COVID-19, SARS-CoV-2
Conditions
Keywords
COVID-19, sargramostim, Leukine, rhu-GM-CSF, acute hypoxemia, iLeukPulm, SARS-CoV-2
Brief summary
The purpose of this research is to find out if a drug (sargramostim) also known as Leukine® could help patient recover faster from COVID-19. Sargramostim may help the lungs recover from the effects of COVID-19, and this research study will help to find this out.
Detailed description
This Phase 2 study is designed as a proof of concept study and will randomize 2:1 approximately 120 patients with COVID-19 associated acute hypoxemia: of which 80 patients will receive sargramostim plus standard of care, and 40 patients who will receive standard of care alone. The aim of the study is to determine if inhaled sargramostim, as an adjunct to institutional standard of care, improves clinical outcomes in patients with COVID-19-associated acute hypoxemia. All patients on the sargramostim arm will be treated with 125 mcg inhaled sargramostim twice daily for 5 days, in addition to institutional standard of care. If required, upon progression to an invasive mechanical ventilator, administration of sargramostim may be delivered by intravenous infusion to complete a total of 5 days (including days delivered via inhalation). GM-CSF is a critical cytokine for healthy pulmonary function and is necessary for the maturation and maintenance of alveolar macrophages. Preclinical studies have shown GM-CSF confers resistance to influenza by enhancing innate immune mechanisms that depend on alveolar macrophages for their health and normal functioning. Clinical studies of sargramostim in patients with severe sepsis and respiratory dysfunction or acute respiratory distress syndrome have shown improvements in oxygenation and lung compliance.
Interventions
DRUGSargramostim
Sargramostim is a glycosylated, yeast-derived recombinant human granulocyte-macrophage colony stimulating factor (rhu-GM-CSF). Dosage for inhaled sargramostim: 125 mcg twice a day. Dosage for intravenous sargramostim: 125mcg/m2/day given over a 4 hour period.
DRUGStandard of care
Standard of care for COVID-19
Sponsors
United States Department of Defense
Partner Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This Phase 2, randomized, open-label study will enroll approximately 120 patients with COVID-19 associated acute hypoxemia. It is a randomized 2:1 study to evaluate sargramostim treatment plus institutional standard of care compared to institutional standard of care alone.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients aged ≥ 18 years * Patients (or legally authorized decision maker) must provide informed consent * Test positive for SARS-CoV-2 virus by PCR * Admitted to hospital * Presence of acute hypoxemia defined as (either or both) * saturation below 93% on ≥ 2 L/min oxygen supplementation * PaO2/FiO2 below 350
Exclusion criteria
* Patients requiring invasive (mechanical ventilation) or non-invasive (CPAP, BiPAP for hypoxemia) ventilation or ECMO (Note: oxygen supplementation using high flow oxygen systems or low flow oxygen systems would not exclude patients from this study) * Intractable metabolic acidosis * Cardiogenic pulmonary edema * Hypotension requiring use of vasopressors * Hyperferritinemia (serum ferritin ≥2,000 mcg/L) * White blood cell count \> 50,000/mm3 * Participation in another interventional clinical trial for COVID-19 therapy * Highly immunosuppressive therapy or anti-cancer combination chemotherapy within 24 hours prior to first dose of sargramostim * Known or suspected intolerance or hypersensitivity to sargramostim, or any component of the product * Previous experience of severe and unexplained side effects during aerosol delivery of any kind of medical product * Presence of any preexisting illness that, in the opinion of the Investigator, would place the patient at an unreasonably increased risk through participation in this study * Pregnant or breastfeeding females * Severe or uncontrolled pulmonary comorbid conditions, including systemic steroid dependent asthma, systemic steroid dependent COPD, oxygen dependent COPD, lung transplant, known interstitial lung disease, or cystic fibrosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygenation Parameter of P(A-a)O2 Gradient by Day 6 | 1-6 days | The P(A-a)O2 gradient is a measure of how well the oxygen moves from the lungs into the bloodstream. Patients with a high gradient have less oxygen in the bloodstream. |
