Currently, there is no approved treatment for COVID-19 in France, either for the acute phase, nor for the late chronic phase. the investigator suggest that nintedanib has the potential to block the development of lung fibrosis when initiated early enough to inhibit the activation of mesenchymal cells and the progression of virus-induced pulmonary fibrosis. Computerized Tomography (CT) manifestations of fibrosis or fibrous stripes are described in COVID-19 (Ye, Eur Radiol 2020). Pan et al observed fibrous stripes in 17% patients in the early phase of the disease (Pan, Eur Radiol 2020). Ye et al observed bronchiectasis in 2 patients (15.4%) and evidence of pulmonary fibrosis in 3 patients (23.7%) at HRCT performed at 4 weeks (Ye, Eur Radiol 2020). Long term data are still lacking in patients with COVID-19 and the investigators do not know how many patients will have fibrotic sequelae from the acute illness.
At present, investigators have a very limited view on the long-term pulmonary sequelae after
COVID-19 pneumonia, particularly in the most severe forms requiring hospitalization. Early
thoracic HRCT is a useful tool for the evaluation of patients suspected of COVID-19
pneumonia. Typical features are evocative of the disease in an epidemic context, with
multifocal ground-glass opacities, being nodular or not, or crazy-paving with or without
consolidations, with a bilateral, peripheral or mixed distribution and involvement of the
posterior zones. CT manifestations of fibrosis or fibrous stripes are described in COVID-19.
Pan et al observed fibrous stripes in 17% patients in the early phase of the disease. Ye et
al observed bronchiectasis in 2 patients (15.4%) and evidence of pulmonary fibrosis in 3
patients (23.7%) at HRCT performed at 4 weeks. Long term data are still lacking in patients
with COVID-19 and the investigators do not know how many patients will have fibrotic sequelae
from the acute illness.
Drug: Nintedanib 150 MG [Ofev]
Experimental group will receive nintedanib 150mg BID for 12 months in addition to standard of care (SoC). Nintedanib dose could be reduced to 100mg BID depending on tolerance according to investigator in charge of the patient. The prescription of SoC drugs or procedure will be let to the choice of the investigator in charge of the patient.
Other: Placebo
Placebo
Other Name: NaCl
Inclusion Criteria:
- History of hospitalization for COVID-19 infection documented with positive PCR or
positive serology in the previous 2 to 12 months
- Lung opacities on HRCT involving more than 10% of the lung volume, with fibrotic
features
- DLCO≤ 70% of the predicted value
Exclusion Criteria:
- Pre-existing lung disorder with abnormal HRCT (including COPD, lung cancer, or
pulmonary fibrosis)
- Laboratory parameter thresholds:
- renal insufficiency with following criteria: Creatinine clearance <30 ml/min estimated
by the Cockcroft-Gault equation.
- any of the following liver test criteria above the specified limit: Total bilirubin >
1.5 above the upper limit of the normal range (ULN), except in patients with
predominantly unconjugated hyperbilirubinemia (e.g., Gilbert's syndrome). Aspartate or
alanine aminotransferase (AST or ALT) >3 × ULN (refer to the protocol, Table 3 p 34
for the management of liver enzyme elevation).
- Recent surgery with wound healing in progress(<7days )
- Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic
impairment).
- Significant pulmonary arterial hypertension (PAH) defined by any of the following:
1. Previous clinical or echocardiographic evidence of significant right heart
failure
2. History of right heart catheterisation showing a cardiac index ≤2 L/min/m²
3. PAH requiring parenteral therapy with epoprostenol/treprostinil.
- History of cardiovascular diseases, any of the following:
1. Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6
months of Visit 1
2. Myocardial infarction within 6 months of Visit 1
3. Unstable cardiac angina within 6 months of Visit 1.
- Bleeding risk, any of the following:
1. Known genetic predisposition to bleeding.
2. Patients who require
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists,
direct thrombin inhibitors, heparin, hirudin) ii. High dose antiplatelet therapy.
- Alcohol or drug abuse which in the opinion of the treating physician would interfere
with treatment.
- Ongoing or past antifibrotic treatment with pirfenidone or nintedanib
- Hypersensitivity to nintedanib, peanut or soya or to any of the excipients of the
specialty Ofev®
- Patients not able to understand and follow study procedures including completion of
self-administered questionnaires without help.
- No written informed consent from the patient
- Absence of affiliation to the French social security
- Participation in another interventional research
Pneumologie
Paris, France
Investigator: Crestani Bruno, MD
Contact: 0140256863
bruno.crestani@aphp.fr
Bruno Crestani, MD,PHD
01 40 25 68 00
bruno.crestani@aphp.fr