A Trial of Pirfenidone in Hospitalized Adult Patients with Severe Coronavirus Disease 2019
The outbreak of Coronavirus Disease 2019 (COVID-19) in 2019 has led to a global pandemic, causing significant morbidity and mortality. Similar to the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) outbreak in 2003, SARS-CoV-2, the virus responsible for COVID-19, can induce acute lung injury and cytokine storms characterized by elevated levels of interleukin (IL)-8, IL-6, and tumor necrosis factor-alpha (TNF-α). Studies on survivors of the 2003 SARS epidemic revealed that many patients developed varying degrees of pulmonary interstitial fibrosis. Similarly, patients with severe COVID-19 often exhibit diffuse alveolar damage and alveolar interstitial fibrosis. Given these similarities, there is a growing interest in exploring therapeutic strategies that can mitigate lung fibrosis and inflammation in COVID-19 patients.
Pirfenidone, a drug developed by Beijing Contini Pharmaceutical Co., Ltd., has shown promise in inhibiting fibroblast activity, reducing matrix collagen deposition, preventing inflammasome activation, and limiting oxidative stress responses. These properties support its therapeutic potential in idiopathic pulmonary fibrosis (IPF). Given the presence of alveolar interstitial fibrosis in severe COVID-19 patients and pirfenidone’s anti-inflammatory and anti-fibrotic effects, it was hypothesized that pirfenidone could play a beneficial role in treating COVID-19 patients, potentially reducing complications associated with SARS-CoV-2 infection. To test this hypothesis, a clinical trial was conducted to assess the therapeutic effects of pirfenidone in severe COVID-19 patients.
Study Design and Methodology
The trial, registered under ClinicalTrials.gov number NCT04282902 and Chinese Clinical Trial Register number ChiCTR2000030333, was conducted from January 31 to March 3, 2020, at Tongji Hospital (Headquarters Campus, Caidian Campus, Guanggu Campus) and Jingzhou Hospital in Hubei, China. The study was approved by the Institutional Review Boards of both hospitals. Eligible participants included male and non-pregnant female COVID-19 patients aged 18 years or older with a blood oxygen saturation (SaO2) of 94% or less and a ratio of partial oxygen pressure (PaO2) to inhaled oxygen (FiO2) of 300 mmHg or less. Exclusion criteria included patient disinterest in the study, hypersensitivity to pirfenidone, liver disease (e.g., alanine aminotransferase levels >5 times the upper limit of normal or aspartate aminotransferase levels >5 times the upper limit of normal), contraindications to pirfenidone, and pre-existing interstitial lung disease (ILD).
Participants who met the inclusion criteria were randomly assigned in a 1:1 ratio to receive either pirfenidone plus standard therapy or standard therapy alone. Pirfenidone was administered at a dose of 200 mg three times daily for the first two days, followed by 400 mg three times daily thereafter. For patients unable to swallow, pirfenidone was administered via a nasogastric tube.
Primary and Secondary Endpoints
The primary endpoint of the study was the absolute change from baseline in the total score on the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire at the 4th week. A change of 4 to 8 points on the K-BILD questionnaire is considered clinically meaningful. Secondary endpoints included the absolute change in computed tomography (CT) values, where the total CT value was the sum of individual lobe values, ranging from 0 (no involvement) to 25 (maximum involvement). Other secondary outcomes included clinical laboratory findings (e.g., cytokine levels, biochemical indicators) and the proportion of patients with clinical improvement. Safety outcomes were also assessed, including adverse events and premature discontinuation of treatment. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
Patient Characteristics and Baseline Data
A total of 146 COVID-19 patients were recruited, with 124 patients from Tongji Hospital and 22 from Jingzhou Central Hospital. Seventy-three patients were randomly assigned to the pirfenidone treatment group, and the remaining 73 received standard therapy alone. The median age of the patients was 62.0 years (interquartile range [IQR] 53.5–68.5 years), and 64.38% of the patients were male. The median interval between symptom onset and randomization was 40 days (IQR 25–50 days). At baseline, there were no significant differences between the two groups in terms of demographic characteristics, laboratory assays, K-BILD scores, or CT scores.
