Clinical trial NCT04541680: Nintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis
Official title: "Nintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis"
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: SARS-Cov-2 Induced Pulmonary Fibrosis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2020-09-09
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: The primary objective is to assess whether nintedanib slows the progression of lung fibrosis in COVID-19 survivors as assessed by the decline in the forced vital capacity (FVC) over 12 months compared to placebo.
timeFrame: at inclusion and 12 months.
Secondary outcomes:
measure: compare the rate of decline of DLCO over 12 months
timeFrame: at inclusion, 6 and 12 months
measure: compare exercise capacity at 12 months
timeFrame: at 12 months
measure: compare high resolution CT (HRCT) lung opacities extension at 12 months
timeFrame: at inclusion and 12 months
measure: compare change in health-related quality of life
timeFrame: at 12 months
measure: compare the evolution of dyspnea over time
timeFrame: at 3, 6, 9 and 12 months
measure: compare change in Depression and anxiety over time
timeFrame: at 3, 6, 9 and 12 months
measure: compare change in lung injury, pulmonary hypertension and inflammation biomarkers
timeFrame: at inclusion and 12 months
measure: pulmonary hypertension prevalence at inclusion and 12 months
timeFrame: at inclusion and 12 months
measure: association between genetic susceptibility (MUC5B polymorphism) and lung fibrosis in COVID-19 survivors
timeFrame: at inclusion
measure: safety of nintedanib
timeFrame: over 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Pneumologie
Study officials:
References: