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    Summary
    EudraCT Number:2020-001391-15
    Sponsor's Protocol Code Number:V323Oct2020
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-03-31
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2020-001391-15
    A.3Full title of the trial
    A randomized double-blind placebo-controlled, pilot trial of intravenous plasma-purified alpha-1 antitrypsin for severe COVID-19 illness.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized double-blind placebo-controlled, pilot trial of intravenous plasma-purified alpha-1 antitrypsin for severe COVID-19 illness.
    A.4.1Sponsor's protocol code numberV323Oct2020
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRoyal College of Surgeons Ireland
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHealth Research Board
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoyal College of Surgeons Ireland
    B.5.2Functional name of contact pointMandy Jackson
    B.5.3 Address:
    B.5.3.1Street AddressRCSI Smurfit Building
    B.5.3.2Town/ citydublin
    B.5.3.3Post codecounty dub
    B.5.3.4CountryIreland
    B.5.4Telephone number+353852147569
    B.5.6E-mailmandyjackson@Rcsi.ie
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Prolastin
    D.2.1.1.2Name of the Marketing Authorisation holderGrifols Deutschland GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHUMAN ALPHA1-PROTEINASE INHIBITOR
    D.3.9.1CAS number 9041-92-3
    D.3.9.3Other descriptive nameHUMAN ALPHA1-PROTEINASE INHIBITOR
    D.3.9.4EV Substance CodeSUB130886
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number120
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    acute respiratory distress sydnrome (ARDS) secondary to Covid-19
    E.1.1.1Medical condition in easily understood language
    acute respiratory distress sydnrome (ARDS) secondary to Covid-19
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10051905
    E.1.2Term Coronavirus infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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 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.
    E.2.2Secondary objectives of the trial
    determine the safety and tolerability of [IV Prolastin administered once at 120mg/kg of body weight] and [IV Prolastin administered weekly at 120mg/kg of body weight for 4 weeks], as assessed by the number of AEs and SAEs and determine the effects of [IV Prolastin administered once at 120mg per kilogram of body weight] and [IV Prolastin administered weekly at 120mg per kilogram of body weight for 4 weeks] on:
    Physiological indices of respiratory dysfunction reflecting severity of ARDS, as measured by oxygenation index (OI), respiratory compliance
    Sequential organ failure assessment (SOFA) score
    Mortality
    Time on ventilator in days
    Circulating alpha-1 antitrypsin (AAT) levels
    Circulating levels of IL-1β, IL-8, IL-10, soluble TNF receptor 1
    Development of shock
    Acute kidney injury
    Need for renal replacement therapy
    Clinical relapse
    Length of ICU stay in days
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Laboratory confirmed diagnosis of COVID-19 infection
    2. Moderate to severe ARDS with a PaO2/FiO2 ratio <200
    3. >18 years of age
    4. Patients receiving invasive mechanical ventilation or non-invasive ventilation
    E.4Principal exclusion criteria
    1. Not receiving invasive mechanical ventilation or non invasive ventilation
    2. More than 96 hours from the onset of ARDS
    3. Age < 18 years
    4. Known to be pregnant or breastfeeding
    5. Participation in a clinical trial of interferon therapies, immune plasma therapies or immunoglobulin within 30 days
    6. Major trauma in the prior 5 days
    7. Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year
    8. WHO Class III or IV pulmonary hypertension
    9. Pulmonary embolism within past 3 months
    10. Currently receiving extracorporeal life support (ECLS)
    11. Currently receiving renal replacement therapy
    12. Severe chronic liver disease with Child-Pugh score > 12
    13. DNAR (Do Not Attempt Resuscitation) order in place
    14. Treatment withdrawal imminent within 24 hours
    15. Prisoners
    16. 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
    E.5 End points
    E.5.1Primary end point(s)
    The primary effectiveness outcome measure, a continuous variable, is IL-6 in plasma as measured by ELISA.
    E.5.1.1Timepoint(s) of evaluation of this end point
    day 2 , day 7, day 14, day 21 and day 28
    E.5.2Secondary end point(s)
    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
    E.5.2.1Timepoint(s) of evaluation of this end point
    day 2 , day 7, day 14, day 21 and day 28
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial will be defined as the last patient visit for the last patient enrolled to the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Given that participants are critically unwell, they will be unable to provide consent to participate prior to enrolment. The Investigator or nominee will obtain assent from the next of kin as soon as possible and regained capacity consent if possible
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 36
    F.4.2.2In the whole clinical trial 36
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There are no arrangements in place for the IMP to be provided to trial subjects post trial participation. However, the manufacturer are willing to explore compassionate-use supply to these individuals should a clinical improvement occur in response to therapy
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-04-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-04-12
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