COVID-19
Conditions
Keywords
Anti-Inflammatory Agents
Brief summary
This is a randomized, double-blind, placebo-controlled, superiority phase IIa trial to assess the safety and efficacy of dupilumab use in hospitalized patients with moderate to severe COVID-19 infection. Subsequently, we conducted a 1 year follow up study to investigate the occurrence of Post COVID conditions (PCC) in our study population through assessment of pulmonary function, symptoms, neurocognition and immune biomarkers to observe for any treatment group differences.
Detailed description
A total of 40 eligible subject were enrolled and randomized in a 1:1 ratio to receive either dupilumab or placebo, stratifying on the disease severity measured by the required oxygen ≤ 15L or \> 15L by nasal cannula. Both arms received standard of care management per current National Institutes of Health (NIH) COVID-19 treatment guideline in addition to their randomized treatments. Patients were then followed prospectively for up to 360 days after enrollment. As an extension to the randomized double-blind placebo-controlled trial assessing dupilumab for treatment of those hospitalized with acute moderate to severe COVID-19, subjects were followed up at 1 year for evaluation of pulmonary function testing (PFT), pulmonary imaging, immune biomarkers, neurocognition and symptoms.
Interventions
BIOLOGICALDupilumab
Participants will receive a loading dose of dupilumab (600 mg, given as two 300 mg subcutaneous injections) on day 0/1. If participants are still hospitalized a second and third dose (300 mg) will be given on days 14 and 28.
DRUGPlacebo
Normal Saline.
Sponsors
The Paul Manning Foundation
Virginia Catalyst
University of Virginia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female 18 years of age or older at the time of enrollment. * Patients hospitalized with a positive RT-PCR for SARS-CoV-2 within the last 14 days, with illness duration within the last 14 days, and evidence of moderate to severe COVID-19 infection as defined by NIH COVID-19 Severity Categorization (8): * Moderate illness: Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have saturation of oxygen SpO2≥ 94% on room air at sea level. * Severe illness: Individuals who have SpO2 \<94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) \<300 mm Hg, respiratory frequency \>30 breaths/min, or lung infiltrates \>50%. * Patient and/or legally authorized representative is willing and able to provide written informed consent and comply with all protocol requirements. * Patients with hematologic malignancies or solid tumors are eligible. * Patients with autoimmune disorders are eligible. * Patients with immunodeficiency and organ or stem cell transplant recipients are eligible. * Patients with acute or chronic renal injury/failure are eligible. * Patients with neutropenia/lymphopenia are eligible. * Patients with elevated liver function tests are eligible. * Women who are not taking contraception are eligible. * Patients who are currently or have recently received steroids and/or remdesivir are eligible. * Patient agrees to not participate in another clinical trial for the treatment of COVID-19 through end of study period.
Exclusion criteria
* Patients who do not require inpatient admission for COVID-19 infection. * Patients who require invasive mechanical ventilation at time of enrollment. * A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the individual at a substantially increased risk due to study participation. * Pregnancy or breast feeding (lactating women who agree to discard breast milk from day 1 until two weeks after the last study product is given are not excluded). * Allergy to Dupilumab or its excipients. * Received any of the following in the two weeks prior to screening as treatment of COVID-19: * small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib, acalabrutinib, etc.); * monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 \[IL-1\], anti-IL-6 \[or sarilumab\], etc.); * monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19; * Any other immunomodulatory (other than steroids) medications within 5 half-lives or 30 days prior to randomization. * Current acute parasitic helminth infection or history of chronic parasitic infection. * History of ocular scleritis, uveitis, keratitis or recent (\<6 months) eye injury (chemical or traumatic), infection or vascular occlusion. * Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations is allowed for all subjects.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Day 28 Ventilator Free Survival | at 28 Days ± 2d | Proportion of patients alive and free of invasive mechanical ventilation |
| Follow up Study 1 Year Outcome: Pulmonary Function Testing- Oxygen Diffusion and 6 Minute Walk Testing | 365 ± 90 days | Proportion of patients with abnormal diffusing capacity for carbon monoxide (DLCO) and/or 6 minute walk testing 1 year after acute COVID-19 infection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Grade 3 and 4 Clinical Adverse Events, Serious Adverse Events (SAEs) or Death | Day 0 through Day 60 | defined as number of new events divided by the total number of individuals in the population at risk for the time interval |
| SARS-CoV-2 Variants | Day 0 | Prevalence of delta variant in study population. |
| Change in Plasma Total Immunoglobulin E (IgE) Levels | Day 0 and Day 14 | Change in levels (difference between day 14- day 0 levels). |
| Change in C-reactive Protein (CRP) | Day 0 through Day 14 | Change in levels (difference between day 14- day 0 levels) |
| Change in Ferritin | Day 0 through Day 14 | Change in levels (difference between day 14- day 0 levels). |
| Duration of Hospitalization | Day 0 through Day 30 | Measured in days |
| Day 60 All Cause Mortality | Day 60 | All cause mortality by day 60 |
| Day 28 All-cause Mortality Rate | at Day 28 | Mortality rate |
| Proportion of Patients With Eosinophilia | Day 0 through Day 60 | defined as an absolute eosinophil count \> 0.6 k/µl at ≥ 1 measurement throughout the study period |
| Percentage of Patients Needing Extracorporeal Membrane Oxygenation (ECMO) | Day 0 through Day 60 | Percentage |
| Percentage of Patients Needing Vasopressors | Day 0 through Day 60 | Percentage |
| Follow Up Study 1 Year Outcome: All-cause Mortality at 1 Year | 365 days | Percent of subjects who died by 1 year. |
| Follow-up Study 1 Year Outcome: Differences in High Resolution Computed Tomography (HRCT) Chest Scan Appearance Post Recovery | 365 ± 90 days | Compare Enrollment HRCT to 1 year HRCT. Percent of abnormal on CT. Reported as percent of subjects with any abnormality on CT. |
| Follow-up Study 1 Year Outcome: Conduct a 6 Minute Walk Testing | 365 ± 90 days | Proportion of patients with greater than 3% oxygen desaturation during 6 minute walk testing |
| Follow up Study 1 Year Outcome: Pulmonary Function Testing- Abnormal Spirometry | 365 ± 90 days | Percentage of subjects with a percent of predicted (compared to Global Lung Function Initiative (GLI) predicted values based on age, sex, height and ethnicity) below normal for forced expiratory volume (FEV1) or forced vital capacity (FVC), which are measures used to determine the volume of air that can be exhaled in one breath. |
| Follow-up Study 1 Year Outcome: Assess Neurocognitive Function Using the MOCA | 365 ± 90 days | Determine the proportion of patients with reduce neurocognitive function. Neurocognitive testing included completion of Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, PROMIS Depression, the Montreal Cognitive Assessment (MOCA), the Insomnia Severity Index (ISI), the Katz Index of Independence In Activities of Daily Living (Katz-ADL), EuroQOL (EQ)-5D-5L and Neuro- Quality of Life (QoL) questionnaires. Reduced neurocognitive function was determined if scoring from at least one of these tests was deemed a variation from population norm per scoring instructions. |
| Day 60 Ventilator Free Survival | Day 60 | Proportion of patients alive and free of invasive mechanical ventilation |
| Percentage of Patients Needing Renal Replacement Therapy | Day 0 through Day 60 | Percentage |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dupilimab Participants will receive a loading dose of dupilumab (600 mg, given as two 300 mg subcutaneous injections) on day 0/1. If participants are still hospitalized a second and third dose (300 mg) will be given on days 14 and 28. | 19 |
| Placebo Participants will receive a loading dose of normal saline (2 ml, given as two one ml subcutaneous injections) on day 0/1. If participants are still hospitalized a second and third dose (1 ml) will be given on days 14 and 28. | 21 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 1 Year Follow up (Phone Call) | Death | 1 | 3 |
| 1 Year Follow up Visits | Lost to Follow-up | 6 | 7 |
| Phase IIa 60 Day Study | Death | 2 | 5 |
Baseline characteristics
| Characteristic | Dupilimab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 59 years | 63 years | 61.5 years |
| Body Mass Index | 33.6 kg/m^2 | 32.3 kg/m^2 | 33 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 18 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 10 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 13 Participants | 14 Participants | 27 Participants |
| Region of Enrollment United States | 19 participants | 21 participants | 40 participants |
| Sex: Female, Male Female | 12 Participants | 5 Participants | 17 Participants |
| Sex: Female, Male Male | 7 Participants | 16 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 19 | 8 / 21 |
| other Total, other adverse events | 0 / 19 | 0 / 21 |
| serious Total, serious adverse events | 11 / 19 | 6 / 21 |
Outcome results
Primary
Day 28 Ventilator Free Survival
Proportion of patients alive and free of invasive mechanical ventilation
Time frame: at 28 Days ± 2d
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Day 28 Ventilator Free Survival | 0.79 proportion of participants |
| Placebo | Day 28 Ventilator Free Survival | 0.86 proportion of participants |
Primary
Follow up Study 1 Year Outcome: Pulmonary Function Testing- Oxygen Diffusion and 6 Minute Walk Testing
Proportion of patients with abnormal diffusing capacity for carbon monoxide (DLCO) and/or 6 minute walk testing 1 year after acute COVID-19 infection.
