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A randomized double-blind placebo-controlled trial of intravenous plasma-purified alpha-1 antitrypsin for severe COVID-19 illness.

Trial Profile

A randomized double-blind placebo-controlled trial of intravenous plasma-purified alpha-1 antitrypsin for severe COVID-19 illness.

Status: Completed
Phase of Trial: Phase II

Latest Information Update: 15 Apr 2021

At a glance

  • Drugs Alpha 1-antitrypsin (Primary)
  • Indications Adult respiratory distress syndrome; COVID 2019 infections; COVID-19 respiratory infection; Respiratory distress syndrome
  • Focus Therapeutic Use
  • Most Recent Events

    • 15 Apr 2021 Status changed from recruiting to completed.
    • 26 Oct 2020 Planned End Date changed from 24 Aug 2020 to 24 Apr 2021.
    • 26 Apr 2020 Status changed from planning to recruiting.

Trial Overview

Purpose

The aim of the study is to conduct a clinical trial of IV AAT as a prospective anti-inflammatory therapy for severely ill COVID-19 patients with ARDS requiring ICU admission. The primary objective is to demonstrate a biological effect of IV Prolastin administered weekly at 120mg per kilogram of ideal body weight in patients with severe COVID-19 illness requiring intubation and mechanical ventilation for ARDS by reducing circulating levels of IL-6 as measured by plasma ELISA. The study sample size is sufficient to demonstrate a significant difference in patients receiving Prolastin versus patients receiving placebo.

Primary Endpoints

The primary effectiveness outcome measure, a continuous variable, is IL-6 in plasma as measured by ELISA.

Timepoint: day 2 , day 7, day 14, day 21 and day 28

Other Endpoints

Safety and tolerability of IMP in the respective groups, as defined by the number of SEAs and AEs, binary variable
• PaO2/FiO2 ratio, continuous variable
• Respiratory compliance, continuous variable
• Sequential organ failure assessment (SOFA) score, continuous variable
• Mortality, binary variable
• Time on ventilator in days, continuous variable
• Circulating AAT levels as measured by nephelometry, continuous variable
• Plasma levels of IL-1β as measured by ELISA, continuous variable
• Plasma levels of IL-8 as measured by ELISA, continuous variable
• Plasma levels of IL-10 as measured by ELISA, continuous variable
• Plasma levels levels of soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF-α) as measured by ELISA, continuous variable
• Development of shock, defined for the purpose of this study as life-threatening organ dysfunction caused by a dysregulated response to infection, with critical reduction in tissue perfusion and acute failure of multiple organs, including the lungs, kidneys, and liver, binary variable
• Acute kidney injury defined as an abrupt sustained rise in urea and creatinine, binary variable
• Need for renal replacement therapy, binary variable
• Clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO2/FiO2 or development of shock or mortality following a period of sustained clinical improvement, binary variable
• Secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture, binary variable
Timepoint: day 2 , day 7, day 14, day 21 and day 28 [1]

Diseases Treated

Indication Qualifiers Patient Segments
Adult respiratory distress syndrome treatment -
COVID 2019 infections treatment -
COVID-19 respiratory infection treatment severe
Respiratory distress syndrome treatment -

Subjects

  • Subject Type patients
  • Number

    Planned: 36

  • Sex male & female
  • Age Group ≥ 18 years; adult; elderly

Patient Inclusion Criteria

- Have a diagnosis of congenital Alpha1-antitrypsin deficiency (AATD) with an allelic combination of ZZ, SZ, Z(null), (null)(null), S(null), or "at-risk" alleles (subjects with "at-risk" alleles must be individually evaluated for eligibility by the Medical Monitor). - Have a documented pre-Alpha1-Proteinase Inhibitor (PI) augmentation therapy serum alpha-1 antitrypsin (AAT) level <11 micrometer (μM) (80 milligrams per decilitre (mg/dL) if measured by radial immunodiffusion or 50 mg/dL if measured by nephelometry). - Currently receiving Alpha1-PI augmentation therapy or has received Alpha1-PI augmentation therapy within the past. If the subject is currently receiving Alpha1-PI augmentation therapy of any kind, he/she must be willing to discontinue that treatment at the Week 1 (Baseline) Visit and remain off any kind of Alpha1-PI treatment, other than the IPs for this study, while participating in the study. Note: Subjects must not be naïve to Alpha1-PI augmentation therapy for study participation. - At the Screening Visit, have a post-bronchodilator forced expiratory volume (FEV1) ≥30% and <80% of predicted and FEV1/forced vital capacity (FVC) <70% (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II or III).

