Randomized Double-Blind Placebo-Controlled Clinical Trial to Assess the Efficacy of Mycophenolate Mofetil in Subclinical Interstitial Lung Disease Associated With Systemic Sclerosis: a Feasibility Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 35
- 试验地点
- 3
- 主要终点
- Monthly rate of randomized participants per site
研究概览
简要总结
The goal of this pilot study is to assess the feasibility of a larger study on the efficacy of mycophenolate mofetil in people diagnosed with systemic sclerosis with mild lung involvement. Participants will be recruited over 12 months at 3 academic centers and assigned randomly to receive either mycophenolate mofetil or placebo, a look-alike substance that contains no active drug, for 96 weeks.
详细描述
Background: Systemic sclerosis (SSc, scleroderma) is a rare but life-threatening systemic autoimmune disease characterized by microvasculopathy, serum autoantibodies, inflammation and fibrosis of the skin and internal organs. Early rapidly progressive SSc remains the most lethal autoimmune rheumatic disease, with over 60% mortality at 5 years in high-risk patients. Interstitial lung disease (ILD) is the leading cause of SSc-related mortality and affects over half of SSc patients. SSc-ILD is currently treated with immunosuppressive and anti-fibrotic drugs, with the first-line treatment being mycophenolate mofetil (MMF), although treatments have modest benefits when initiated in advanced stages of disease. Emerging data suggest that earlier treatment, when lung function is still normal despite evidence of ILD on computed tomography scan ("subclinical SSc-ILD"), may lead to improved outcomes, suggesting a window of treatment opportunity.
Research Aims: The goal of the proposed pilot RCT is to establish the feasibility of a phase III RCT that will assess the efficacy of MMF in subclinical SSc-ILD. Specifically, we aim to:
- Determine the rate of patient recruitment at three centers over one year, and identify barriers and solutions to recruitment;
- Determine the proportion of participants receiving the allocated treatment and with complete primary efficacy outcome data at 48 and 96 weeks; and
- Generate preliminary data on clinical efficacy outcomes that will contribute information to the analysis of the phase III trial through a Bayesian inference framework.
Methods: Participants will be adults with SSc, ILD diagnosed within the past 3 years and a normal forced vital capacity (≥ 80%). Participants will be recruited over 12 months at 3 academic centers affiliated to the Canadian Scleroderma Research Group. Eligible participants will be assigned using stratified randomization to receive either MMF (up to 2 grams daily) or placebo for 96 weeks. The primary feasibility outcome will be the rate of recruitment per site over 12 months. A Bayesian approach will be used to estimate the probability of reaching the target sample size based on observed recruitment rates, with decision rules to continue, adapt, or stop the trial. Data collected on the primary clinical efficacy outcome (annual rate of decline in forced vital capacity over 96 weeks) will be used to inform the analysis of the phase III trial (as an informative prior) through a Bayesian inference framework.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The participant, the physician, the study investigators and the research personnel will be blinded to treatment allocation, whereas the dispensing pharmacy will not.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able and willing to provide informed consent and adhere to study protocol;
- •Women and men of all race/ethnicity, aged 18 years and older;
- •SSc based on 2013 ACR-EULAR classification criteria;
- •Presence of interstitial lung disease on HRCT scan, obtained within 12 months before screening, that shows fibrosis affecting less than 20% of the lungs, as confirmed by an expert radiologist;
- •Diagnosis of ILD within 7 years before screening;
- •Forced vital capacity of 80% predicted and above, on pulmonary function tests obtained within 6 months before screening;
- •Able to communicate in French or English;
排除标准
- •Progressive pulmonary fibrosis, defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation, as defined by the 2022 ATS/ERS/JRS/ALAT Clinical Practice Guideline;
- •Use of medications with putative lung disease-modifying properties:
- •Current use of MMF, mycophenolic acid, azathioprine, calcineurin inhibitors (e.g. tacrolimus, cyclosporin A), tocilizumab, nintedanib, pirfenidone or corticosteroids (Prednisone equivalent dose >10 mg/day) at time of screening
- •Cyclophosphamide within one year prior to screening
- •Rituximab within 6 months prior to screening
- •Cell therapies (including stem cell transplantation) within one year prior to screening
- •Current use of other biological, targeted synthetic or investigational products with immunosuppressive effects (e.g. TNF inhibitors, abatacept, tofacitinib) at time of screening
- •Any contraindication to MMF, including:
- •Pregnancy and/or breastfeeding
- •Female of childbearing potential not using reliable method of contraception
- •Persistent leucopenia (white blood cell count <3.0 x103/μL)
- •Persistent thrombocytopenia (platelet count <100 x103/μL)
- •Persistent anemia (hemoglobin <100 g/L)
- •Baseline liver enzymes (alanine transaminase (ALT) or aspartate transaminase (AST)) or bilirubin >1.5 times the upper limit of normal, other than due to Gilbert's disease
- •Uncontrolled congestive heart failure
- •Active infection (lung or elsewhere)
- •Active solid or hematological malignancy (other than basal cell cancer of the skin or cervical carcinoma in situ removed entirely by biopsy)
- •Active peptic ulcer disease
- •Other serious concomitant medical illness, unreliability or drug abuse that might compromise the patient's ability to safely take MMF
- •Use of drugs or products with significant interactions with MMF
研究组 & 干预措施
Mycophenolate mofetil
2 to 4 capsules of mycophenolate mofetil twice daily.
干预措施: Mycophenolate Mofetil (Drug)
Placebo
2 to 4 capsules of placebo twice daily.
干预措施: Placebo (Other)
结局指标
主要结局
Monthly rate of randomized participants per site
时间窗: Over one year
Proportion of potentially eligible patients who provide consent per site
时间窗: Over one year
Total number of potentially eligible patients identified per site
时间窗: Over one year
Proportion of consented participants who meet the eligibility criteria per site
时间窗: Over one year
Adherence to treatment as assessed by Participant Dosing Diaries
时间窗: From the first dose to the last dose taken for each participant, up to 96 weeks
Drug adherence rate as assessed by Pharmacy Accountability Logs
时间窗: From the first dose to the last dose taken for each participant, up to 96 weeks
Adherence to the study protocol as assessed by the number of protocol deviations
时间窗: Over total study period (up to 96 weeks per participant)
Proportion of participants intolerant to the study drug who discontinue trial treatment
时间窗: Over total study period (up to 96 weeks per participant)
Proportion of participants receiving the allocated treatment at 48 weeks
时间窗: At 48 weeks
Proportion of participants receiving the allocated treatment at 96 weeks
时间窗: At 96 weeks
Proportion of participants with complete primary efficacy outcome data at 48 weeks
时间窗: At 48 weeks
Proportion of participants with complete primary efficacy outcome data at 96 weeks
时间窗: At 96 weeks
Proportion of participants lost to follow-up
时间窗: Over total study period (up to 96 weeks per participant)
次要结局
- Frequency of treatment-related adverse events(Over total study period (up to 96 weeks per participant))