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Background. Severe COVID-19 infection is characterized by a dysregulated hyperinflammatory state that contributes to morbidity and mortality. Immunomodulatory therapy has been shown to improve outcomes. We investigated if the TNF-alpha inhibitor, infliximab (IFX), provides additional benefit over standard of care. Methods. We conducted a double-blind, randomized, placebo-controlled trial of IFX (single infusion of 5 mg/kg) compared to standard of care (including remdesivir and dexamethasone) in patients hospitalized with COVID-19 pneumonia. The primary outcome was time to recovery by day 29. Key secondary endpoints included 14-day clinical status and 28-day mortality. Results. A total of 1033 patients received study agent (517 assigned to IFX, 516 to common placebo), constituting the analyzed modified intention-to-treat cohort. Mean age 54.8 years, 60.3% were male, 48.6% Hispanic/Latino and 14% Black. Randomization was balanced for severity of illness and comorbidities. Participants randomized to IFX did not show a statistically significant difference in the primary endpoint with a recovery rate ratio of 1.13 (95% CI 0.99-1.27, p=0.0631) compared to placebo. The median (IQR) time to recovery was 8 days (7, 9) for IFX and 9 days (8, 10) for placebo. Patients assigned to IFX were more likely to have an improved clinical status at day 14 (OR 1.32;95% CI 1.05, 1.66). The 28-day mortality was 10.1% in the IFX arm and 14.5% in the placebo (OR 0.59 (95% CI 0.39, 0.90)), with a 40.7% lower odds of dying in patients receiving IFX. The improvement in mortality was demonstrated in patients requiring low- or high-flow O2 at baseline but not in those requiring mechanical ventilation or ECMO. Subgroup analysis identified the strongest effect in those with baseline CRP >75mg/ml. There was no imbalances in serious adverse events. Secondary infections were similar between groups (IFX 18.0%, placebo 16.5%). Conclusion. Although single-dose IV IFX did not demonstrate statistically significant improvement in time to recovery, it was associated with improvement in clinical status at day 14 and showed a substantial reduction in 28 day mortality compared to standard of care.
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Background. Severe COVID-19 infection is characterized by a dysregulated hyperinflammatory state that contributes to morbidity and mortality. Immunomodulatory therapy has been shown to improve outcomes. We investigated if abatacept, CTLA-4-Ig, a selective costimulation modulator, provides additional benefit when added to standard of care. Methods. We conducted a double-blind, randomized, placebo-controlled trial evaluating abatacept (given as a single infusion of 10mg/kg, to a maximum of 1000 mg) compared to standard of care (including remdesivir and dexamethasone) in patients hospitalized with COVID-19 pneumonia. The primary outcome was median time to recovery by day 29. Key secondary endpoints included 28-day mortality. Results. A total of 1019 patients received an infusion (509 assigned to abatacept and 510 to placebo), constituting the analyzed modified intention-to-treat cohort. The mean age 54.9 years (SD 14.65), 60.5% were male, 44.2% Hispanic or Latino and 13.7% black. Patients were evenly matched in terms of severity of illness, and comorbidities. Participants randomized to abatacept did not show a statistically significant difference in the primary endpoint with a recovery rate ratio of 1.135 (95% CI 0.996-1.294, p=0.057) compared to placebo. The median (IQR) time to recovery was 9 days (8, 10) for both groups. The 28-day mortality in the abatacept arm was 11.0% and in control arm 15.0% (OR 0.62 (95% CI 0.41, 0.94)), with a 37.8% lower odds of dying in patients receiving abatacept. The improvement in mortality was demonstrated for patients requiring low or high flow O2 at baseline but was not seen in patients who required mechanical ventilation or ECMO at time of randomization. Subgroup analysis identified the strongest effect in those with baseline CRP >75mg/L, age >65 and diabetics. Safety data demonstrated slightly lower risk of adverse events. Rates of secondary infections were similar (abatacept 16.1% and placebo 14.3%). Conclusion. Although single-dose IV abatacept did not demonstrate statistically significant improvement in time to recovery, it did show a substantial reduction in 28-day mortality compared to standard of care.
RESUMO
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing, interstitial pneumonia which ultimately leads to an irreversible loss of lung function and respiratory compromise. The anti-fibrotic agents, pirfenidone and nintedanib have been shown to slow the rate of decline in forced vital capacity (FVC) but, neither treatment halts disease progression. Pentraxin-2 plays important biologically relevant roles in wound repair and prevention of fibrosis. Pentraxin-2, inhibits monocyte differentiation into pro-fibrotic fibrocytes and pro-inflammatory macrophages. Plasma pentraxin-2 concentrations are reduced in patients with IPF and correlate with disease severity. Recombinant human pentraxin-2 (rhPTX-2;also known as PRM-151) was evaluated for its therapeutic potential within a phase II trial (NCT02550873). This trial demonstrated statistically significant and clinically meaningful outcomes of rhPTX-2 treatment in patients with IPF. Here we report the phase III study design to further evaluate these findings. METHODS: STARSCAPE (NCT04552899) is a phase III, multi-center, randomized, double-blind, placebo controlled trial. 658 patients with IPF will be randomized (1:1) to receive either intravenous rhPTX-2 or matching placebo administered on Days 1, 3, 5 and every 4 weeks thereafter through 48 weeks. The primary endpoint is absolute change from baseline to Week 52 in FVC [mL]. The key secondary endpoint is absolute change from baseline to Week 52 in 6-minute walk distance. Eligible patients are 40-85 years, with a documented diagnosis of IPF confirmed centrally by high resolution computed tomography scan (and lung biopsy if available). Patients must demonstrate FVC ≥ 45%, FEV1/FVC ratio > 0.70 and DLCO ≥ 30% and ≤ 90% during screening. Patients are permitted to take background therapy with nintedanib or pirfenidone. Initiating a global phase III trial during the COVID-19 pandemic brings unique and unprecedented challenges. A large number of countries and sites will be included in order to mitigate potential regional recruitment challenges that may arise during the pandemic. In addition, SARS-CoV-2 serology testing will be conducted to allow exploratory analyses on the impact of COVID-19 on lung function parameters in patients with IPF. CONCLUSIONS: rhPTX-2 has demonstrated preliminary evidence of clinical efficacy on top of approved standard of care. The phase III STARSCAPE trial aims to confirm the therapeutic potential of rhPTX-2 through evaluation of a broad range of efficacy, safety, quality of life, pharmacokinetic and biomarker assessments over 52 weeks. Patients that complete this 52-week trial may be eligible to enroll into an open label extension trial.