Clinical trial NCT04326920: Sargramostim in Patients With Acute Hypoxic Respiratory Failure Due to COVID-19 (SARPAC)
Official title: 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 (Corona Virus Disease) Patients With Acute Hypoxic Respiratory Failure.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID-19
Keywords: GM-CSF
Acute Lung Injury
Hypoxia
Acute Respiratory Distress Syndrome
Corona virus
COVID-19
SARS (Severe Acute Respiratory Syndrome)
Alveolar Macrophage
Acute Hypoxic respiratory failure
Lead sponsor: University Hospital, Ghent
Sponsor class: OTHER
Collaborators: name: Flemish institute of biotechnology (VIB)
First posted: 2020-03-30
Enrollment: 87
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Phase IV study to evaluate the effectiveness of additional inhaled sargramostim (GM-CSF) versus standard of care on blood oxygenation in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure.

Detailed description: Leukine® is a yeast-derived recombinant humanized granulocyte-macrophage colony stimulating factor (rhuGM-CSF, sargramostim) and the only FDA approved GM-CSF. GMCSF, a pleiotropic cytokine, is an important leukocyte growth factor known to play a key role in hematopoiesis, effecting the growth and maturation of multiple cell lineages as well as the functional activities of these cells in antigen presentation and cell mediated immunity.

Leukine inhalation or intravenous administration, as an adjuvant therapy, may confer benefit to patients with ARDS (Acute Respiratory Distress Syndrome) due to COVID-19 exposure, who are at significant risk of mortality. While there is no active IND (Investigational New Drug) for Leukine in the proposed patient population, Leukine is being studied in Fase II as an adjuvant therapy in the management of life-threatening infections to boost the hosts innate immune response to fight infection, reduce the risk of secondary infection, and in varied conditions as prevention of infection during critical illness. Inhaled Leukine has also been successfully used as primary therapy to improve oxygenation in patients with disordered gas exchange in the lungs. We propose that based on preclinical and clinical data, Leukine inhalation, as an adjuvant therapy, has an acceptable benefit-risk for use in patients with hypoxic respiratory failure and ARDS due to COVID-19 exposure, who are at significant risk of mortality.

Confirmed COVID19 patients with hypoxic respiratory failure (saturation below 93% on minimal 2 l/min O2) will be randomized to receive sargramostim 125mcg twice daily for 5 days as a nebulized inhalation on top of standard of care, or to receive standard of care treatment. Upon progression of disease requiring initiation of mechanical ventilatory support within the 5 day period, in patients in the active group, inhaled sargramostim will be replaced by intravenous sargramostim 125mcg/m2 body surface area until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment. In the control group progressive disease requiring mechanical ventilatory support, from day 6 onwards, the treating physician will have the option to initiate IV sargramostim 125mcg/m2 body surface area for 5 days. Safety data, including blood leukocyte counts, will be collected in all patients. Efficacy data will also be collected and will include arterial blood gases, oxygenation parameters, need for ventilation, lung compliance, organ function, radiographic changes, ferritin levels, etc. as well as occurrence of secondary bacterial infections.

Eligibility criteria: Inclusion Criteria:

* Recent (≤2weeks prior to Randomization) confident diagnosis of COVID-19 confirmed by antigen detection and/or PCR (Polymerase Chain Reaction), 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 300
* Admitted to specialized COVID-19 ward
* Age 18-80
* Male or Female
* Willing to provide informed consent

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)

Primary outcomes:
measure: Improvement in Oxygenation
timeFrame: on Day 6 or hospital discharge, whichever came first
Secondary outcomes:
measure: Mean Change in 6-point Ordinal Scale for Clinical Improvement
timeFrame: at Baseline, at Day 6
measure: Number of Days in Hospital
timeFrame: through study completion, an average of 5 months
measure: Number of Participants With Nosocomial Infection no./Total no (%)
timeFrame: during hospital admission (up to 28 days)
measure: Death
timeFrame: at 28 days
measure: Number of Participants Progressed to Mechanical Ventilation and/or ARDS
timeFrame: during hospital admission (up to 28 days)
measure: Time to Clinical Sign Score < 6 for at Least 24h
timeFrame: During hospital admission (up to 28 days)
measure: Change in Clinical Sign Score
timeFrame: at baseline, at day 6
measure: Change in (National Early Warning Score2) NEWS2 Score
timeFrame: at baseline, at day 6
measure: Change in Sequential Organ Failure Assessment (SOFA Score)
timeFrame: at baseline, at day 6
measure: Change in Ferritin Level
timeFrame: at baseline, at day 6
measure: Change in D-dimer Level
timeFrame: at baseline, at day 6
measure: Change in CRP Level
timeFrame: at baseline, at day 6
measure: Change in Lymphocyte Count
timeFrame: at baseline, at day 6
measure: Change in Eosinophil Count
timeFrame: at baseline, at day 6
measure: HRCT (High-Resolution Computed Tomography) Fibrosis Score
timeFrame: at follow-up, 10-20 weeks after day 10 or discharge, whichever comes first
Other outcomes:
Locations:
city: Brugge
country: Belgium
facility: AZ Sint Jan Brugge
city: Gent
country: Belgium
facility: University Hospital Ghent
city: Jette
country: Belgium
facility: UZ Brussel
city: Roeselare
country: Belgium
facility: AZ Delta Roeselare
Study officials:
affiliation: University Hospital, Ghent
name: Bart Lambrecht
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mehta P, Porter JC, Manson JJ, Isaacs JD, Openshaw PJM, McInnes IB, Summers C, Chambers RC. Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities. Lancet Respir Med. 2020 Aug;8(8):822-830. doi: 10.1016/S2213-2600(20)30267-8. Epub 2020 Jun 16.
citation: Bosteels C, Maes B, Van Damme K, De Leeuw E, Declercq J, Delporte A, Demeyere B, Vermeersch S, Vuylsteke M, Willaert J, Bolle L, Vanbiervliet Y, Decuypere J, Libeer F, Vandecasteele S, Peene I, Lambrecht B. Sargramostim to treat patients with acute hypoxic respiratory failure due to COVID-19 (SARPAC): A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Jun 5;21(1):491. doi: 10.1186/s13063-020-04451-7.