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

Phase 2

Completed

Conditions: COVID-19

Interventions: Drug: Placebo
Biological: Dupilumab

Registration Number: NCT04920916

Lead Sponsor: University of Virginia

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
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.
Dupilimab	Dupilumab	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
Change in C-reactive Protein (CRP)	Day 0 through Day 14	Change in levels (difference between day 14- day 0 levels)
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
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.
Change in Ferritin	Day 0 through Day 14	Change in levels (difference between day 14- day 0 levels).
Percentage of Patients Needing Extracorporeal Membrane Oxygenation (ECMO)	Day 0 through Day 60	Percentage
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: 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.
SARS-CoV-2 Variants	Day 0	Prevalence of delta variant in study population.
Day 60 All Cause Mortality	Day 60	All cause mortality by day 60
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
Change in Plasma Total Immunoglobulin E (IgE) Levels	Day 0 and Day 14	Change in levels (difference between day 14- day 0 levels).
Duration of Hospitalization	Day 0 through Day 30	Measured in days
Follow Up Study 1 Year Outcome: All-cause Mortality at 1 Year	365 days	Percent of subjects who died by 1 year.
Percentage of Patients Needing Vasopressors	Day 0 through Day 60	Percentage
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.
Day 28 All-cause Mortality Rate	at Day 28	Mortality rate