatment Randomization) to Week 60)
- Mortality Related to Systemic Lupus Erythematosus (SLE)(Baseline (Treatment Randomization) to Week 60)
- Change From Baseline in the Functional Assessment of Chronic Illness Therapy (FACIT-F) Fatigue Scale (FS): Total Score(Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60)
- Number of Infection-Related Adverse Events (AEs)(Baseline (Treatment Randomization) to Week 60)
- All-Cause Mortality(Baseline (Treatment Randomization) to Week 60)
- Change From Baseline in the Lupus Quality of Life (QoL)Score(Baseline (Treatment Randomization) to Week 24, Week 48, and Week 60)
- Time From Clinically Significant Disease Reactivation to Recovery to Baseline British Isles Lupus Assessment Group (BILAG) Score or BILAG C(Baseline (Treatment Randomization) to Week 60)
- Number of Serious Adverse Events (SAEs).(Baseline (Treatment Randomization) to Week 60)
- Number of Grade 3, 4, or 5 Hematological Adverse Events (AEs).(Baseline (Treatment Randomization) to Week 60)
- Time From Clinically Significant Disease Reactivation to Improvement in British Isles Lupus Assessment Group (BILAG) From Maximum Level During Flare(Baseline (Treatment Randomization) to Week 60)
- Cumulative Excess Systemic Steroid Dose From Time of Clinically Significant Disease Reactivation to Return to Pre-Flare Dose or End of Trial Participation(Baseline (Treatment Randomization) to Week 60)
- Number of Grade 3, 4, or 5 Adverse Events (AEs) Related to Systemic Lupus Erythematosus (SLE)(Baseline (Treatment Randomization) to Week 60)
研究者
研究点 (19)
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