Efficacy Outcomes
After 4 weeks of treatment, the difference in K-BILD scores between the pirfenidone group and the standard therapy group did not reach statistical significance (75.93 ± 10.07 vs. 76.33 ± 9.15, P = 0.911). However, there was a trend toward an increase in K-BILD scores from baseline in the pirfenidone group compared to the standard therapy group (ΔK-BILD, 26.53 ± 11.12 vs. 22.73 ± 8.00; 3.80 [95% confidence interval, CI = -4.87 to 12.47]). Similarly, there was no significant difference in CT scores between the two groups after 4 weeks of treatment (P = 0.745). However, some score changes were observed, including consolidation (0.30 ± 0.65 vs. 1.07 ± 1.17, P = 0.007), ground-glass opacity (GGO) (-12.27 ± 5.72 vs. -11.57 ± 4.07; between-group difference = -0.70, 95% CI = -2.97 to 1.57), and reticulation (-0.90 ± 5.26 vs. -0.30 ± 6.98; between-group difference = -0.60, 95% CI = -3.40 to 2.20). These changes reflected improvements in lung inflammation and interstitial changes.
Inflammatory and Coagulopathy Biomarkers
The levels of pulmonary inflammatory cytokines and coagulopathy biomarkers decreased significantly from baseline to the 4th week in the pirfenidone group compared to the standard therapy group. Notable reductions were observed in IL-2R (-299.00, 95% CI = -430.50 to -105.00, P = 0.010), TNF-α (-3.50, 95% CI = -5.00 to -0.10, P = 0.049), and D-Dimer (-4.57, 95% CI = -8.98 to -0.16, P = 0.021).
Clinical Outcomes and Safety
The duration of hospitalization and intensive care unit (ICU) stay was reduced by 2 days in the pirfenidone group compared to the standard therapy group (11.21 ± 10.06 vs. 13.21 ± 16.63 days, -2 days, 95% CI = -9.27 to 5.27; 19.00 [IQR 15.00–22.00] vs. 22.00 [IQR 16.50–25.50]; -2 days, 95% CI = -3.50 to 8.50). However, there were no significant differences in other outcomes, such as clinical improvement time, duration of oxygen therapy, or time from randomization to death. Notably, all patients in the pirfenidone group survived, while two patients in the standard therapy group died.
The percentages of patients experiencing adverse events or serious adverse events were similar between the two groups. Among patients in the pirfenidone group, 11% (8/73) required a dose reduction, and 3% (2/73) discontinued treatment. The most common adverse event was diarrhea, reported in 15% (11/73) of patients in the pirfenidone group. Some patients also experienced elevated alanine aminotransferase and aspartate aminotransferase levels.
Discussion
The study aimed to evaluate the potential therapeutic effects of pirfenidone in severe COVID-19 patients, particularly in mitigating lung fibrosis and inflammation. Although pirfenidone did not significantly improve interstitial changes in the lungs, it demonstrated a strong effect on reducing cytokine storms, which are responsible for complications in severe COVID-19 patients. Significant reductions in IL-2R and TNF-α levels were observed in the pirfenidone group, indicating its anti-inflammatory potential.
Interestingly, pirfenidone also significantly decreased D-Dimer levels, which are associated with coagulopathy. Given that COVID-19 patients are at increased risk for acute pulmonary embolism, and anticoagulant therapy has been linked to improved outcomes, pirfenidone may have the potential to reduce thrombotic complications in these patients.
The safety profile of pirfenidone in COVID-19 patients was consistent with its known profile in IPF patients. Although some adverse events were reported, they were manageable with dose adjustments or discontinuation. No fatal events were reported, confirming the drug’s safety even in fragile patients.
Limitations
The study has several limitations. First, the sample size was relatively small, which may limit the generalizability of the findings. Second, despite efforts to minimize bias, it cannot be entirely ruled out. Third, the trial lacked dynamic clinical and laboratory data, such as immune cell subsets. Finally, the observation period was limited to 4 weeks, which may not be sufficient to confirm pirfenidone’s anti-fibrotic effects. Additionally, the use of glucocorticoids, which were not significantly different between the two groups, could have influenced the results.
Conclusion
Although pirfenidone did not significantly improve interstitial changes in severe COVID-19 patients, it demonstrated benefits in reducing inflammatory responses and potentially lowering the risk of thrombotic complications. The study confirms that pirfenidone is a viable treatment option for severe COVID-19 patients, with a favorable safety profile. Further research with larger sample sizes and longer observation periods is needed to fully evaluate pirfenidone’s therapeutic potential in COVID-19.
doi.org/10.1097/CM9.0000000000001614
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