Sargramostim in Patients With Acute Hypoxic Respiratory Failure Due to COVID-19 (SARPAC)

Sponsor

University Hospital, Ghent (Other)

Overall Status

Completed

CT.gov ID

NCT04326920

Collaborator

Flanders Institute of Biotechnology (Other)

Enrollment

Locations

Arms

11.1

Actual Duration (Months)

Patients Per Site

1.8

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Sargramostim Other: Control	Phase 4

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 desease 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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.

Actual Study Start Date :

Mar 24, 2020

Actual Primary Completion Date :

Sep 28, 2020

Actual Study Completion Date :

Feb 26, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Active sargramostim treatment group Inhaled sargramostim 125mcg twice daily for 5 days on top of standard of care. Upon progression to ARDS and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125mcg/m2 body surface area once daily 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	Drug: Sargramostim Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration Other Names: LEUKINE
Placebo Comparator: Control group standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards, will have the option (clinician's decision) to initiate IV sargramostim 125mcg/m2 body surface area once daily for 5 days	Drug: Sargramostim Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration Other Names: LEUKINE Other: Control Standard of care

Arm

Intervention/Treatment

Active Comparator: Active sargramostim treatment group

Inhaled sargramostim 125mcg twice daily for 5 days on top of standard of care. Upon progression to ARDS and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125mcg/m2 body surface area once daily 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

Drug: Sargramostim

Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration

Other Names:

LEUKINE

Placebo Comparator: Control group

standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards, will have the option (clinician's decision) to initiate IV sargramostim 125mcg/m2 body surface area once daily for 5 days

Drug: Sargramostim

Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration

Other Names:

LEUKINE

Other: Control

Standard of care

Outcome Measures

Primary Outcome Measures

Improvement in oxygenation at a dose of 250 mcg daily during 5 days improves oxygenation in COVID-19 patients with acute hypoxic respiratory failure [at end of 5 day treatment period]
by mean change in PaO2/FiO2 (PaO2=Partial pressure of oxygen; FiO2= Fraction of inspired oxygen)

Secondary Outcome Measures

Incidence of AE (Adverse Event) [at end of 5 day treatment period, 10 day period, 10-20 weeks]
Incidence of SAEs (Serious Adverse Event) [at end of 5 day treatment period, 10 day period, 10-20 weeks]
Clinical Status using 6-point ordinal scale [at end of 5 day treatment period, 10 day period, 10-20 weeks]
Clinical Status using Clincal sign score [at end of 5 day treatment period, 10 day period,10-20 weeks]
Clinical Status using SOFA score (Sequential Organ Failure Assessment score), [at end of 5 day treatment period, 10 day period, 10-20 weeks]
Clinical Status using NEWS2 score (National Early Warning Score) [at end of 5 day treatment period, 10 day period, 10-20 weeks]
incidence of severe or life-threatening bacterial, invasive fungal or opportunistic infection [during hospital admission (up to 28 days)]
demonstrated by bacterial or fungal culture
number of patients requiring initiation of mechanical ventilation [during hospital admission (up to 28 days)]
Number of deaths due to any cause at 4 weeks [4 weeks post inclusion]
Number of deaths due to any cause at 20 weeks [20 weeks post inclusion]
number of patients developing features of secondary haemophagocytic lymphohistiocytosis [at enrolment, end of 5 day treatment period, 10 day period, 10-20 weeks]
defined by HS (Hemophagocytic Syndrome) score
long term Clinical status defined by 6-point ordinal scale [10-20 week]
long term Clinical status defined by chest X-ray [10-20 weeks]
long term Clinical status defined lung function [10-12 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)