Patient Exclusion Criteria

1. Not receiving invasive mechanical ventilation or non invasive ventilation2. More than 96 hours from the onset of ARDS3. Age < 18 years4. Known to be pregnant or breastfeeding5. Participation in a clinical trial of interferon therapies, immune plasma therapies or immunoglobulin within 30 days6. Major trauma in the prior 5 days7. Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year8. WHO Class III or IV pulmonary hypertension9. Pulmonary embolism within past 3 months10. Currently receiving extracorporeal life support (ECLS)11. Currently receiving renal replacement therapy12. Severe chronic liver disease with Child-Pugh score > 1213. DNAR (Do Not Attempt Resuscitation) order in place14. Treatment withdrawal imminent within 24 hours15. Prisoners16. Non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available.17. Enrolled in a concomitant clinical trial of interferon therapies, immune plasma therapies or immunoglobulin.18. IgA deficiency

Trial Details

Identifiers

Identifier Owner
EudraCT2020-001391-15 European Clinical Trials Database
V1Mar2020 -
V323Oct2020 -

Organisations

  • Affiliations Grifols

Trial Dates

  • Initiation Dates

    Actual : 24 Apr 2020

  • End Dates

    Planned : 24 Apr 2021

Other Details

  • Design double-blind; parallel; prospective; randomised
  • Phase of Trial Phase II
  • Location Ireland
  • Focus Therapeutic Use

Interventions

Drugs Route Formulation
Alpha 1-antitrypsinPrimary Drug Intravenous Infusion

INN-Proposed INN: HUMAN ALPHA1-PROTEINASE INHIBITOR
Investigational Medicinal Product Trade Name: Prolastin
Name of the Marketing Authorisation Holder: Grifols Deutschland GmbH
Country which granted the Marketing Authorisation: Germany
Pharmaceutical Form: Powder and solvent for solution for infusion
IMP Routes of Administration: Intravenous use
Active Substance CAS number: 9041-92-3
Active Substance other descriptive name: HUMAN ALPHA1-PROTEINASE INHIBITOR
EV Substance code: SUB130886
Active Substance INN: HUMAN ALPHA1-PROTEINASE INHIBITOR
Active Substance Concentration unit: mg milligram(s)
Active Substance Concentration type: not less then
Active Substance Concentration: 120
Chemical Origin Active Substance: yes

Number Of treatment arms In the trial: 3

Is placebo used in this trial?: yes

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
Mandy Jackson
RCSI Smurfit Building
dublin
Postcode: county dub
Ireland
Telephone: +353852147569
mandyjackson@Rcsi.ie
show details
Royal College of Surgeons Ireland Ireland

Centres

Centre Name Location Trial Centre Country
Royal College of Surgeons Ireland Dublin Ireland

Trial History

Event Date Event Type Comment
15 Apr 2021 Status change - completed Status changed from recruiting to completed. Updated 15 Apr 2021
15 Apr 2021 Other trial event Last checked against European Clinical Trials Database record. Updated 15 Apr 2021
26 Oct 2020 Completion date Planned End Date changed from 24 Aug 2020 to 24 Apr 2021. Updated 27 Oct 2020
28 Apr 2020 Other trial event New source identified and integrated European Clinical Trials Database (EudraCT2020-001391-15). Updated 28 Apr 2020
26 Apr 2020 Status change - recruiting Status changed from planning to recruiting. Updated 28 Apr 2020
30 Mar 2020 New trial record New trial record Updated 30 Mar 2020
25 Mar 2020 Other trial event According to a Grifols media release, the company will is collaborating with certain hospitals in the design of this study. Updated 30 Mar 2020

References

  1. European Clinical Trials Database. Trial-Reg 2016;.

    Available from: URL: https://www.clinicaltrialsregister.eu
  2. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2016;.

    Available from: URL: http://clinicaltrials.gov
  3. Grifols. Grifols Announces Formal Collaboration with US Government to Produce the First Treatment Specifically Targeting COVID-19. Media-Rel 2020;.

    Media Release
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