| Number of Patients Who Have Been Intubated by Day 14 | 1-14 days | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Treatment-related Adverse Events | 1-58 days | Number of patients with side effects related to treatment with sargramostim. Patients on the control arm did not receive sargramostim. |
| Survival Time of Patients | Day 1-90 | — |
| Causes of Death | Day 1-90 | — |
| Change From Baseline in P/F Ratio | From Day 1 up to Day 6 | The P/F ratio is a simple way to assess severity of low blood oxygen. It's the ratio of PaO2 (arterial oxygen partial pressure obtained from an arterial blood gas) to FiO2 (fraction of inspired oxygen expressed as a decimal). A normal arterial blood is gas 80 to 100 mm Hg. Normal room air has 21% or 0.21 oxygen. So a normal P/F ratio is about 380-475. A high P/F ratio means more oxygen in the bloodstream and a low P/F ratio means less oxygen in the bloodstream. This outcome measure compares the improvement (increase) in P/F ratio between treatment arms. |
| Change in Ordinal Scale | 1-28 days | The ordinal scale was used, where 0 is not hospitalized, no clinical or virological evidence of infection, and 8 is death. |
| Number of Patients Requiring Invasive Mechanical Ventilation | Day 1-90 | The is the number of patients that needed to be placed on a ventilator. |
| Duration of Invasive, Non-invasive and Supplemental Oxygen | Day 1-90 | This endpoint includes duration of any/all types of respiratory support |
| Duration of Hospitalization | Day 1-90 | — |
| Time to Normalization of White Blood Cells and Lymphocytes | Day 1-90 | Normalization of WBC and lymphocyte count is defined as whether WBC and lymphocyte count results are normal or below normal or above normal ranges at available visits. |
| Number of Participants Wtih Nosocomial Infections | Day 1-90 | Nosocomial infections also referred to as healthcare-associated infections (HAI), are infection(s) acquired during the process of receiving health care that was not present during the time of admission. |
| All Cause 28-day Mortality | 1-28 days | — |
Countries
United States
Participant flow
Pre-assignment details
One participant was randomized to the sargramostim arm and then withdrew consent prior to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Sargramostim Arm Day 1 - 5: Sargramostim treatment in addition to standard of care for COVID-19
Sargramostim: Sargramostim is a recombinant human granulocyte-macrophage colony stimulating factor (rhu-GM-CSF). Dosage for inhaled sargramostim: 125 mcg twice a day. Dosage for intravenous sargramostim: 125mcg/m2/day given over a 4 hour period.
Standard of care: Standard of care for COVID-19 | 78 |
| Control Arm Standard of care for COVID-19
Standard of care: Standard of care for COVID-19 | 44 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow up Period | Death | 11 | 8 |
| Follow up Period | Lost to Follow-up | 5 | 6 |
| Follow up Period | Withdrawal by Subject | 2 | 0 |
| Treatment Period | Adverse Event | 3 | 0 |
| Treatment Period | Discharged from hospital | 18 | 7 |
| Treatment Period | Missed 1 or more doses | 8 | 0 |
| Treatment Period | Transferred to another hospital | 0 | 1 |
Baseline characteristics
| Characteristic | Sargramostim Arm | Control Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 31 Participants | 14 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 47 Participants | 30 Participants | 77 Participants |
| Age, Continuous | 61.7 years STANDARD_DEVIATION 13 | 58.2 years STANDARD_DEVIATION 10.61 | 60.4 years STANDARD_DEVIATION 12.26 |
| Body Mass Index | 34.86 kilograms/meter squared STANDARD_DEVIATION 8.988 | 35.44 kilograms/meter squared STANDARD_DEVIATION 9.647 | 35.07 kilograms/meter squared STANDARD_DEVIATION 9.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 11 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants | 33 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 20 Participants | 9 Participants | 29 Participants |
| Race (NIH/OMB) White | 48 Participants | 33 Participants | 81 Participants |
| Sex: Female, Male Female | 43 Participants | 18 Participants | 61 Participants |
| Sex: Female, Male Male | 35 Participants | 26 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 78 | 8 / 44 |
| other Total, other adverse events | 47 / 78 | 30 / 44 |
| serious Total, serious adverse events | 15 / 78 | 14 / 44 |
Outcome results
Primary
Change in Oxygenation Parameter of P(A-a)O2 Gradient by Day 6
The P(A-a)O2 gradient is a measure of how well the oxygen moves from the lungs into the bloodstream. Patients with a high gradient have less oxygen in the bloodstream.
Time frame: 1-6 days
Population: Patients analyzed if they had both a baseline and at least 1 post-baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sargramostim Arm | Change in Oxygenation Parameter of P(A-a)O2 Gradient by Day 6 | -102.3 millimeters of mercury (mmHg) | Standard Error 19.44 |
| Control Arm | Change in Oxygenation Parameter of P(A-a)O2 Gradient by Day 6 | -30.5 millimeters of mercury (mmHg) | Standard Error 26.88 |
Primary
Number of Patients Who Have Been Intubated by Day 14
Time frame: 1-14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sargramostim Arm | Number of Patients Who Have Been Intubated by Day 14 | 9 Participants |
| Control Arm | Number of Patients Who Have Been Intubated by Day 14 | 7 Participants |
Secondary
All Cause 28-day Mortality
Time frame: 1-28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sargramostim Arm | All Cause 28-day Mortality | 9 Participants |
| Control Arm | All Cause 28-day Mortality | 6 Participants |
Secondary
Causes of Death
Time frame: Day 1-90
Population: Patients alive at Day 90 were not analyzed
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sargramostim Arm | Causes of Death | Acute respiratory distress syndrome | 4 Participants |
| Sargramostim Arm | Causes of Death | Respiratory failure | 6 Participants |
| Sargramostim Arm | Causes of Death | Cardiorespiratory arrest | 1 Participants |
| Sargramostim Arm | Causes of Death | Septic shock | 0 Participants |
| Control Arm | Causes of Death | Septic shock | 1 Participants |
| Control Arm | Causes of Death | Acute respiratory distress syndrome | 2 Participants |
| Control Arm | Causes of Death | Cardiorespiratory arrest | 2 Participants |
| Control Arm | Causes of Death | Respiratory failure | 3 Participants |
Secondary
Change From Baseline in P/F Ratio
The P/F ratio is a simple way to assess severity of low blood oxygen. It's the ratio of PaO2 (arterial oxygen partial pressure obtained from an arterial blood gas) to FiO2 (fraction of inspired oxygen expressed as a decimal). A normal arterial blood is gas 80 to 100 mm Hg. Normal room air has 21% or 0.21 oxygen. So a normal P/F ratio is about 380-475. A high P/F ratio means more oxygen in the bloodstream and a low P/F ratio means less oxygen in the bloodstream. This outcome measure compares the improvement (increase) in P/F ratio between treatment arms.
Time frame: From Day 1 up to Day 6
Population: Patients were analyzed if they had both a baseline and at least 1 post-baseline measurement of P/F ratio.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sargramostim Arm | Change From Baseline in P/F Ratio | 65.70 ratio | Standard Deviation 97.964 |
| Control Arm | Change From Baseline in P/F Ratio | 47.24 ratio | Standard Deviation 99.942 |
Secondary
Change in Ordinal Scale
The ordinal scale was used, where 0 is not hospitalized, no clinical or virological evidence of infection, and 8 is death.
Time frame: 1-28 days
Population: Only 86 patients had follow up data at Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sargramostim Arm | Change in Ordinal Scale | -2.6 score on a scale | Standard Deviation 1.49 |
| Control Arm | Change in Ordinal Scale | -2.5 score on a scale | Standard Deviation 1.48 |
Secondary
Duration of Hospitalization
Time frame: Day 1-90
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sargramostim Arm | Duration of Hospitalization | 12.1 Days | Standard Deviation 9.39 |
| Control Arm | Duration of Hospitalization | 11.8 Days | Standard Deviation 8.63 |
Secondary
Duration of Invasive, Non-invasive and Supplemental Oxygen
This endpoint includes duration of any/all types of respiratory support
Time frame: Day 1-90
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sargramostim Arm | Duration of Invasive, Non-invasive and Supplemental Oxygen | 37.9 Days | Standard Deviation 35.64 |
| Control Arm | Duration of Invasive, Non-invasive and Supplemental Oxygen | 32.8 Days | Standard Deviation 34.25 |
Secondary
Number of Participants Wtih Nosocomial Infections
Nosocomial infections also referred to as healthcare-associated infections (HAI), are infection(s) acquired during the process of receiving health care that was not present during the time of admission.
Time frame: Day 1-90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sargramostim Arm | Number of Participants Wtih Nosocomial Infections | 0 Participants |
| Control Arm | Number of Participants Wtih Nosocomial Infections | 0 Participants |
Secondary
Number of Patients Requiring Invasive Mechanical Ventilation
The is the number of patients that needed to be placed on a ventilator.
Time frame: Day 1-90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sargramostim Arm | Number of Patients Requiring Invasive Mechanical Ventilation | 12 Participants |
| Control Arm | Number of Patients Requiring Invasive Mechanical Ventilation | 9 Participants |
Secondary
Number of Patients With Treatment-related Adverse Events
Number of patients with side effects related to treatment with sargramostim. Patients on the control arm did not receive sargramostim.
Time frame: 1-58 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sargramostim Arm | Number of Patients With Treatment-related Adverse Events | 5 Participants |
| Control Arm | Number of Patients With Treatment-related Adverse Events | 0 Participants |
Secondary
Survival Time of Patients
Time frame: Day 1-90
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sargramostim Arm | Survival Time of Patients | 76.0 Days | Standard Deviation 27.05 |
| Control Arm | Survival Time of Patients | 72.6 Days | Standard Deviation 28.56 |
Secondary
Time to Normalization of White Blood Cells and Lymphocytes
Normalization of WBC and lymphocyte count is defined as whether WBC and lymphocyte count results are normal or below normal or above normal ranges at available visits.
Time frame: Day 1-90
Population: Of 78 and 44 participants in the Sargramostim and Control Arms, respectively, only 28 (35.8%) and 17 (38.6%) had both baseline and post-baseline values available for evaluation at the Day 6 timepoint of interest.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sargramostim Arm | Time to Normalization of White Blood Cells and Lymphocytes | NA Days |
| Control Arm | Time to Normalization of White Blood Cells and Lymphocytes | NA Days |