A Two-center, Randomized, Double-blind, Placebo-controlled Study of Intravenous Plasma-purified Alpha-1 Antitrypsin for Hospitalized Patients With COPD Exacerbations (AECOPD Study)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Change in level of circulating IL-6 in plasma
研究概览
简要总结
Intravenous augmentation therapy with purified preparations of AAT (Alpha1-antitrypsin) derived from human plasma is a well consolidated specific therapeutic option to treat the severe deficient state of AAT. Prolastin is used to restore the balance between AAT and elastases in the lung and consequently to prevent a further deterioration in the pulmonary emphysema. Recently, in patients with COVID-19, without genetically lowered AAT levels with moderate to severe ARDS, treatment with AAT was demonstrated to be safe, feasible, and biochemically efficacious as an anti-inflammatory therapeutic therapy.
The aim of the study, based on biological plausibility, is to evaluate the safety and efficacy (from a biological perspective) of the administration of intravenous plasma-purified AAT as an anti-inflammatory treatment for patients admitted to hospital because of a COPD exacerbation leading to an acute or an acute on chronic respiratory failure.
Thirty-six adult patients hospitalized because of a COPD exacerbation leading to an acute or an acute on chronic respiratory failure will be enrolled by the two sites involved in the study, the Pneumology Unit of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) and the Pneumology Unit of IRCCS Istituto Clinico Humanitas, Rozzano (Milano, Italy).
Participants will be randomized 2:1 in the active treatment group (standard treatment + IV administration of Prolastin) or in the placebo group (standard treatment+ IV administration of 0.9% sodium chloride).
To address the clinical question from a biological perspective, we will investigate the decrease in inflammatory markers in the active treated group in comparison with the placebo group.
The primary objective is to demonstrate a significant reduction in systemic inflammation by IV Prolastin administered once at 120 mg per kilogram of body weight in patients with moderate to severe AECOPD, as assessed by the change in plasma concentration of IL6 at 7 days after randomization, in the active treatment group with respect to placebo group.
Secondary outcomes are:
- Difference in change in plasma concentration of IL-1b, IL-5, IL-8, IL-10, and soluble TNF receptor 1 (sTNFR1), CRP at 7 days after randomization.
- Differences in AAT antielastase activity, the amount of active elastase, the AAT levels in serum at baseline and at 7 days after randomization.
- Difference in treatment failure rate. Treatment failure is a composite endpoint of need for either NIV or CPAP or need of ETI or need of transfer to ICU or in-hospital death after randomization
- Impact of AECOPD on overall health, daily life, and perceived well-being in patients with obstructive airways disease by the change of St. George's Respiratory Questionnaire (SGRQ) score from Day 7 to follow-up (30 days after hospital discharge).
- Differences in type and number of AEs and SAEs in the two groups
The expected duration of subject participation is from randomization to 30 days after hospital discharge, with a follow up phone contact.
详细描述
COPD is the third leading cause of death in the world and it is characterized by airflow limitation, breathlessness, and exacerbations. Exacerbations are important events with a significant influence on prognosis and survival. Neutrophils, eosinophils, other inflammatory cells in the lung, as well as systemic inflammation and inflammatory biomarkers increase during exacerbations. Alpha1-antitrypsin (AAT) is an acute phase protein with antineutrophil elastase properties and several studies have demonstrated an elevation of acute phase proteins during COPD exacerbations. Intravenous augmentation therapy with purified preparations of AAT, derived from human plasma, is a well consolidated specific therapeutic option to treat the severe deficient state of AAT. In turn, the abrupt cessation of AAT augmentation therapy for patients with a hereditary deficiency of the protein results in increased systemic inflammation and subsequent progression of emphysema and COPD. Recently, in patients with COVID-19, without genetically lowered AAT levels with moderate to severe ARDS (Acute Respiratory Distress Syndrome), treatment with AAT was demonstrated to be safe, feasible, and biochemically efficacious as an anti-inflammatory therapy. This suggests a potential protective effect of AAT in treating COPD exacerbations in subjects without the genetic deficiency of AAT because of the anti-inflammatory effect of AAT.
