Study of Therapeutic Plasma Exchange, Rituximab and Intravenous Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary Fibrosis (STRIVE-IPF)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 82
- 试验地点
- 7
- 主要终点
- %Survival
研究概览
简要总结
Acute exacerbations (AE) are a dreaded manifestation of idiopathic pulmonary fibrosis (IPF) that presents with rapidly worsening respiratory function over days to weeks. AE account for about 1/2 the deaths in IPF patients, and are refractory to all medical therapies attempted to date.
Considerable preliminary data shows pathological B-cell abnormalities and autoantibodies are present in AE-IPF and associated with disease severity.
The experimental therapy here (therapeutic plasma exchange plus rituximab plus intravenous immunoglobulin) is mechanistically targeted to ameliorate autoantibody-mediated pulmonary injury. Anecdotal pilot studies indicate these treatments have significant benefit for a disease syndrome that has, until now, been almost invariably inexorable. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF.
详细描述
The primary goal of clinical trial is to determine effects of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG) in comparison to effects of treatment as usual (TAU), among AE-IPF patients.
Our central hypothesis is "AUTOANTIBODY REDUCTION IS BENEFICIAL FOR AE-IPF PATIENTS." A corollary of this hypothesis is that antibody-mediated autoimmunity can play an important role in IPF exacerbations.
Following baseline screening assessments, hospitalized AE-IPF patients at the collaborating sites that meet all inclusion/exclusion criteria will be randomly assigned to receive one of the following treatments in a ratio of 2:1:
• Arm A (n=34) - Experimental Treatment:
Steroids: Prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent). Methyl-prednisolone 100 mg i.v. will be administered on days 6 and 15, as a premedication prior to the rituximab.
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
- 40 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age between 40-85 years old.
- •A diagnosis of IPF that fulfills ATS/ERS Consensus Criteria.1
- •Worsening or new development of dyspnea or hypoxemia within the last 30 days.
- •Ground-glass abnormality and/or consolidation superimposed on a reticular or honeycomb usual interstitial pneumonitis (UIP) pattern on locally read chest CT scan.
- •Ability and willingness to give informed consent (no surrogates) and adhere to study requirements.
排除标准
- •Diagnoses of current infection per clinical or microbial assessments.
- •Diagnoses of an additional or alternative etiology for respiratory dysfunction based upon clinical assessment, including congestive heart failure, sepsis, thromboembolism, etc.
- •History or serologic evidence of hepatitis B or C infection.
- •Coagulopathy, defined as a International Normalized Ratio (INR) >1.6, partial thromboplastin time (PTT) > 2x control, fibrinogen <100 mg/dL, or platelet count <50 thousand (K) unless these abnormalities can be reversed safely.
- •Hyperosmolar state or diabetic ketoacidosis to suggest uncontrolled diabetes, or uncontrolled hypertension (systolic BP >160 mm Hg and diastolic BP >100 mm Hg) that would contraindicate use of corticosteroids.
- •Hemodynamic instability, defined as an inotrope or vasopressor requirement.
- •History of reaction to blood products or murine-derived products or prior rituximab use.
- •History of malignancy, excluding basal or squamous cell skin cancer and low-risk prostate cancer, the latter defined as stage T1 or T2a, with prostate specific antigen (PSA) less than 10 ng/dl. The experimental treatments are not known to promote cancer progression, and these criteria are within current guidelines.
- •Unwillingness to accept blood product transfusion.
- •Diagnosis of major comorbidities expected to interfere with study participation.
- •Treatment for >14 days within the preceding month with >20 mg. prednisone (or equivalent) or any treatment during the last month with a cellular immuno-suppressant (e.g., cyclophosphamide, methotrexate, calcineurin inhibitors, mycophenolate, azathioprine, etc.). An exception will be made if the patient has a bronchoalveolar lavage (BAL) negative for pathogens.
- •Current treatment with an angiotensin converting enzyme inhibitor that cannot be discontinued and/or substituted (to obviate hemodynamic complications during TPE).
- •Concurrent participation in other experimental trials.
- •Fertile females who do not agree to contraception or abstinence, or have a positive pregnancy test (urine or blood). IPF is a disease of older adults, and male predominant, so this will not be a frequent consideration.
- •Presence of positive (abnormal) classical autoimmune tests: anti-nuclear antibody (ANA), rheumatoid factor (RF), Anti- Sjögren's-syndrome-related antigen (SSA) , and Anti-Cyclic Citrullinated Peptide (CCP). This criterion will eliminate patients with confounding classical autoimmune syndromes. Many IPF patients will have already had these tests, which are standard of practice (SOP) at many IPF centers, and these prior results will suffice if the tests were performed within the last year. Otherwise, these tests need to be performed prior to enrollment and they can usually be procured in 1-2 days. Based on experience, we anticipate ~10% of patients who fulfill all other IPF criteria will nonetheless be positive for one of these classical autoantibody tests.
- •IgA deficiency (IgA level <7 mg/dL)- to preclude IVIG reactions.
研究组 & 干预措施
Autoantibody Reductive Therapy
Therapeutic Plasma Exchange (TPE) consisting of 1x estimated plasma volume exchanges for 3 successive days (1-3) and then, after a one day interval to enable equilibration of autoantibodies between intra- and extra-vascular spaces, again on days 5, 6, 9, 11, 13, and 15.
Rituximab: One gm i.v. will be administered on day 6 and day 15 after completion of the TPE on those days.
Intravenous immunoglobulin (IVIG): 0.5 gm/kg/day i.v. on days 16-19
All subjects in this trial, including patients in this arm, will receive identical empiric antibiotics and steroids. The steroid dose is: Prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent). Methylprednisolone 100 mg i.v. will be administered on days 6 and 15, as a premedication prior to the rituximab.
干预措施: Autoantibody Reductive Therapy (Drug)
Treatment as Usual (TAU)
The same steroid regimen as described for the experimental arm, i.e., prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent), and methylprednisolone 100 mg i.v. administered on days 6 and 15, as well as empiric antibiotics.
干预措施: Treatment as Usual (TAU) (Drug)
结局指标
主要结局
%Survival
时间窗: 6 months
Actuarial survival
次要结局
- Percentage of Participants With a Change in Oxygen Requirements to Maintain Adequate SaO2(before and immediately after hospital treatment)
- Walk Distance(6 months)
研究者
Steven R. Duncan, MD
Prinicpal Investigator
University of Alabama at Birmingham