Nintedanib in Patients With Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation (HSCT)- a Multicentre Phase II Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 20
- 试验地点
- 3
- 主要终点
- adverse event rate leading to interruption/ discontinuation of study treatment
研究概览
简要总结
This study investigates the safety and tolerability of Nintedanib in patients with bronchiolitis obliterans syndrome (BOS) following allogeneic hematopoietic cell transplantation. All study patients with BOS will be treated with the study drug Nintedanib (300 mg/day) as an add-on therapy to their basic immunosuppressive treatment over a 12-months treatment period.
详细描述
Allogeneic hematopoietic stem cell transplantation (HCT) is an established treatment option for several malignant and non-malignant disorders. An important limitation of long-term survival after HCT is chronic graft-versus-host disease (cGvHD). The manifestation of cGvHD in the lungs, bronchiolitis obliterans (BO - if proven by lung biopsy) or bronchiolitis obliterans syndrome (BOS - clinical diagnosis), has a reported incidence between 5 and 20%. Despite different treatment approaches, prognosis of BO remains poor, with an overall 3-year mortality of up to 65%. Nintedanib is an orally available indolinone derivate that competitively binds to the vascular endothelial growth factor (VEGF) receptors, fibroblast growth factor (FGF) receptors, and platelet derived growth factor (PDGF) receptors. The anti-fibrotic activities of Nintedanib may impact the progressive course of fibrotic lung diseases like BO. This study investigates the safety and tolerability of Nintedanib in patients with bronchiolitis obliterans syndrome following allogeneic hematopoietic cell transplantation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •Time interval from transplant </= 5 years at the time of inclusion
- •BOS as defined per the National Institute of Health (NIH) criteria:
- •FEV1/vital capacity < 0.7 or the fifth percentile of predicted.
- •FEV1 < 75% of predicted with ≥ 10% decline over less than 2 years.
- •Absence of infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as chest radiographs, computed tomographic (CT) scans, or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, and broncho-alveolar lavage).
- •One of the 2 supporting features of BOS:
- •Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution chest CT, or
- •Evidence of air trapping by PFTs: residual volume > 120% of predicted or residual volume/total lung capacity elevated outside the 90% confidence interval and prior or current diagnosis of cGvHD per NIH criteria or histologically proven BO
- •Diagnosis of BOS within 6 months before enrollment or prior diagnosis of BOS with an absolute decline of the percentage of predicted forced expiratory volume in 1 second (FEV1) by >/= 10% within the past 12 months before inclusion
- •Exclusion Criteria
- •Known intolerance to Nintedanib or any of its component
- •Pregnancy or nursing
- •Serum ALT > 5 x upper limit of normal (ULN) unless explained entirely by liver GvHD or total bilirubin > 3x ULN unless explained entirely by liver GvHD
- •Any acute pulmonary infection with viruses, bacteria or fungi within four weeks before study inclusion
- •Chronic oxygen therapy; non-invasive ventilation
- •Inability to give informed consent or to perform repeated pulmonary function tests (PFT)
- •Life expectancy < 1 year at the time of enrolment as suggested by the treating physician
- •Hematologic malignancy in hematologic relapse
- •Symptomatic angina pectoris
- •Therapeutic anticoagulation (primary or secondary prophylactic platelet anti-aggregation allowed)
- •Recent abdominal surgery or untreated gastric ulcer
排除标准
- 未提供
研究组 & 干预措施
Nintedanib
Nintedanib 150 mg Kps bid (oral)
干预措施: Nintedanib (Drug)
结局指标
主要结局
adverse event rate leading to interruption/ discontinuation of study treatment
时间窗: from screening to month 12 after screening
adverse events of the following severity according to Common terminology criteria for adverse events(CTCAE): Diarrhoea ≥ grade 3; Nausea ≥ grade 3; Vomiting ≥ grade 3; Abdominal pain ≥ grade 3; Elevation of liver enzymes (AST, ALT) ≥ grade 2; Elevation of total bilirubin ≥ 2
次要结局
- change in total lung capacity (TLC)(Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months)
- change of the percent of predicted forced expiratory volume in 1 second (FEV1)(Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months)
- change in forced vital capacity (FVC)(Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months)
- Change in exhaled nitric oxide (eNO)(Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months)
- changes in St. George's Respiratory Questionnaire (SGRQ)(assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months)
- changes in NIH GvHD grading score(assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months)
- Change in diffusion capacity of the lung for carbon monoxide (DLCO)(Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months)
- Nitrogen (N2)-washout(Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months)
- changes in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire(assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months)
- changes in in 6 minutes walking distance (6-MWD)(6-MWD will be performed at screening, after 6, after 12 months)
- cumulative steroid doses(assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months)
- overall survival(assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months)
- occurrence of GvHD in other organs(assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months)
- disease-free survival of underlying hematologic disease(assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months)