Time frame: 365 ± 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Follow up Study 1 Year Outcome: Pulmonary Function Testing- Oxygen Diffusion and 6 Minute Walk Testing | 0.30 proportion of participants |
| Placebo | Follow up Study 1 Year Outcome: Pulmonary Function Testing- Oxygen Diffusion and 6 Minute Walk Testing | 1.0 proportion of participants |
Secondary
Change in C-reactive Protein (CRP)
Change in levels (difference between day 14- day 0 levels)
Time frame: Day 0 through Day 14
Population: One and two patients in the placebo and dupilumab groups, respectively, were unable to undergo day 14 CRP assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dupilimab | Change in C-reactive Protein (CRP) | 5.5 mg/dL |
| Placebo | Change in C-reactive Protein (CRP) | 8.9 mg/dL |
Secondary
Change in Ferritin
Change in levels (difference between day 14- day 0 levels).
Time frame: Day 0 through Day 14
Population: One and two patients in the placebo and dupilumab groups, respectively, were unable to undergo day 14 ferritin level assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dupilimab | Change in Ferritin | 384 ng/mL |
| Placebo | Change in Ferritin | 545 ng/mL |
Secondary
Change in Plasma Total Immunoglobulin E (IgE) Levels
Change in levels (difference between day 14- day 0 levels).
Time frame: Day 0 and Day 14
Population: Two subjects in the both the dupilumab and placebo groups were unable to undergo day 14 IgE assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dupilimab | Change in Plasma Total Immunoglobulin E (IgE) Levels | 17.5 U/mL |
| Placebo | Change in Plasma Total Immunoglobulin E (IgE) Levels | 16.3 U/mL |
Secondary
Cumulative Incidence of Grade 3 and 4 Clinical Adverse Events, Serious Adverse Events (SAEs) or Death
defined as number of new events divided by the total number of individuals in the population at risk for the time interval
Time frame: Day 0 through Day 60
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Cumulative Incidence of Grade 3 and 4 Clinical Adverse Events, Serious Adverse Events (SAEs) or Death | 58 percent of participants |
| Placebo | Cumulative Incidence of Grade 3 and 4 Clinical Adverse Events, Serious Adverse Events (SAEs) or Death | 29 percent of participants |
Secondary
Day 28 All-cause Mortality Rate
Mortality rate
Time frame: at Day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Day 28 All-cause Mortality Rate | 5 percentage of participants |
| Placebo | Day 28 All-cause Mortality Rate | 14 percentage of participants |
Secondary
Day 60 All Cause Mortality
All cause mortality by day 60
Time frame: Day 60
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Day 60 All Cause Mortality | 11 percentage of participants |
| Placebo | Day 60 All Cause Mortality | 24 percentage of participants |
Secondary
Day 60 Ventilator Free Survival
Proportion of patients alive and free of invasive mechanical ventilation
Time frame: Day 60
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Day 60 Ventilator Free Survival | 0.90 proportion of participants |
| Placebo | Day 60 Ventilator Free Survival | 0.76 proportion of participants |
Secondary
Duration of Hospitalization
Measured in days
Time frame: Day 0 through Day 30
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dupilimab | Duration of Hospitalization | 6 days |
| Placebo | Duration of Hospitalization | 6 days |
Secondary
Follow Up Study 1 Year Outcome: All-cause Mortality at 1 Year
Percent of subjects who died by 1 year.
