Using GM-CSF as a Host Directed Therapeutic Against COVID-19
Condition: COVID; Sars-CoV2; ARDS, Human
MeSH terms: COVID-19; Respiratory Distress Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      The coronavirus disease 2019 (COVID-19) has rapidly become a pandemic. COVID-19 poses a
      mortality risk of 3-7%, rising to 20% in older patients with co-morbidities. Of all infected
      patients, 15-20% will develop severe respiratory symptoms necessitating hospital admission.
      Around 5% of patients will require invasive mechanical ventilation, and up to 50% will die.

      Evidence in severe COVID-19 suggests that these patients experience cytokine storm and
      progressed rapidly with acute respiratory distress syndrome and eventual multi-organ failure.
      Early identification and immediate treatment of hyperinflammation is thus recommended to
      reduce mortality. Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) has been shown to
      be a myelopoietic growth factor that has pleiotropic effects in promoting the differentiation
      of immature precursors into polymorphonuclear neutrophils, monocytes/ macrophages and
      dendritic cells, and also in controlling the function of fully mature myeloid cells. It plays
      an important role in priming monocytes for production of proinflammatory cytokines under TLR
      and NLR stimulation. It has a broad impact on the processes driving DC differentiation and
      affects DC effector function at the mature state. Importantly, GM-CSF plays a critical role
      in host defense and stimulating antiviral immunity. Detailed studies have also shown that
      GM-CSF is necessary for the maturation of alveolar macrophages from foetal monocytes and the
      maintenance of these cells in adulthood. The known toxicology, pharmacologic and safety data
      also support the use of Leukine® in hypoxic respiratory failure and ARDS due to COVID-19.

      This study aims to recruit patients with evidence of pneumonia and hypoxia who have increased
      risk for severe disease and need for mechanical ventilation. The overall hypothesis is that
      GM-CSF has antiviral immunity, can provide the stimulus to restore immune homeostasis in the
      lung with acute lung injury from COVID-19, and can promote lung repair mechanisms, which
      would lead to improvement in lung oxygenation parameters.
    

Detailed description: 
      The hypothesis of the proposed intervention is that GM-CSF has profound effects on antiviral
      immunity, can provide the stimulus to restore immune homeostasis in the lung with acute lung
      injury post COVID-19, and can promote lung repair mechanisms, which would lead to an
      improvement in lung oxygenation parameters. This hypothesis is based on experiments performed
      in mice showing that GM-CSF treatment can prevent mortality and prevent ARDS in mice with
      post-viral acute lung injury.

      In the interim analysis of the SARPAC trial, patients who received nebulised Leukine® via a
      mesh inhaler showed a trend in improvement in their P(A-a)O2 gradient at day 6 compared to
      the SOC group. There are however, anticipated logistical difficulties of training and
      infection control concerns with administering of nebulised Leukine® via a specialised inhaler
      in the negative pressure room. Hence we propose to randomize patients with confirmed COVID-19
      and acute hypoxic respiratory failure (saturation < 94% on room air or PaO2/FiO2 <350) to
      receive iv Leukine® 125mcg/m2 once a day for 5 days on top of SOC (treatment group A), or to
      receive SOC treatment only (placebo group B). Dosing of systemic Leukine® is based on prior
      experience of using this drug in patients with pneumonia-associated ARDS.

      To measure the effectiveness of Leukine® in restoring lung homeostasis, the primary endpoint
      of this intervention is measuring oxygenation after 5 days of intravenous treatment through
      assessment of pre-treatment and post-treatment 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 inpatients. 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 these
      parameters could also be an indicator that our hypothesis is correct.

      Comparison will be between group A receiving iv Leukine® on top of standard of care (SOC) and
      placebo group B receiving SOC only. Data from the Wuhan COVID-19 epidemic show that patients
      that deteriorate are facing a prolonged period of mechanical ventilation. Therefore, the
      study will be unblinded at day 5, or at any time within the first 5 days of study should the
      patient deteriorate clinically with need for supplemental oxygen FiO2 requirement ≥ 0.5.
      Patients in group B will then have the option to receive 5 days of iv Leukine®, based on the
      treating physician's assessment. This group will be group D. Patients who require mechanical
      ventilation also have the option to receive an additional 5 days of iv Leukine®, based on the
      treating physician's assessment (group C and E).

      A total of 30 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be
      enrolled, 15 who will receive Leukine® + SOC, and 15 who will receive placebo + SOC. The
      target group of subjects is defined as confirmed COVID-19 patients with acute hypoxic
      respiratory failure admitted to the COVID-19 isolation ward. Subjects will be recruited from
      the isolation wards located in Singapore General Hospital (SGH). Subjects will be identified
      by the primary managing physicians who are infectious diseases physicians.

      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,
      triglyceride levels, etc. as well as occurrence of secondary bacterial infections.

      Patients will stop the investigational drug if there is unacceptable toxicity according to
      investigator's judgement.
    

Intervention name(s): Sargramostim; Normal Saline 0.9%
Intervention type(s): Drug; Other
Intervention description(s): Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.; IV normal saline 0.9% for 5 days
Other intervention name(s): GM-CSF; Granulocyte-Macrophage Colony Stimulating Factor; Leukine®
Intervention MeSH terms: Molgramostim; Sargramostim
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a randomized, double-blind, placebo-controlled clinical trial of iv Leukine® in 30 patients with confirmed COVID-19 and acute hypoxic respiratory failure.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: pandemic; host-directed therapeutic; GM-CSF; COVID-19; ARDS; SARS-CoV2