Clinical trial NCT04856111: Pirfenidone vs. Nintedanib for Fibrotic Lung Disease After Coronavirus Disease-19 Pneumonia
Official title: A Study of the Efficacy and Safety of Pirfenidone vs. Nintedanib in the Treatment of Fibrotic Lung Disease After Coronavirus Disease-19 Pneumonia
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Novel Coronavirus-induced Lung Fibrosis
Lead sponsor: PGIMER
Sponsor class: UNKNOWN
First posted: 2021-04-22
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The antifibrotic agents, namely pirfenidone and nintedanib have been found to be effective in the treatment of idiopathic pulmonary fibrosis (IPF). Nintedanib has also been found to be effective in treating systemic sclerosis-related interstitial lung disease (ILD) and non-IPF progressive fibrosing ILDs. Pirfenidone has also been found beneficial unclassifiable ILDs. Whether these drugs would be effective in treating post-COVID lung fibrosis also is unknown. As the final pathway of lung fibrosis appears to be common among different diffuse parenchymal lung diseases (DPLDs), it is hoped that these antifibrotic agents might be helpful in post-COVID fibrosis. There are no randomized studies that have assessed the role of pirfenidone or nintedanib in post COVID fibrosis. In the current study, we aim to assess the efficacy and safety of pirfenidone and compare it with nintedanib in the treatment of post-COVID lung fibrosis.

Detailed description: Since the early part of 2020, the entire world has been affected by a pandemic of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease has a short incubation period (median, 3 days) and is highly transmissible. This disease may manifest as an asymptomatic infection and through an entire range of symptoms of varying severity to severe, life-threatening disease. Although diverse systemic features might be present, the usual presentation is with lower respiratory tract involvement in the form of pneumonia often resulting in the development of the acute respiratory distress syndrome (ARDS). In some patients, multi-organ failure sets in, possibly as a result of a cytokine storm interplaying with a thrombotic microangiopathy.

Early lung disease is characterized pathologically by neutrophilic and exudative capillaritis in the lungs with some evidence of microthrombosis.2 This may be followed by a picture of diffuse alveolar damage along with ongoing intravascular thrombosis in the pulmonary vessels. In late stages, an organizing pneumonia (OP) develops with extensive proliferation of fibroblasts within the airspaces. Clinically, most patients make a complete recovery after COVID pneumonia. Other patients may demonstrate some signs of recovery from the acute illness with resolution of fever and recovery of organ functions, however they continue to have some degree of breathlessness, persistent infiltrates on radiologic studies, and/or hypoxemia. The CT abnormalities in these patients are commonly characterized by patchy, multifocal consolidation and ground-glass opacities suggestive of the OP pattern. Coarse reticulation and parenchymal bands may also be present.

Patients with such diffuse lung disease after COVID-19, herein referred to as post-COVID diffuse lung disease (PC-DLD) are often treated with glucocorticoids. Although most patients with a predominant OP pattern of injury would have a resolution of lung parenchymal abnormalities either spontaneously or with glucocorticoids, some of them might develop signs of lung fibrosis, in the form of traction bronchiectasis and/or honeycombing. Some subjects have ongoing respiratory symptoms despite treatment with steroids, and they may be found to have persistent reticulation or non-resolving consolidation on chest imaging that may represent early fibrosis.

The antifibrotic agents, namely pirfenidone and nintedanib have been found to be effective in the treatment of idiopathic pulmonary fibrosis (IPF). Nintedanib has also been found to be effective in treating systemic sclerosis-related interstitial lung disease (ILD) and non-IPF progressive fibrosing ILDs. Pirfenidone has also been found beneficial unclassifiable ILDs. Whether these drugs would be effective in treating post-COVID lung fibrosis also is unknown. As the final pathway of lung fibrosis appears to be common among different diffuse parenchymal lung diseases (DPLDs), it is hoped that these antifibrotic agents might be helpful in post-COVID fibrosis. There are no randomized studies that have assessed the role of pirfenidone or nintedanib in post COVID fibrosis. In the current study, we aim to assess the efficacy and safety of pirfenidone and compare it with nintedanib in the treatment of post-COVID lung fibrosis.

Eligibility criteria: Inclusion Criteria:

1. Age above 18 years
2. Diagnosed to have COVID-19 by means of a real-time reverse transcription polymerase chain reaction (rRT-PCR) test performed on a respiratory (upper or lower respiratory) sample or positive IgM antibody test or a rapid antigen test with consistent clinicoradiologic findings within the previous 4 months
3. Persistent respiratory symptoms
4. Having post-COVID parenchymal involvement \>10% of the lung parenchyma on visual inspection of the scans with the presence of radiologic signs of fibrosis (traction bronchiectasis/traction bronchiolectasis or honeycombing or reduced lung volumes), or having persistent reticulation or persistent consolidation despite a trial of glucocorticoids (minimum prednisolone dose of 10 mg/day, or equivalent) for a minimum period of 4 weeks after discharge for the acute COVID-19 illness

Exclusion Criteria:

1. Pregnant or lactating women
2. Having absolute contraindication for pirfenidone or nintedanib (advanced liver cirrhosis, persistent elevation of liver transaminases, documented hypersensitivity to pirfenidone or nintedanib, receiving anticoagulants or high dose aspirin or having a vascular stent in situ)
3. Known patient with diffuse lung disease prior to the diagnosis of COVID

Primary outcomes:
measure: Change in the forced vital capacity (FVC)
timeFrame: 24 weeks
Secondary outcomes:
measure: Proportion of subjects with improvement or stabilization
timeFrame: 24 weeks
measure: Proportion of subjects with a good composite response
timeFrame: 24 weeks
measure: Change in dyspnea score on modified Medical Research Council scale
timeFrame: 24 weeks
measure: Severity of dyspnea on the Functional Assessment of Chronic Illness Therapy - Dyspnea-10 item scale
timeFrame: 24 weeks
measure: Change in resting oxygen saturation
timeFrame: 24 weeks
measure: Proportion of subjects with oxygen desaturation on exercise testing
timeFrame: 24 weeks
measure: Percentage change in the six-minute walk distance
timeFrame: 24 weeks
measure: Proportion of participants who need rescue treatment
timeFrame: 24 weeks
measure: Change in health-related quality of life using the Short Form-36 questionnaire
timeFrame: 24 weeks
measure: Change in respiratory health status using the King's Brief ILD questionnaire
timeFrame: 24 weeks
measure: Changes in HRCT scores using the modified Salisbury system
timeFrame: 24 weeks
measure: Proportion of subjects who develop adverse effects due to either study drug
timeFrame: 24 weeks
measure: Predictors of response to antifibrotic agents, pirfenidone and nintedanib
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research
Study officials:
References: