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    Summary
    EudraCT Number:2020-001254-22
    Sponsor's Protocol Code Number:SARPAC
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-03-24
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2020-001254-22
    A.3Full title of the trial
    A prospective, randomized, open-label, interventional study to investigate the efficacy of sargramostim (Leukine®) in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Sargramostim in patients with acute hypoxic respiratory failure due to COVID-19
    A.3.2Name or abbreviated title of the trial where available
    SARPAC
    A.4.1Sponsor's protocol code numberSARPAC
    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 SponsorUniversity Hospital Ghent
    B.1.3.4CountryBelgium
    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 supportUniversity Hospital Ghent
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportPartner Therapeutics
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Ghent
    B.5.2Functional name of contact pointHIRUZ CTU
    B.5.3 Address:
    B.5.3.1Street AddressC. Heymanslaan 10
    B.5.3.2Town/ cityGhent
    B.5.3.3Post code9000
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3293320500
    B.5.5Fax number+3293320520
    B.5.6E-mailhiruz.ctu@uzgent.be
    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 Leukine
    D.2.1.1.2Name of the Marketing Authorisation holderPartner Therapeutics
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.1Product nameLeukine
    D.3.4Pharmaceutical form Powder for nebuliser solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSARGRAMOSTIM
    D.3.9.1CAS number 123774-72-1
    D.3.9.4EV Substance CodeSUB10450MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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.IMP: 2
    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 Leukine
    D.2.1.1.2Name of the Marketing Authorisation holderPartner Therapeutics
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.1Product nameLeukine
    D.3.4Pharmaceutical form Powder 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 INNSARGRAMOSTIM
    D.3.9.1CAS number 123774-72-1
    D.3.9.4EV Substance CodeSUB10450MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute hypoxic respiratory failure of COVID-19 patients
    E.1.1.1Medical condition in easily understood language
    Acute hypoxic respiratory failure of COVID-19 patients
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10074615
    E.1.2Term Hypoxic respiratory failure
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to investigate whether the administration of inhaled sargramostim (Leukine®) at a dose of 250 mcg daily during 5 days improves oxygenation in COVID-19 patients with acute hypoxic respiratory failure .
    E.2.2Secondary objectives of the trial
    - to study if early intervention with sargramostim is safe (number of AEs/SAEs)
    - to study if early intervention with inhaled sargramostim affects clinical outcome defined by
    duration of hospital stay, 6-point ordinal scale, clinical sign score, SOFA score, NEWS2 score
    - to study if early intervention with sargramostim affects the rate of nosocomial infection
    - to study if early intervention with inhaled sargramostim affects progression to mechanical ventilation and/or ARDS
    - to study if treatment with sargramostim affects all-cause mortality rate at 4 and 20 weeks post inclusion
    -to study if treatment with sargramostim affects features of secondary haemophagocytic lymphohistiocytosis, defined by HS score
    - to study if treatment with sargramostim has a favourable effect on long term 10-20 week follow up
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria

    - Recent (≤2weeks prior to randomization) confident diagnosis of COVID-19 confirmed by antigen detection and/or PCR, and/or seroconversion or any other emerging and validated diagnostic test.
    - In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h) chest-CT scan (confirmed by a radiologist and pulmonary physician as probable COVID-19), a patient can be enrolled as probable COVID-19 infected. In all cases, this needs confirmation by later seroconversion.
    - Presence of acute hypoxic respiratory failure defined as (either or both)
    • saturation below 93% on minimal 2 l/min O2
    • PaO2/FiO2 below 350
    - Admitted to specialized COVID-19 ward
    - Age 18-80
    - Male or Female
    - Willing to provide informed consent
    E.4Principal exclusion criteria
    - Patients with known history of serious allergic reactions, including anaphylaxis, to human granulocyte-macrophage colony stimulating factor such as sargramostim, yeast-derived products, or any component of the product.
    - mechanical ventilation before start of study
    - patients with peripheral white blood cell count above 25.000 per microliter and/or active myeloid malignancy
    -patients on high dose systemic steroids (> 20 mg methylprednisolone or equivalent)
    -patients on lithium carbonate therapy
    - Patients enrolled in another investigational drug study
    - Pregnant or breastfeeding females (all female subjects regardless of childbearing potential status must have negative pregnancy test at screening)
    - Patients with serum ferritin >2000 mcg/ml (which will exclude ongoing HLH)
    E.5 End points
    E.5.1Primary end point(s)
    To measure the effectiveness of sargramostim on restoring lung homeostasis, the primary endpoint of this intervention is measuring oxygenation after 5 DAYS of inhaled (and intravenous) treatment through assessment of pretreatment (day 0) and post-treatment (day 5) ratio of PaO2/FiO2 and through measurement of the P(A-a)O2 gradient, which can easily be performed in the setting of clinical observation of patients admitted to the COVID -19 ward or ICU COVID-19 unit. Preferentially, this measurement should be done in the upright position, while breathing room air for a minimum of 3 minutes.. If this is impossible due to need for supplemental oxygen, FiO2 and oxygen supplementation method should be recorded in patient record, so that A-a gradient can be normalized for age expected normal A-a gradient while on supplemental oxygen use.
    During the 5 day treatment period, we will perform daily measurements of oxygen saturation (pulse oximetry) in relation to FiO2, and the slope of alterations in this parameters could also be an indicator that our hypothesis is correct.
    If the patient leaves hospital prior to the day 6 analysis point, oxygenation at day of discharge will be used as value for measuring primary endpoint.
    E.5.1.1Timepoint(s) of evaluation of this end point
    day 5
    E.5.2Secondary end point(s)
    - to study if early intervention with sargramostim is safe (number of AEs/SAEs)
    Although sargramostim has been given previously by inhalation to patients with ARDS and interstitial lung disease, data on safety in patients with COVID-19 infection are currently lacking. Since we are randomizing against 5 days of no sargramostim treatment, comparison of AEs and SAEs between group A and group B will be very informative.

    -to study if early intervention with inhaled sargramostim affects clinical outcome
    defined by length of hospital stay
    mean change in 6-point ordinal scale change between day 1, day 6 and

    - to study if early intervention with sargramostim affects the rate of nosocomial infection
    Patients with viral respiratory infection are at risk of secondary bacterial infections. As part of routine clinical care, sputum samples will be collected in patients suspected of secondary bacterial pneumonia, and checked for the presence of bacteria.

    -to study if early intervention with inhaled sargramostim affects progression to mechanical ventilation and/or ARDS
    Decreasing oxygenation often leads to the need for non-invasive or invasive mechanical ventilation, and if severe enough to a diagnosis of ARDS. We will therefore as a secondary endpoint also study if early intervention with inhaled sargramostim prevents progression to criteria-defined ARDS (according to the American-European Consensus Conference (AECC) diagnostic criteria for ARDS: acute onset; ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) of 200 or less, regardless of positive end-expiratory pressure; bilateral infiltrates seen on frontal chest radiograph; and pulmonary artery wedge pressure of 18 mm Hg or less when measured, or no clinical evidence of left atrial hypertension), requiring high-flow oxygen devices, non-invasive mechanical ventilation, mechanical ventilation, by measuring the day from admission when this diagnosis is made or therapies are initiated.

    -to study if treatment with sargramostim affects all-cause mortality rate at 4 and 20 weeks post inclusion.

    -to study if treatment with sargramostim affects features of secondary haemophagocytic lymphohistiocytosis.
    A large subset of patients with severe COVID-19 developing respiratory failure might have a cytokine storm syndrome, designated as secondary haemophagocytic lymphohistiocytosis (sHLH). sHLH is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinemia with multi-organ failure. Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; hypertriglyceridemia, pulmonary involvement can present as ARDS. A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α.
    Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297•6 ng/ml in non-survivors vs 614•0 ng/ml in survivors; p<0•001) and IL-6 (p<0•0001), suggesting that mortality might be due to virally driven hyperinflammation.
    To address the effect of sargramostim treatment on sHLH, we will measure levels of ferritin, these chemokines and cytokines at the beginning of the trial day 0 and after the initial 5 day treatment. PBO including leukocytes and lymphocytes are performed on a routine clinical basis in these patients.

    - to study if treatment with sargramostim has a favourable effect on long term 10-20 week follow up
    At 10-20 weeks after discharge from hospital, patients will be seen on routine check-up by pulmonologist, who will perform a clinical exam, pulmonary function tests (including FVC, TLC and diffusion capacity), and a laboratory (ferritin, lymphocytes, leukocytes).

    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 5
    20 weeks post inclusion
    10-12 weeks after discharge from hospital
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    standard of care
    E.8.2.4Number of treatment arms in the trial2
    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 Yes
    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
    LVLS
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-03-24. Yes
    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 No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state80
    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)
    None
    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 Decision2020-03-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-02-26
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