Safety and Efficacy of Dupilumab for Treatment of Hospitalized COVID-19 Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Safety and Efficacy of the Treatment of Hospitalized Patients With COVID 19 Infection With an Inhibitor of IL-4 and IL-13 Signaling: A Phase IIa Trial

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Dupilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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): 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilimab<br>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. | Biological: Dupilumab<br>* 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.<br>* Other names: Dupixent;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Normal Saline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-Inflammatory Agents