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| ID | Type | Description | Link |
|---|---|---|---|
| HSR220171 | Other Identifier | UVA IRB |
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| Name | Class |
|---|---|
| The Paul Manning Foundation | OTHER |
| Virginia Catalyst | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dupilimab | Experimental | Dupilimab: 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. |
|
| Placebo | Placebo Comparator | Normal saline will be 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dupilumab | Biological | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Day 28 Ventilator Free Survival | Proportion of patients alive and free of invasive mechanical ventilation | at 28 Days ± 2d |
| 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. | 365 ± 90 days |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of Patients With Eosinophilia | defined as an absolute eosinophil count > 0.6 k/µl at ≥ 1 measurement throughout the study period | Day 0 through Day 60 |
| Cumulative Incidence of Grade 3 and 4 Clinical Adverse Events, Serious Adverse Events (SAEs) or Death |
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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):
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:
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| Name | Affiliation | Role |
|---|---|---|
| William A Petri Jr., MD, PhD | University of Virginia Division of Infectious Disease | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UVA Health | Charlottesville | Virginia | 22908 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35959207 | Result | Sasson J, Donlan AN, Ma JZ, Haughey HM, Coleman R, Nayak U, Mathers AJ, Laverdure S, Dewar R, Jackson PEH, Heysell SK, Sturek JM, Petri WA Jr. Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019: A Phase 2a Trial. Open Forum Infect Dis. 2022 Jul 27;9(8):ofac343. doi: 10.1093/ofid/ofac343. eCollection 2022 Aug. | |
| 37693596 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Dupilimab | Active Dupilimab: 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. Dupilumab: 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. |
| FG001 | Placebo | Dupilimab Placebo: placebo (normal saline) will be 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. 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase IIa 60 Day Study |
|
| ||||||||||||||||||
| 1 Year Follow up (Phone Call) |
| |||||||||||||||||||
| 1 Year Follow up Visits |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Day 28 Ventilator Free Survival | Proportion of patients alive and free of invasive mechanical ventilation | Posted | Number | proportion of participants | at 28 Days ± 2d |
|
Adverse events were collected on study day 0, 2, 5, 7, 14, 28 and 60 in initial Phase IIa study. Day 7, 28 and 60 were considered optional, although recommended, if patient discharged within the time frame. No SAEs/AEs were collected past day 60. Therefore, while all cause mortality was assessed up to 1 year, other AEs/SAEs were assessed up to day 60.
All cause mortality was assessed up to 1 year. Other AEs/SAEs were assessed only up until day 60.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dupilimab | Active Dupilimab: 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. Dupilumab: 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Injection Site Reactions | Injury, poisoning and procedural complications | DAIDS | Systematic Assessment |
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This was a small study, designed as an early phase trial. Limitations included lack of achievement of the primary endpoint and the wide confidence intervals in the survival benefit of dupilumab at day 60. Additional limitations included unequal gender distribution between groups (also due to small sample size), patients were almost exclusively infected by the Delta variant of SARS CoV-2 and a higher-than-expected overall mortality rate.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| William Petri | University of Virginia Health System | 434-305-9633 | wap3g@virginia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol: Phase IIa Study | Feb 2, 2022 | Sep 13, 2023 | Prot_003.pdf |
| Prot | Yes | No | No | Study Protocol: 1 year follow up of Phase IIa study | Jun 15, 2022 | Sep 13, 2023 | Prot_004.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 29, 2022 | Mar 31, 2022 | SAP_002.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C582203 | dupilumab |
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|
| Placebo | Drug | Normal Saline. |
|
defined as number of new events divided by the total number of individuals in the population at risk for the time interval |
| Day 0 through Day 60 |
| SARS-CoV-2 Variants | Prevalence of delta variant in study population. | Day 0 |
| Change in Plasma Total Immunoglobulin E (IgE) Levels | Change in levels (difference between day 14- day 0 levels). | Day 0 and Day 14 |
| Change in C-reactive Protein (CRP) | Change in levels (difference between day 14- day 0 levels) | Day 0 through Day 14 |
| Change in Ferritin | Change in levels (difference between day 14- day 0 levels). | Day 0 through Day 14 |
| Duration of Hospitalization | Measured in days | Day 0 through Day 30 |
| Day 60 All Cause Mortality | All cause mortality by day 60 | Day 60 |
| Day 28 All-cause Mortality Rate | Mortality rate | at Day 28 |
| Day 60 Ventilator Free Survival | Proportion of patients alive and free of invasive mechanical ventilation | Day 60 |
| Percentage of Patients Needing Extracorporeal Membrane Oxygenation (ECMO) | Percentage | Day 0 through Day 60 |
| Percentage of Patients Needing Renal Replacement Therapy | Percentage | Day 0 through Day 60 |
| Percentage of Patients Needing Vasopressors | Percentage | Day 0 through Day 60 |