Time frame: 365 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Follow Up Study 1 Year Outcome: All-cause Mortality at 1 Year | 16 percentage of participants |
| Placebo | Follow Up Study 1 Year Outcome: All-cause Mortality at 1 Year | 38 percentage of participants |
Secondary
Follow-up Study 1 Year Outcome: Assess Neurocognitive Function Using the MOCA
Determine the proportion of patients with reduce neurocognitive function. Neurocognitive testing included completion of Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, PROMIS Depression, the Montreal Cognitive Assessment (MOCA), the Insomnia Severity Index (ISI), the Katz Index of Independence In Activities of Daily Living (Katz-ADL), EuroQOL (EQ)-5D-5L and Neuro- Quality of Life (QoL) questionnaires. Reduced neurocognitive function was determined if scoring from at least one of these tests was deemed a variation from population norm per scoring instructions.
Time frame: 365 ± 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Follow-up Study 1 Year Outcome: Assess Neurocognitive Function Using the MOCA | 0.90 proportion of participants |
| Placebo | Follow-up Study 1 Year Outcome: Assess Neurocognitive Function Using the MOCA | 0.83 proportion of participants |
Secondary
Follow-up Study 1 Year Outcome: Conduct a 6 Minute Walk Testing
Proportion of patients with greater than 3% oxygen desaturation during 6 minute walk testing
Time frame: 365 ± 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Follow-up Study 1 Year Outcome: Conduct a 6 Minute Walk Testing | 0.10 Proportion of participants |
| Placebo | Follow-up Study 1 Year Outcome: Conduct a 6 Minute Walk Testing | 0.50 Proportion of participants |
Secondary
Follow-up Study 1 Year Outcome: Differences in High Resolution Computed Tomography (HRCT) Chest Scan Appearance Post Recovery
Compare Enrollment HRCT to 1 year HRCT. Percent of abnormal on CT. Reported as percent of subjects with any abnormality on CT.
Time frame: 365 ± 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Follow-up Study 1 Year Outcome: Differences in High Resolution Computed Tomography (HRCT) Chest Scan Appearance Post Recovery | 80 Percentage of participants |
| Placebo | Follow-up Study 1 Year Outcome: Differences in High Resolution Computed Tomography (HRCT) Chest Scan Appearance Post Recovery | 67 Percentage of participants |
Secondary
Follow up Study 1 Year Outcome: Pulmonary Function Testing- Abnormal Spirometry
Percentage of subjects with a percent of predicted (compared to Global Lung Function Initiative (GLI) predicted values based on age, sex, height and ethnicity) below normal for forced expiratory volume (FEV1) or forced vital capacity (FVC), which are measures used to determine the volume of air that can be exhaled in one breath.
Time frame: 365 ± 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Follow up Study 1 Year Outcome: Pulmonary Function Testing- Abnormal Spirometry | 30 percentage of participants |
| Placebo | Follow up Study 1 Year Outcome: Pulmonary Function Testing- Abnormal Spirometry | 67 percentage of participants |
Secondary
Percentage of Patients Needing Extracorporeal Membrane Oxygenation (ECMO)
Percentage
Time frame: Day 0 through Day 60
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Percentage of Patients Needing Extracorporeal Membrane Oxygenation (ECMO) | 0 percentage of participants |
| Placebo | Percentage of Patients Needing Extracorporeal Membrane Oxygenation (ECMO) | 0 percentage of participants |
Secondary
Percentage of Patients Needing Renal Replacement Therapy
Percentage
Time frame: Day 0 through Day 60
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Percentage of Patients Needing Renal Replacement Therapy | 11 percentage of participants |
| Placebo | Percentage of Patients Needing Renal Replacement Therapy | 10 percentage of participants |
Secondary
Percentage of Patients Needing Vasopressors
Percentage
Time frame: Day 0 through Day 60
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Percentage of Patients Needing Vasopressors | 21 percentage of participants |
| Placebo | Percentage of Patients Needing Vasopressors | 19 percentage of participants |
Secondary
Proportion of Patients With Eosinophilia
defined as an absolute eosinophil count \> 0.6 k/µl at ≥ 1 measurement throughout the study period
Time frame: Day 0 through Day 60
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | Proportion of Patients With Eosinophilia | 0.26 proportion of participants |
| Placebo | Proportion of Patients With Eosinophilia | 0.048 proportion of participants |
Secondary
SARS-CoV-2 Variants
Prevalence of delta variant in study population.
Time frame: Day 0
Population: Five and four samples from the placebo and dupilumab groups, respectively, were unable to undergo sequencing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilimab | SARS-CoV-2 Variants | 100 percentage of participants |
| Placebo | SARS-CoV-2 Variants | 94 percentage of participants |