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

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.

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04326920

Acronym

SARPAC

Enrollment

Registered

2020-03-30

Start date

2020-03-24

Completion date

2021-02-26

Last updated

2022-11-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

COVID-19

Keywords

GM-CSF, Acute Lung Injury, Hypoxia, Acute Respiratory Distress Syndrome, Corona virus, COVID-19, SARS (Severe Acute Respiratory Syndrome), Alveolar Macrophage, Acute Hypoxic respiratory failure

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.

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 disease 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.

Interventions

DRUGSargramostim

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

OTHERControl

Standard of care

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

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)

Design outcomes

Primary

Measure	Time frame	Description
Improvement in Oxygenation	on Day 6 or hospital discharge, whichever came first	Mean Change from Baseline in PaO2/FiO2 on Day 6 or hospital discharge, whichever came first

Secondary

Measure	Time frame	Description
Number of Days in Hospital	through study completion, an average of 5 months	—
Number of Participants With Nosocomial Infection no./Total no (%)	during hospital admission (up to 28 days)	—
Death	at 28 days	—
Number of Participants Progressed to Mechanical Ventilation and/or ARDS	during hospital admission (up to 28 days)	—
Time to Clinical Sign Score < 6 for at Least 24h	During hospital admission (up to 28 days)	Clinical Sign score (0-18) by scoring 6 clinical signs from 0 to 3 (0 = absent, 1 = mild, 2 = moderate and 3 = severe): Fever (0 = \<37°C; 1 = 37.1-38°C; 2 = 38.1-39°C; 3 = \>39°C) last 24h; Cough; Fatigue; Shortness of breath; Diarrhea; Body pain. Higher values represent a worse outcome
Change in Clinical Sign Score	at baseline, at day 6	Clinical Sign score (0-18) by scoring 6 clinical signs from 0 to 3 (0 = absent, 1 = mild, 2 = moderate and 3 = severe): Fever (0 = \<37°C; 1 = 37.1-38°C; 2 = 38.1-39°C; 3 = \>39°C) last 24h; Cough; Fatigue; Shortness of breath; Diarrhea; Body pain. Higher values represent a worse outcome.
Change in (National Early Warning Score2) NEWS2 Score	at baseline, at day 6	The NEWS2 score standardises the assessment and response to acute illness. Six physiological parameters form the basis of the scoring system: respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, temperature. The total possible score ranges from 0 to 20. The higher the score the greater the clinical risk
Mean Change in 6-point Ordinal Scale for Clinical Improvement	at Baseline, at Day 6	The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO (Extracorporeal Membrane Oxygenation) ; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome
Change in Ferritin Level	at baseline, at day 6	—
Change in D-dimer Level	at baseline, at day 6	—
Change in CRP Level	at baseline, at day 6	—
Change in Lymphocyte Count	at baseline, at day 6	—
Change in Eosinophil Count	at baseline, at day 6	—
HRCT (High-Resolution Computed Tomography) Fibrosis Score	at follow-up, 10-20 weeks after day 10 or discharge, whichever comes first	The HRCT fibrosis score is a subjective assessment of the overall extent of normal attenuation, reticular abnormalities, honeycombing and traction bronchiectasis . The HRCT findings are graded on a scale of 1-4 based on the classification system: 1. normal attenuation; 2. reticular abnormality; 3. traction bronchiectasis; and 4. honeycombing. The presence of each of the above four HRCT findings is assessed independently in three (upper, middle and lower) zones of each lung. The extent of each HRCT finding was determined by visually estimating the percentage (to the nearest 5%) of parenchymal involvement in each zone. The score for each zone was calculated by multiplying the percentage of the area by the grading scale score (i.e. 1. normal attenuation; 2. reticular abnormality; 3. traction bronchiectasis; and 4. honeycombing). The six zone scores were averaged to determine the total score for each patient. The score ranges from 100 to 400, higher values represent more fibrosis.
Change in Sequential Organ Failure Assessment (SOFA Score)	at baseline, at day 6	The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points.

Countries

Belgium

Participant flow

Recruitment details

87 patients were screened in the period from 25-mar-2020 till 29-sep-2020. 87 patients were included, 81 patients were randomised, 79 patients completed the study

Participants by arm

Arm	Count
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 Sargramostim: Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration	40
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 Sargramostim: Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration Control: Standard of care	41
Total	81

