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

May 15, 2024 updated by: Assistance Publique - Hôpitaux de Paris

"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

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
250

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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.
Time Frame: at inclusion and 12 months.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
compare the rate of decline of DLCO over 12 months
Time Frame: at inclusion, 6 and 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
Time Frame: 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
Time Frame: at inclusion and 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
Time Frame: at 12 months
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
Time Frame: at 3, 6, 9 and 12 months
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
Time Frame: at 3, 6, 9 and 12 months
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
Time Frame: at inclusion and 12 months
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
Time Frame: 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
Time Frame: at inclusion
MUC5B at risk allele detection at inclusion
at inclusion
safety of nintedanib
Time Frame: over 12 months
Incidence of clinical or biological adverse events with nintedanib versus placebo over 12 months
over 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Assistance Publique - Hôpitaux de Paris

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Boehringer Ingelheim

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 29, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 11, 2023

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 17, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 7, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 9, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 16, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 15, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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