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:
1. 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. 2. Differences in AAT antielastase activity, the amount of active elastase, the AAT levels in serum at baseline and at 7 days after randomization. 3. 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 4. 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). 5. 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.
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
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
Parallel
alpha1-proteinase inhibitor, produced from the plasma of human donors (Prolastin 1000 mg, powder and solvent for solution for infusion)
Biological/VaccineIV Prolastin administered once at 120 mg per kilogram of body weight
Placebo
Drug\+ IV administration of 0.9% sodium chloride
Change in level of circulating IL-6 in plasma
change in level of circulating IL-6 in plasma at 7 days after IMP administration, as measured by ELISA
Change in plasma concentration of IL-1b, IL-5, IL-8, IL-10, and soluble TNF receptor 1(sTNFR1), CRP
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 the AAT antielastase activity, the amount of active elastase, the AAT levels in serum
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
treatment failure (need for either NIV or CPAP or ETI or transfer to ICU or in-hospital death after randomization)
Impact of AECOPD on overall health, daily life, and perceived well-being
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 (scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status) from Day 7 to follow-up (30 days after hospital discharge)
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