| Follow Up Study 1 Year Outcome: All-cause Mortality at 1 Year | Percent of subjects who died by 1 year. | 365 days |
| 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. | 365 ± 90 days |
| 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 | 365 ± 90 days |
| 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. | 365 ± 90 days |
| 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. | 365 ± 90 days |
| Result |
| Hendrick J, Ma JZ, Haughey HM, Coleman R, Nayak U, Kadl A, Sturek JM, Jackson P, Young MK, Allen JE, Petri WA Jr. Pulmonary function and survival one year after dupilumab treatment of acute moderate to severe COVID-19: A follow up study from a Phase IIa trial. medRxiv [Preprint]. 2023 Sep 2:2023.09.01.23293947. doi: 10.1101/2023.09.01.23293947. |
| 35411349 | Derived | Sasson J, Donlan AN, Ma JZ, Haughey HM, Coleman R, Nayak U, Mathers AJ, Laverdure S, Dewar R, Jackson PEH, Heysell SK, Sturek JM, Petri WA Jr. Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial. medRxiv [Preprint]. 2022 May 19:2022.03.30.22273194. doi: 10.1101/2022.03.30.22273194. |
| NOT COMPLETED |
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| NOT COMPLETED |
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|
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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | Median | Inter-Quartile Range | kg/m^2 |
|
|
|
| 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. | Posted | Number | proportion of participants | 365 ± 90 days |
|
|
|
| Secondary | Proportion of Patients With Eosinophilia | defined as an absolute eosinophil count > 0.6 k/µl at ≥ 1 measurement throughout the study period | Posted | Number | proportion of participants | Day 0 through Day 60 |
|
|
|
| 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 | Posted | Number | percent of participants | Day 0 through Day 60 |
|
|
|
| Secondary | SARS-CoV-2 Variants | Prevalence of delta variant in study population. | Five and four samples from the placebo and dupilumab groups, respectively, were unable to undergo sequencing. | Posted | Number | percentage of participants | Day 0 |
|
|
|
| Secondary | Change in Plasma Total Immunoglobulin E (IgE) Levels | Change in levels (difference between day 14- day 0 levels). | Two subjects in the both the dupilumab and placebo groups were unable to undergo day 14 IgE assessment. | Posted | Median | Inter-Quartile Range | U/mL | Day 0 and Day 14 |
|
|
|
| Secondary | Change in C-reactive Protein (CRP) | Change in levels (difference between day 14- day 0 levels) | One and two patients in the placebo and dupilumab groups, respectively, were unable to undergo day 14 CRP assessment. | Posted | Median | Inter-Quartile Range | mg/dL | Day 0 through Day 14 |
|
|
|
| Secondary | Change in Ferritin | Change in levels (difference between day 14- day 0 levels). | One and two patients in the placebo and dupilumab groups, respectively, were unable to undergo day 14 ferritin level assessment. | Posted | Median | Inter-Quartile Range | ng/mL | Day 0 through Day 14 |
|
|
|
| Secondary | Duration of Hospitalization | Measured in days | Posted | Median | Inter-Quartile Range | days | Day 0 through Day 30 |
|
|
|
| Secondary | Day 60 All Cause Mortality | All cause mortality by day 60 | Posted | Number | percentage of participants | Day 60 |
|
|
|
| Secondary | Day 28 All-cause Mortality Rate | Mortality rate | Posted | Number | percentage of participants | at Day 28 |
|
|
|
| Secondary | Day 60 Ventilator Free Survival | Proportion of patients alive and free of invasive mechanical ventilation | Posted | Number | proportion of participants | Day 60 |
|
|
|
| Secondary | Percentage of Patients Needing Extracorporeal Membrane Oxygenation (ECMO) | Percentage | Posted | Number | percentage of participants | Day 0 through Day 60 |
|
|
|
| Secondary | Percentage of Patients Needing Renal Replacement Therapy | Percentage | Posted | Number | percentage of participants | Day 0 through Day 60 |
|
|
|
| Secondary | Percentage of Patients Needing Vasopressors | Percentage | Posted | Number | percentage of participants | Day 0 through Day 60 |
|
|
|
| Secondary | Follow Up Study 1 Year Outcome: All-cause Mortality at 1 Year | Percent of subjects who died by 1 year. | Posted | Number | percentage of participants | 365 days |
|
|
|
| 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. | Posted | Number | Percentage of participants | 365 ± 90 days |
|
|
|
| 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 | Posted | Number | Proportion of participants | 365 ± 90 days |
|
|
|
| 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. | Posted | Number | percentage of participants | 365 ± 90 days |
|
|
|
| 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. | Posted | Number | proportion of participants | 365 ± 90 days |
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|
| 3 |
| 19 |
| 11 |
| 19 |
| 0 |
| 19 |
| EG001 | Placebo | Dupilimab Placebo: placebo (normal saline) will be 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. 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. | 8 | 21 | 6 | 21 | 0 | 21 |
| Conjunctivitis | Eye disorders | DAIDS | Systematic Assessment |
|
| Bacterial pneumonia | Respiratory, thoracic and mediastinal disorders | DAIDS | Systematic Assessment |
|
| Herpes viral infection | Infections and infestations | DAIDS | Systematic Assessment |
|
| Eosinophilia | Blood and lymphatic system disorders | DAIDS | Systematic Assessment |
|
| Hypereosinophilic syndrome | Immune system disorders | DAIDS | Systematic Assessment |
|
| Other infections | Infections and infestations | DAIDS | Systematic Assessment | Other infections included Clostridioides difficile infection (1), bacteremia (2), urinary tract infections (2) and oral candidiasis (1). |
|
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| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |