Nintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis

NCT ID: NCT04541680

Last Updated: 2024-05-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-29
• Study Completion Date: 2024-07-31

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.

Conditions

SARS-Cov-2 Induced Pulmonary Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Nintedanib

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.

Group Type: EXPERIMENTAL

Nintedanib 150 MG [Ofev]

Intervention Type: DRUG

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.

Placebo

Control group will receive Placebo BID for 12 months in addition to SoC. The prescription of SoC drugs or procedure will be let to the choice of the investigator in charge of the patient. Standard of care may include pulmonary rehabilitation.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo

Interventions

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.

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: OTHER

Other Intervention Names

NaCl

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 89 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Pneumologie

Paris, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Bruno Crestani, MD,PHD

Role: CONTACT

bruno.crestani@aphp.fr

01 40 25 68 00

Facility Contacts

Crestani Bruno, MD

Role: primary

bruno.crestani@aphp.fr

0140256863

Other Identifiers

APHP200527

Identifier Type: -

Identifier Source: org_study_id