Results from the STOP-COVID trial presented at ERS 2022 showed no clinical benefit with the dipeptidyl peptidase-1 (DPP-1) inhibitor brensocatib compared to placebo in patients hospitalized with COVID-19 in the UK.
“[T]retreatment with brensocatib for 28 days was associated with worse clinical status on the WHO 7-point ordinal scale* at the end of treatment than with placebo,” the researchers said.
This multicenter, double-blind study included 406 patients aged ≥16 years (mean age 62 years) who were hospitalized with confirmed or clinically suspected SARS-CoV-2 infection and had
≥1 risk factors for serious illness. Within 96 hours of hospitalization, they were randomized 1:1 to oral brensocatib (25 mg; n=190) or placebo (n=214) QD for 28 days plus additional therapy.
There was a greater proportion of male participants in the brensocatib group versus placebo (66 percent versus 59 percent). 49 and 46 percent of patients in the brensocatib and placebo groups were never smokers. The most common comorbidities in the brensocatib and placebo groups were hypertension (37 and 42 percent, respectively), obesity (both 22 percent), chronic heart disease (18 and 17 percent, respectively), and asthma (18 percent each).
During hospitalization, 81 and 80 percent of patients in the brensocatib and placebo groups received low-dose dexamethasone, 25 and 24 percent remdesivir, and 4 and 3 percent tocilizumab.
At day 29, patients receiving brensocatib had worse clinical status based on the WHO 7-point ordinal clinical status scale than patients receiving placebo (59 percent vs. 60 percent were not hospitalized but had activity limitations; adjusted odds ratio [OR]0.72, 95 percent confidence interval [CI], 0.57–0.92; p=0.0077). [ERS 2022, session ALERT 3: COVID and interstitial lung diseases;
Lancet Respir Med 2022;doi:10.1016/S2213-2600(22)00261-2]
Results of the primary outcome were consistent across all subgroups evaluated in the prespecified subgroup analysis.
Clinical improvement (time between randomization and first day s
≥1-point improvement on the WHO ordinal scale) occurred in 84 and 87 percent of patients in the brensocatib and placebo groups (adjusted hazard ratio [adjHR], 0.87). Time to Hospital Discharge or National Early Warning Score (NEWS) ≤2 was comparable between groups (adjHR, 0.98).
The median number of days without oxygen support was 24.0 days in the brensocatib group and 24.5 days in the placebo group. The new requirement for supplemental oxygen among hospitalized patients who did not require oxygen at baseline was comparable between groups. Among patients who did not require ventilation at baseline, brensocatib patients were more likely than placebo patients to require ventilation (adjusted incidence ratio, 1.13), although there was no significant difference between groups in ventilation-free days.
Adverse events (AEs) occurred at comparable rates between the brensocatib and placebo groups (45 percent vs. 46 percent; OR, 0.94; p=0.77), while 21 and 16 percent, respectively, experienced serious AEs (IRR, 1.27; p= 0.30). Nineteen and 16 percent of patients in the brensocatib group and 16 percent of patients in the brensocatib and placebo groups, respectively, discontinued trial treatment, primarily due to participant choice or adverse events. The most common AEs in both groups were gastrointestinal disorders (9 percent vs 14 percent) and infections and infestations (16 percent vs 15 percent). Fourteen and 11 serious AEs in the brensocatib and placebo groups were related to infections and infestations, respectively. There were 29 and 23 deaths in the brensocatib group (15 percent vs 11 percent;
adjHR, 1.41), during the 28-day follow-up period, although only one death in the placebo group was considered related to the study drug.
“[O]your study does not support targeting neutrophilic inflammation with DPP-1 inhibition as a therapeutic strategy in patients hospitalized with COVID-19. The worse clinical status in the brensocatib group suggests the need for caution in targeting DPP-1 or DPP-1-dependent proteases in patients hospitalized with COVID-19,” the researchers said.
However, the researchers did not rule out the possibility that the results were a “chance finding” based on previous trials of tocilizumab or dexamethasone in COVID-19 that were initially negative but later shown to be effective in larger studies or certain subgroups.
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