Using GM-CSF as a Host Directed Therapeutic Against COVID-19

NCT04400929 | Completed Phase 2 FDA Drug

• 1 other identifier: SH-Leuk-01
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

COVID; Sars-CoV2; ARDS, Human

Keywords

pandemic; host-directed therapeutic; GM-CSF; COVID-19; ARDS; SARS-CoV2

Outcome Measures

Primary Outcomes (1)

• Measuring oxygenation

  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.

  Day 1 to Day 6

Study Arms (5)

Group A: Treatment Group

EXPERIMENTAL

Day 1 - 5: Receive study medication Leukine® 125mcg/m2 body surface area daily (via infusion into the vein) in addition to standard of care treatments

Drug: Sargramostim

Group B: Placebo Group

PLACEBO COMPARATOR

Day 1 - 5: Receive normal saline 0.9% daily (via infusion into the vein) in addition to standard of care treatments

Other: Normal Saline 0.9%

Group C

EXPERIMENTAL

Day 6 - 10: Subjects in Group A who require mechanical ventilation to receive an additional 5 days of IV Leukine® 125mcg/m2 body surface area daily, in addition to standard of care treatments (based on the treating physician's assessment)

Drug: Sargramostim

Group D

EXPERIMENTAL

Day 6 - 10: Subjects from Group B to receive study medication (based on the treating physician's assessment), Leukine® 125mcg/m2 body surface area daily (via infusion into the vein) in addition to standard of care treatments

Drug: Sargramostim

Group E

EXPERIMENTAL

Day 11 - 15: Subjects in Group D who require mechanical ventilation to receive an additional 5 days of IV Leukine® 125mcg/m2 body surface area daily, in addition to standard of care treatments (based on the treating physician's assessment)

Drug: Sargramostim

Interventions

Sargramostim DRUG

Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.

Also known as: GM-CSF, Granulocyte-Macrophage Colony Stimulating Factor, Leukine®

Group A: Treatment Group; Group C; Group D; Group E

Normal Saline 0.9% OTHER

IV normal saline 0.9% for 5 days

Group B: Placebo Group

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• SARS-CoV-2 PCR-confirmed COVID-19 infection
• Presence of acute hypoxic respiratory failure defined as (either or both)
• Saturation \< 94% on room air or requiring supplemental oxygen
• PaO2/FiO2 below 350
• Age 21-80
• Able and willing to provide informed consent

You may not qualify if:

• Patients who are already on supplemental oxygen of FiO2 ≥ 0.4
• Patients with known history of serious allergic reactions, including anaphylaxis, to human GM-CSF such as Leukine®, yeast-derived products, or any component of the product.
• Mechanical ventilation before start of study
• Patients enrolled in another investigational drug study
• Pregnant or breastfeeding females (all female subjects of childbearing potential status must have negative pregnancy test at screening)
• Patients with peripheral white blood cell count above 25,000 per microliter and/or active myeloid malignancy
• Patients on high dose systemic steroids (\> 20mg methylprednisolone or equivalent)
• Patients on lithium carbonate therapy
• Patients with serum ferritin \>2000 mcg/ml (which will exclude ongoing HLH)

Sponsors & Collaborators

• Singapore General Hospital: lead

Study Sites (1)

Singapore General Hospital

Singapore, Singapore

Location

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MeSH Terms

Conditions

Respiratory Distress Syndrome; COVID-19

Interventions

sargramostim; Granulocyte-Macrophage Colony-Stimulating Factor; Colony-Stimulating Factors; Saline Solution

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections

Intervention Hierarchy (Ancestors)

Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Jenny Low, MBBS

  Singapore General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This is a double-blind study to investigate immediate versus delayed treatment of iv Leukine® in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 8, 2020
• First Posted: May 26, 2020
• Study Start: June 2, 2020
• Primary Completion: January 26, 2022
• Study Completion: February 4, 2022
• Last Updated: May 10, 2022

Record last verified: 2022-05

Locations

SG (1)