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

Abstract

Background: We previously conducted a Phase IIa randomized placebo-controlled trial of 40 subjects to assess the efficacy and safety of dupilumab use in those hospitalized with COVID-19 (NCT04920916). Based on our pre-clinical data suggesting downstream pulmonary dysfunction with COVID-19 induced type 2 inflammation, we contacted patients from our Phase IIa study at 1 year for assessment of Post Covid-19 Conditions (PCC).

Methods: Subjects at 1 year after treatment underwent pulmonary function testing (PFTs), high resolution computed tomography (HRCT) imaging, symptom questionnaires, neurocognitive assessments, and serum immune biomarker analysis, with subject survival also monitored. The primary outcome was the proportion of abnormal PFTs, defined as an abnormal diffusion capacity for carbon monoxide (DLCO) or 6-minute walk testing (6MWT) at the 1-year visit.

Results: Sixteen of the 29 one-year survivors consented to the follow up visit. We found that subjects who had originally received dupilumab were less likely to have abnormal PFTs compared to those who received placebo (Fisher's exact p=0.011, adjusted p=0.058). We additionally found that 3 out of 19 subjects (16%) in the dupilumab group died by 1 year compared to 8 out of 21 subjects (38%) in the placebo group (log rank p=0.12). We did not find significant differences in neurocognitive testing, symptoms or CT chest imaging between treatment groups but observed evidence of reduced type 2 inflammation in those who received dupilumab.

Conclusions: We observed evidence of reduced long-term morbidity and mortality from COVID-19 with dupilumab treatment during acute hospitalization when added to standard of care regimens.

Fig 1:

Bar graph illustrating the percent of patients who had abnormal pulmonary function testing (defined by abnormal DLCO or 6MWT) by treatment group at 1-year follow up. The orange box depicts the patients randomized to placebo during initial COVID-19 admission and blue box depicts the subjects randomized to dupilumab during initial COVID-19 admission. Actual number and percentages are displayed in the table at the bottom of the chart. ** indicates two missing values.

Fig 2:

Box plots of percent predicted pulmonary function measures and 6-minute walk test distance (in meters) between treatment groups. The orange boxes depict the patients randomized to placebo and the blue boxes depict the subjects randomized to dupilumab during initial COVID-19 admission. The solid horizontal line within box is representative of median value and the open circle within box is representative of the mean value. FEV1= Forced expiratory volume in 1 second; DLCO= Diffusing capacity of the lungs for carbon monoxide; FVC= Forced vital capacity; 6MWT= Six-minute walk test.

Fig 3:

Kaplan Meier curve depicting 1-year mortality between the two treatment groups. Dupilumab group is represented by blue line. Placebo group is represented by the orange line. Adjusted p value indicative of adjustment for sex in the Cox regression.

Fig 4:

Kaplan Meier curve depicting 1-year mortality between the two treatment groups stratified by lymphopenia (defined as a lymphocyte count less than 1,000 cells/μL). Dupilumab group is represented by blue line. Placebo group is represented by the orange line. Adjusted p value indicative of adjustment for sex in the Cox regression.

Fig 5:

Bar graph illustrating the percent of patients who died or had abnormal pulmonary function testing (defined by abnormal DLCO or 6MWT) by treatment group at 1-year follow up. The orange box depicts the patients randomized to placebo during initial COVID-19 admission and blue box depicts the subjects randomized to dupilumab during initial COVID-19 admission. Actual percent displayed at the top of each bar for corresponding treatment group.

Fig 6:

Heatmap showing the standardized differences between baseline and 1-year cytokine, chemokine, or growth factor levels between treatment groups. Each column represents an individual subject. Treatment group is indicated by the top horizontal bar with the blue bar representing the dupilumab group and the orange bar representing the placebo group. Pulmonary function testing (PFTs) status is represented by the second horizontal bar with subjects who had abnormal PFTs at 1 year (defined as abnormal DLCO or 6MWT) represented by the grey bar and those who had normal testing represented by the green bar. Each biomarker is listed on the right of the plot. Those that had significant differences in 1-year changes between treatment groups are marked with a “*” and those with significant differences between 1-year PFT status are marked with a “^”. Note: IL1Ra p=0.065.