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

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Biological: Dupilumab; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • UVA Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dupilimab; 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; 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.; Other Names: Dupixent
Placebo Comparator: 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.	Drug: Placebo; Normal Saline.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in National Institute of Allergy and Infectious Diseases 8-point ordinal scale	Change in scale at Day 0, 2, 5, 7, 14, 28, 60, 180 and 360	Day 0 through Day 360
Percentage of patients needing vasopressors	Percentage	Day 0 through Day 60
Percentage of patients needing renal replacement therapy	Percentage	Day 0 through Day 60
Percentage of patients needing extracorporeal membrane oxygenation (ECMO)	Percentage	Day 0 through Day 60
ICU length of stay (LOS)	compare LOS between placebo vs dupilumab groups	Day 0 through Day 30

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: PBM C19 Research, LLC (a COVID-19 research entity of the Paul Manning Foundation); Virginia Catalyst, Virginia Biosciences Health Research Corporation (VBHRC)
• Investigators: Principal Investigator: William A Petri Jr., MD, PhD, University of Virginia Division of Infectious Disease

Publications and helpful links

General Publications

• 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. 2022 May 19:2022.03.30.22273194. doi: 10.1101/2022.03.30.22273194. Preprint.
• 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.
• Hendrick J, Ma JZ, Haughey HM, Coleman R, Nayak U, Kadl A, Sturek JM, Jackson P, Young MK, Allen JE, Petri WA. 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. 2023 Sep 2:2023.09.01.23293947. doi: 10.1101/2023.09.01.23293947. Preprint.

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2021
• Primary Completion (Actual): April 18, 2023
• Study Completion (Actual): April 18, 2023

Study Registration Dates

• First Submitted: June 8, 2021
• First Submitted That Met QC Criteria: June 8, 2021
• First Posted (Actual): June 10, 2021

Study Record Updates

• Last Update Posted (Estimated): November 3, 2023
• Last Update Submitted That Met QC Criteria: October 9, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Anti-Inflammatory Agents
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: HSR210184; HSR220171 (Other Identifier: UVA IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No