Intravenous Alpha-1 Antitrypsin for Hospitalized Patients With COPD Exacerbations (AECOPD Study)

A Two-center, Randomized, Double-blind, Placebo-controlled Study of Intravenous Plasma-purified Alpha-1 Antitrypsin for Hospitalized Patients With COPD Exacerbations (AECOPD Study)

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.

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:

1. 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

2. to identify treatment failure as assessed by:

   1. need for either NIV or CPAP
   2. need of ETI
   3. need of transfer to ICU
   4. in-hospital death after randomization

3. to evaluate the impact of AECOPD on overall health, daily life, and perceived well-being in patients with obstructive airways disease at discharge

4. to determine the safety of IV Prolastin administered once at 120 mg per kilogram of body weight, as assessed by the type and number of AEs and SAEs in the two groups.

   Primary study outcome:

   • change in level of circulating IL-6 in plasma at 7 days after IMP administration, as measured by ELISA.

   Secondary study outcomes:

   • 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 at baseline and at 7 days after randomization
   • treatment failure (need for either NIV or CPAP or ETI or transfer to ICU or in-hospital death after randomization)
   • differences in SGRQ score at discharge
   • differences in type and number of AEs and SAEs in the two groups.

   Recruitment will take place at the Pneumology Unit of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) and at the Pneumology Unit of IRCCS Istituto Clinico Humanitas, Rozzano (Milano, Italy), during the hospitalization because of a COPD exacerbation leading to an acute or an acute on chronic respiratory failure.

   At the Screening day, the following data will be collected: demographics (date of birth, sex, ethnicity), medical history and medications (previous and concomitant, including those administered at emergency room access), vital signs (systolic/diastolic blood pressure, heart rate, peripheral oxygen saturation, respiratory rate), electrocardiogram. The following screening assessments will be undertaken to ensure that a patient meets the criteria for enrolment:

   • chest imaging review (X-ray or CT scan performed per routine clinical practice at the hospital admission)
   • physical examination
   • confirmation of a moderate to severe ECOPD (exacerbations of COPD), according to the Rome proposal
   • sputum NEAT stik

   At the Baseline day (if different from the screening day), a physical examination will be performed and vital signs will be collected again. Before randomization, the following laboratory assessments will be carried out as per routine clinical care (blood count, basic liver/renal/bone profile biochemistry, standard markers of inflammation such as C-reactive protein, arterial blood gas analysis). A plasma sample will be obtained for cytokine measurements (IL-6, IL-1b, IL-5, IL-8, IL-10, sTNFR1), for AAT antielastase activity, active elastase ad serum AAT level before randomization. Within 24 hours by the admission to the respiratory ward, subjects who meet inclusion criteria will be randomized 2:1 to one of the two study arms (Prolastin or placebo), according to a computer-generated random blocks randomization list. Both the active drug and matching placebo will be prepared by unblinded trial personnel.

   At the Baseline day the investigational product (Prolastin or placebo) will be administered, concomitant medications will be collected and the adverse events evaluation will be performed.

   At Day 7 (seven day after IMP administration) the following assessments will be performed:

   • physical examination
   • vital signs collection (blood pressure, mean arterial pressure, heart rate, temperature, peripheral oxygen saturation, respiratory rate, where appropriate)
   • electrocardiogram
   • blood sample for CRP, ABG analysis, as per normal clinical practice
   • plasma sample collection for cytokine measurements (IL-6, IL-1b, IL-5, IL-8, IL-10, sTNFR1), for AAT antielastase activity, active elastase and serum AAT level
   • adverse events evaluation
   • concomitant medication collection
   • St. George's Respiratory Questionnaire (SGRQ) administration

   At the Hospital Discharge Day, the following data will be collected:

   • physical examination
   • vital signs (blood pressure, mean arterial pressure, heart rate, temperature, peripheral oxygen saturation, respiratory rate, where appropriate)
   • adverse events
   • concomitant medication
   • additional clinical findings occurred during the hospital stay (need for either NIV or CPAP or ETI or ICU admission and total days in ICU)

   A Phone contact, 30 days after discharge, will be done to record:

   • adverse events
   • concomitant medication
   • SGRQ responses
   • additional clinical findings after hospital discharge

Inclusion Criteria:

1. Informed Consent as documented by signature
2. Male and female ≥40 years old
3. Previous COPD diagnosis with a documented post-bronchodilator FEV1 to FVC ratio (FEV1/FVC) equal to or less than 0.70 or LLN
4. Hospitalized for a moderate to severe exacerbation, according to the Rome proposal
5. Admission to the respiratory ward by ≤24 hours
6. 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
7. A positive sputum NEATstik®, that corresponds to an approximate neutrophil elastase concentration of 8 μg·mL-1 (rapid point-of-care test)

Exclusion Criteria:

1. 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)

2. 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

3. Current diagnosis of asthma according to the GINA, prior history of asthma, or asthma-COPD overlap

4. Known AATD as homozygous or composite heterozygous mutation

5. Presence of any active malignancy (other than non-melanoma skin cancer)

6. 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:

   1. Affect the safety of the participant throughout the study
   2. Influence the findings of the study or their interpretation

7. Known diagnosis of selective IgA deficiency defined as a serum IgA of less than 7 mg/dl (0.07 g/L)

8. Patient with the immediate need for ETI of NIV (patients already on CPAP or NIV can be included)

9. Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product

10. Women who are of childbearing potential*

11. Participants that have previously received Prolastin® 1000 mg/40 ml

12. 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.