Primary objective:
- to demonstrate a significant reduction in systemic inflammation by IV Prolastin administered once at 120 mg per kilogram of body weight in patients with moderate to severe AECOPD, as assessed by the change in plasma concentration of IL6 at 7 days after randomization, in the active treatment group with respect to placebo group.
Secondary objectives:
- to determine the anti-inflammatory and immunomodulatory effects of IV Prolastin administered once at 120 mg per kilogram of body weight on plasma concentration of other biomarkers which have been implicated in pulmonary and systemic inflammation, and also to be suppressed by AAT in vivo
- to identify treatment failure as assessed by:
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed Consent as documented by signature
- •Male and female ≥40 years old
- •Previous COPD diagnosis with a documented post-bronchodilator FEV1 to FVC ratio (FEV1/FVC) equal to or less than 0.70 or LLN
- •Hospitalized for a moderate to severe exacerbation, according to the Rome proposal
- •Admission to the respiratory ward by ≤24 hours
- •Acute respiratory failure with SpO2 <92% at room air, or PaO2< 60 mmHg at room air, or acute on chronic respiratory failure defined as higher Increased oxygen requirements compared with the home standard oxygen prescription
- •A positive sputum NEATstik®, that corresponds to an approximate neutrophil elastase concentration of 8 μg·mL-1 (rapid point-of-care test)
排除标准
- •Clinically important pulmonary disease other than COPD (e.g., clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, and primary ciliary dyskinesia)
- •Presence of pneumonia or other pleuroparenchymal abnormalities on either chest X-ray or Chest CT scan, performed per routine clinical practice at the hospital admission
- •Current diagnosis of asthma according to the GINA, prior history of asthma, or asthma-COPD overlap
- •Known AATD as homozygous or composite heterozygous mutation
- •Presence of any active malignancy (other than non-melanoma skin cancer)
- •Any unstable disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric disorder, major physical and/or cognitive impairment that, in the opinion of the Investigator, could:
- •Affect the safety of the participant throughout the study
- •Influence the findings of the study or their interpretation
- •Known diagnosis of selective IgA deficiency defined as a serum IgA of less than 7 mg/dl (0.07 g/L)
- •Patient with the immediate need for ETI of NIV (patients already on CPAP or NIV can be included)
- •Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product
- •Women who are of childbearing potential*
- •Participants that have previously received Prolastin® 1000 mg/40 ml
- •Participation in another interventional clinical trials with investigational drugs within the 30 days preceding and during the present study. * A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the randomisation without an alternative medical cause.
研究组 & 干预措施
Prolastin
Alpha1-proteinase inhibitor (human), commercially available as Prolastin
干预措施: alpha1-proteinase inhibitor, produced from the plasma of human donors (Prolastin 1000 mg, powder and solvent for solution for infusion) (Biological)
Placebo
0.9% sodium chloride solution for infusion ("normal saline")
干预措施: Placebo (Drug)
结局指标
主要结局
Change in level of circulating IL-6 in plasma
时间窗: at 7 days after IMP administration
change in level of circulating IL-6 in plasma at 7 days after IMP administration, as measured by ELISA
次要结局
- Change in plasma concentration of IL-1b, IL-5, IL-8, IL-10, and soluble TNF receptor 1(sTNFR1), CRP(at 7 days after after randomization)
- Differences in the AAT antielastase activity, the amount of active elastase, the AAT levels in serum(at baseline and at 7 days after randomization)
- Treatment failure(from randomization to 30 days after hospital discharge)
- Impact of AECOPD on overall health, daily life, and perceived well-being(from Day 7 to 30 days after hospital discharge)
- Type and number of AEs and SAEs(from randomization to 30 days after hospital discharged)
研究者
Angelo Guido Corsico
MD
Fondazione IRCCS Policlinico San Matteo di Pavia