Baseline characteristics

Characteristic	Total	Active Sargramostim Treatment Group	Control Group
6-category ordinal scale at baseline 3 Hospitalized, Non Invasive Mechanical Ventilation (NIMV) or High Flow Oxygen Device (HFOD)	6 Participants	1 Participants	5 Participants
6-category ordinal scale at baseline 4 Hospitalized, supplemental oxygen	71 Participants	38 Participants	33 Participants
6-category ordinal scale at baseline 5 Hospitalized, no supplemental oxygen	4 Participants	1 Participants	3 Participants
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	26 Participants	11 Participants	15 Participants
Age, Categorical Between 18 and 65 years	55 Participants	29 Participants	26 Participants
Age, Continuous	60 years	59 years	60 years
Biomarkers in serum -C5a at baseline	9.94 ng/mL	11.18 ng/mL	8.83 ng/mL
Biomarkers in serum - GM-CSF at baseline	9.12 fg/mL	9.13 fg/mL	9.12 fg/mL
Biomarkers in serum - IL-18 at baseline	131.00 pg/mL	101.3 pg/mL	150.7 pg/mL
Biomarkers in serum - IL1RA at baseline	1162 ng/mL	839.3 ng/mL	1288 ng/mL
Biomarkers in serum - IL-6 at baseline	11.54 pg/mL	11.47 pg/mL	11.54 pg/mL
Biomarkers in serum - IL-8 at baseline	23.99 pg/mL	22.51 pg/mL	27.44 pg/mL
Biomarkers in serum - TNF at baseline	14.99 pg/mL	16.32 pg/mL	14.77 pg/mL
Body Mass Index (BMI) at baseline	28.0 kg/m^2	28.6 kg/m^2	27.6 kg/m^2
Comorbidity at baseline Arterial hypertension	14 Participants	7 Participants	7 Participants
Comorbidity at baseline Cancer	4 Participants	2 Participants	2 Participants
Comorbidity at baseline Cardiovascular disease	1 Participants	0 Participants	1 Participants
Comorbidity at baseline Chronic kidney disease	1 Participants	0 Participants	1 Participants
Comorbidity at baseline Chronic lung disease	0 Participants	0 Participants	0 Participants
Comorbidity at baseline Diabetes mellitus	16 Participants	9 Participants	7 Participants
Comorbidity at baseline Patients without reported comorbidities	45 Participants	22 Participants	23 Participants
Comorbidity at baseline Severe liver disease	0 Participants	0 Participants	0 Participants
Concomitant medication at randomization Antibiotics	3 Participants	1 Participants	2 Participants
Concomitant medication at randomization Antiviral drugs (Remdesivir)	3 Participants	3 Participants	0 Participants
Concomitant medication at randomization Glucocorticoids	20 Participants	11 Participants	9 Participants
Concomitant medication at randomization Hydroxychloroquine	50 Participants	24 Participants	26 Participants
Concomitant medication at randomization Patients without reported concomitant medication	5 Participants	1 Participants	4 Participants
Days since hospitalization at baseline	3.0 days	3 days	3 days
Days since symptom onset at baseline	11.0 day	11 day	10 day
Lab values - alanine aminotransferase at baseline	0.58 ukat/L	0.59 ukat/L	0.57 ukat/L
Lab values - aspartate aminotransferase at baseline	0.65 ukat/L	0.62 ukat/L	0.65 ukat/L
Lab values - C-reactive protein at baseline	74.5 mg/L	73.2 mg/L	83 mg/L
Lab values - creatinine at baseline	77.35 micromol/L	75.14 micromol/L	78.68 micromol/L
Lab values - D-dimer at baseline	3.81 nmol/L	4.36 nmol/L	3.61 nmol/L
Lab values - eosinophil count at baseline	0.02 cells x10^9/L	0.01 cells x10^9/L	0.02 cells x10^9/L
Lab values - ferritin at baseline	721 mcg/L	736.5 mcg/L	721 mcg/L
Lab values - lactate dehydrogenase at baseline	5.26 ukat/L	4.98 ukat/L	5.98 ukat/L
Lab values - lymphocyte count at baseline	1.00 cells x10^9/L	1.08 cells x10^9/L	0.88 cells x10^9/L
Oxygenation - P(A-a)O2 gradient at baseline	47.65 mmHg	50.15 mmHg	45.55 mmHg
Oxygenation - PaO2/FiO2 ratio at baseline	295 ratio	291.5 ratio	297 ratio
Race/Ethnicity, Customized Arabian	4 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Black	4 Participants	4 Participants	0 Participants
Race/Ethnicity, Customized White	73 Participants	34 Participants	39 Participants
Sex: Female, Male Female	30 Participants	14 Participants	16 Participants
Sex: Female, Male Male	51 Participants	26 Participants	25 Participants
Smoking status at baseline Current	3 Participants	0 Participants	3 Participants
Smoking status at baseline Former	34 Participants	18 Participants	16 Participants
Smoking status at baseline Never	44 Participants	22 Participants	22 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	4 / 40	8 / 41
other Total, other adverse events	22 / 40	20 / 41
serious Total, serious adverse events	6 / 40	6 / 41

Outcome results

Primary

Improvement in Oxygenation

Mean Change from Baseline in PaO2/FiO2 on Day 6 or hospital discharge, whichever came first

Time frame: on Day 6 or hospital discharge, whichever came first

Population: 73 of the 81 patients reached the evaluable primary endpoint. 2 patient discontinued prematurely, 3 patients refused arterial puncture at day 6, 3 patients were excluded because they had a negative P(A-a)O2 gradient at randomization or day 6, signifying an error in FiO2 recording.

Arm	Measure	Value (MEAN)	Dispersion
Active Sargramostim Treatment Group	Improvement in Oxygenation	25.7 ratio	Standard Deviation 85.3
Control Group	Improvement in Oxygenation	29.7 ratio	Standard Deviation 71.88

Secondary

Change in Clinical Sign Score

Clinical Sign score (0-18) by scoring 6 clinical signs from 0 to 3 (0 = absent, 1 = mild, 2 = moderate and 3 = severe): Fever (0 = \<37°C; 1 = 37.1-38°C; 2 = 38.1-39°C; 3 = \>39°C) last 24h; Cough; Fatigue; Shortness of breath; Diarrhea; Body pain. Higher values represent a worse outcome.