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

May 8, 2022 updated by: Singapore General Hospital

Using GM-CSF as a Host Directed Therapeutic Against COVID-19 - a Phase 2 Investigator Initiated Trial

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
2

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Singapore
      • Singapore, Singapore
        • Singapore General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

21 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Group A: Treatment Group
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
Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.
Other Names:
  • GM-CSF
  • Leukine®
  • Granulocyte-Macrophage Colony Stimulating Factor
PLACEBO_COMPARATOR: Group B: Placebo Group
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%
IV normal saline 0.9% for 5 days
EXPERIMENTAL: Group C
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
Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.
Other Names:
  • GM-CSF
  • Leukine®
  • Granulocyte-Macrophage Colony Stimulating Factor
EXPERIMENTAL: Group D
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
Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.
Other Names:
  • GM-CSF
  • Leukine®
  • Granulocyte-Macrophage Colony Stimulating Factor
EXPERIMENTAL: Group E
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
Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.
Other Names:
  • GM-CSF
  • Leukine®
  • Granulocyte-Macrophage Colony Stimulating Factor

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Measuring oxygenation
Time Frame: Day 1 to Day 6
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Singapore General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 2, 2020

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 26, 2022

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 4, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 8, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 21, 2020

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 26, 2020

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 10, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 8, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • SH-Leuk-01

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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