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

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

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.

Study Overview

• Status: Recruiting
• Conditions: SARS-Cov-2 Induced Pulmonary Fibrosis
• Intervention / Treatment: Other: Placebo; Drug: Nintedanib 150 MG [Ofev]

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.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bruno Crestani, MD,PHD; Phone Number: 01 40 25 68 00; Email: bruno.crestani@aphp.fr

Study Locations

• France
  • Paris, France, 95018
    • Recruiting
    • Pneumologie
    • Contact: Crestani Bruno, MD; Phone Number: 0140256863; Email: bruno.crestani@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	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.
Placebo Comparator: 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.	Other: Placebo; Placebo; Other Names: NaCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Change in Forced Vital Capacity over 12 months assessed by Annual Rate of Decline in FVC in Overall Population	at inclusion and 12 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
compare the rate of decline of DLCO over 12 months	Rate of decline in DLCO estimated by linear regression of DLCO from baseline to 12 months from DLCO measurement at inclusion, 6 and 12 months	at inclusion, 6 and 12 months
compare exercise capacity at 12 months	Absolute change from baseline in the Six-minute walk test (6MWT) at 12 months	at 12 months
compare high resolution CT (HRCT) lung opacities extension at 12 months	HRCT fibrosis score and HRCT fibrosis extension (visual and computer-based assessment) at inclusion and 12 months	at inclusion and 12 months
compare change in health-related quality of life	Absolute change from baseline in the total score on the St. George's Respiratory Questionnaire questionnaire at 12 months	at 12 months
compare the evolution of dyspnea over time	Absolute change from baseline in the Dyspnea score (Multidimensional Dyspnea Profile and mMRC score) at 3, 6, 9 and 12 months	at 3, 6, 9 and 12 months
compare change in Depression and anxiety over time	The absolute change from baseline Hospital Anxiety and Depression score at 3, 6, 9 and 12 months	at 3, 6, 9 and 12 months
compare change in lung injury, pulmonary hypertension and inflammation biomarkers	Biomarker assay (KL-6, NT-proBNP, CRP, D-dimers) at inclusion and 12 months	at inclusion and 12 months
pulmonary hypertension prevalence at inclusion and 12 months	Percentage of patients with a tricuspid regurgitation velocity > 2.5, 2.8 and 3.4 m/sec evaluated at baseline and at 12 months.	at inclusion and 12 months
association between genetic susceptibility (MUC5B polymorphism) and lung fibrosis in COVID-19 survivors	MUC5B at risk allele detection at inclusion	at inclusion
safety of nintedanib	Incidence of clinical or biological adverse events with nintedanib versus placebo over 12 months	over 12 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Boehringer Ingelheim

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2020
• Primary Completion (Actual): October 11, 2023
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: August 17, 2020
• First Submitted That Met QC Criteria: September 7, 2020
• First Posted (Actual): September 9, 2020

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 15, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Interstitial; Fibrosis; Pulmonary Fibrosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: APHP200527

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No