Pirfenidone to Prevent Fibrosis in ARDS. A Randomized Controlled Trial - PIONEER
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 130
- 试验地点
- 34
- 主要终点
- The number of ventilator free days (VFD) at day 28.
研究概览
简要总结
Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury and a major cause of Intensive Care Unit (ICU) admission worldwide. Despite a large number of randomized clinical trials, a specific and effective pharmacological approach for patients with ARDS is still lacking.
Fibroproliferation is a crucial part of the host defence response, and severe fibrotic lung disease affects ARDS patients even years after acute phase resolution.
Pirfenidone is an oral anti-fibrotic drug, approved and largely used for treatment of idiopathic pulmonary fibrosis (IPF). The effect of Pirfenidone in ARDS has been evaluated only in animal models.
This is a randomized controlled study to evaluate for the first time the efficacy of Pirfenidone in ARDS.
详细描述
Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury, associated with increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue.
ARDS represents 10.4% of total ICU admissions and 23.4% of all patients requiring mechanical ventilation and the hospital mortality rate remains as high as 40%.
Optimal care for patients with ARDS includes PEEP, muscle relaxation, protective ventilation, prone position, conservative fluid strategy.
Pharmacological interventions focused on dampening the pro-inflammatory response in the initial phase of ARDS, on reduction of pulmonary oedema and on improvement of repair mechanisms. Besides treatment with glucocorticosteroids, none of the other pharmacological interventions tested so far in clinical trials showed a significant reduction in morbidity and mortality.
Many ARDS patients survive the acute inflammation phase but develop remarkable pulmonary fibrosis. In hospital mortality is significantly lower (24%) than 1-y mortality after hospital discharge (41%) regardless of the etiology of ARDS. Although a protective ventilation strategy can improve short-term survival in ARDS subjects, there is no difference in pulmonary function compared with standard ventilation treatment up to 2 years after the acute-phase resolution.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Concomitant presence of:
- •ARDS (moderate and severe) - Berlin definition
- •Within 1 week of a known clinical insult or new or worsening respiratory symptoms
- •Bilateral opacities on CXR which are not fully explained by effusions, lobar/lung collapse or nodules
- •Respiratory failure not fully explained by cardiac failure or fluid overload
- •PaO2/FiO2<200 mmHg with PEEP<=5 cmH2O (invasive mechanical ventilation)
- •Inflammatory ARDS phenotype (28), defined by at least one of the following:
- •High plasma levels of inflammatory biomarkers
- •Vasopressor dependence
- •Lower serum bicarbonate or increased serum lactate
- •Informed consent expressed by the patient or by legal representative or on the Ethical Committee indication.
- •Age >=18 years
排除标准
- •Intubated and mechanically ventilated via an endotracheal or tracheostomy tube (>7 days) up to the time of randomization
- •ARDS severe or moderate for more than 36 hours
- •Untreated pulmonary embolism, pleural effusion or pneumothorax as the primary cause of ARF
- •ARF fully explained by left ventricular failure or fluid overload
- •Consent declined
- •Severe chronic respiratory disease requiring domiciliary ventilation
- •Clinical suspicion for significant restrictive lung disease
- •Pregnant women or women of childbearing potential who are sexually active
- •Known allergy to pirfenidone
- •Concomitant use of fluvoxamine
- •Known severe hepatic failure
- •Known severe renal failure or necessity of dialysis not related to acute disease
- •Little chance of survival (SAPS II score>75)
研究组 & 干预措施
Placebo
Patients randomized to Placebo Group will receive 5 ml of Water
干预措施: Placebo (Drug)
Pirfenidone
Patients randomized to Pirfernidone Group will receive tables of 267 mg
干预措施: Pirfenidone (Drug)
结局指标
主要结局
The number of ventilator free days (VFD) at day 28.
时间窗: 28 days
The primary outcome will be calculated following these rules: 1. the total number of days from day 1 to 28 post randomization on which a patient is alive and receives no assistance from mechanical ventilation, if any period of ventilator liberation lasts at least 48 consecutive hours. 2. study day 1 is the day of enrolment. 3. if patients are on mechanical ventilation they will be classified as being on mechanical ventilation for that entire study day. 4. to be considered liberated from mechanical ventilation, the patient will need to have at least 48 consecutive hours without mechanical ventilation. 5. non-invasive mechanical ventilation will not be considered assistance if it is provided by face or nasal mask. 6. patients dead before weaning will be allocated the value of 0 ventilator free days. Any patient who dies after weaning from mechanical ventilation but before day 28 will not have the days after their death until day 28 considered as a VFD.
次要结局
- ICU-free days at day 28(28 days)
- Cumulative SOFA-free point at day 28(28 days)
- Hospital length of stay.(28 days or until discharge)
- Fibroproliferative changes on high-resolution CT performed at ICU discharge(28 days or until discharge)
- Mortality at ICU/hospital discharge(28 days or until discharge)
- Quality of life assessment at follow-up (6 12 months) with SF-36 .(through study completion, an average of 1 year)
- Quality of life assessment at follow-up (6 12 months) with EQ-5D score.(through study completion, an average of 1 year)
- Percentage change in the spirometric values, such as FEV1 (% and L/min), FVC (% and L/min) and DLCO (%).(28 days or until discharge)
- Proportion of subjects who develop right and/or left heart dysfunction(28 days or until discharge)
- Adverse event rate(28 days or until discharge)
- Use of rescue therapies for severe hypoxaemia(28 days or until discharge)
- Broncoalveolar lavage fluid (BAL) speciments(28 days or until discharge)
研究者
Giovanni Landoni
MD, Associate Professor
Università Vita-Salute San Raffaele