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

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ClinicalTrials.gov Identifier: NCT04400929
Recruitment Status : Recruiting
First Posted : May 26, 2020
Last Update Posted : July 7, 2020
Sponsor:
Information provided by (Responsible Party):
Singapore General Hospital

Tracking Information
First Submitted Date  ICMJE May 8, 2020
First Posted Date  ICMJE May 26, 2020
Last Update Posted Date July 7, 2020
Actual Study Start Date  ICMJE June 2, 2020
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 21, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Using GM-CSF as a Host Directed Therapeutic Against COVID-19
Official Title  ICMJE Using GM-CSF as a Host Directed Therapeutic Against COVID-19 - a Phase 2 Investigator Initiated Trial
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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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)
Masking Description:
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.
Primary Purpose: Treatment
Condition  ICMJE
  • COVID
  • Sars-CoV2
  • ARDS, Human
Intervention  ICMJE
  • Drug: Sargramostim
    Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.
    Other Names:
    • GM-CSF
    • Granulocyte-Macrophage Colony Stimulating Factor
    • Leukine®
  • Other: Normal Saline 0.9%
    IV normal saline 0.9% for 5 days
Study Arms  ICMJE
  • 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
    Intervention: Drug: Sargramostim
  • 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
    Intervention: Other: Normal Saline 0.9%
  • 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)
    Intervention: Drug: Sargramostim
  • 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
    Intervention: Drug: Sargramostim
  • 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)
    Intervention: Drug: Sargramostim
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 21, 2020)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2022
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jenny Low, MBBS 65767757 jenny.low@singhealth.com.sg
Listed Location Countries  ICMJE Singapore
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04400929
Other Study ID Numbers  ICMJE SH-Leuk-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Singapore General Hospital
Study Sponsor  ICMJE Singapore General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jenny Low, MBBS Singapore General Hospital
PRS Account Singapore General Hospital
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP