Back to resultsNintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis (NINTECOR)
Primary Purpose
SARS-Cov-2 Induced Pulmonary Fibrosis
Status
Recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Nintedanib 150 MG [Ofev]
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for SARS-Cov-2 Induced Pulmonary Fibrosis
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:
- Previous clinical or echocardiographic evidence of significant right heart failure
- History of right heart catheterisation showing a cardiac index ≤2 L/min/m²
- PAH requiring parenteral therapy with epoprostenol/treprostinil.
History of cardiovascular diseases, any of the following:
- Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 months of Visit 1
- Myocardial infarction within 6 months of Visit 1
- Unstable cardiac angina within 6 months of Visit 1.
Bleeding risk, any of the following:
- Known genetic predisposition to bleeding.
- 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
Sites / Locations
- PneumologieRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Nintedanib
Placebo
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
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
compare exercise capacity at 12 months
Absolute change from baseline in the Six-minute walk test (6MWT) 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
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
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
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
compare change in lung injury, pulmonary hypertension and inflammation biomarkers
Biomarker assay (KL-6, NT-proBNP, CRP, D-dimers) 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.
association between genetic susceptibility (MUC5B polymorphism) and lung fibrosis in COVID-19 survivors
MUC5B at risk allele detection at inclusion
safety of nintedanib
Incidence of clinical or biological adverse events with nintedanib versus placebo over 12 months
Full Information
NCT ID
NCT04541680
First Posted
August 17, 2020
Last Updated
May 2, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Boehringer Ingelheim
1. Study Identification
Unique Protocol Identification Number
NCT04541680
Brief Title
Nintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis
Acronym
NINTECOR
Official Title
"Nintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis"
Study Type
Interventional
2. Study Status
Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 29, 2020 (Actual)
Primary Completion Date
October 2023 (Anticipated)
Study Completion Date
May 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Boehringer Ingelheim
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
SARS-Cov-2 Induced Pulmonary Fibrosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
250 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Nintedanib
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Nintedanib 150 MG [Ofev]
Intervention Description
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
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
NaCl
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
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.
Description
Change in Forced Vital Capacity over 12 months assessed by Annual Rate of Decline in FVC in Overall Population
Time Frame
at inclusion and 12 months.
Secondary Outcome Measure Information:
Title
compare the rate of decline of DLCO over 12 months
Description
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
Time Frame
at inclusion, 6 and 12 months
Title
compare exercise capacity at 12 months
Description
Absolute change from baseline in the Six-minute walk test (6MWT) at 12 months
Time Frame
at 12 months
Title
compare high resolution CT (HRCT) lung opacities extension at 12 months
Description
HRCT fibrosis score and HRCT fibrosis extension (visual and computer-based assessment) at inclusion and 12 months
Time Frame
at inclusion and 12 months
Title
compare change in health-related quality of life
Description
Absolute change from baseline in the total score on the St. George's Respiratory Questionnaire questionnaire at 12 months
Time Frame
at 12 months
Title
compare the evolution of dyspnea over time
Description
Absolute change from baseline in the Dyspnea score (Multidimensional Dyspnea Profile and mMRC score) at 3, 6, 9 and 12 months
Time Frame
at 3, 6, 9 and 12 months
Title
compare change in Depression and anxiety over time
Description
The absolute change from baseline Hospital Anxiety and Depression score at 3, 6, 9 and 12 months
Time Frame
at 3, 6, 9 and 12 months
Title
compare change in lung injury, pulmonary hypertension and inflammation biomarkers
Description
Biomarker assay (KL-6, NT-proBNP, CRP, D-dimers) at inclusion and 12 months
Time Frame
at inclusion and 12 months
Title
pulmonary hypertension prevalence at inclusion and 12 months
Description
Percentage of patients with a tricuspid regurgitation velocity > 2.5, 2.8 and 3.4 m/sec evaluated at baseline and at 12 months.
Time Frame
at inclusion and 12 months
Title
association between genetic susceptibility (MUC5B polymorphism) and lung fibrosis in COVID-19 survivors
Description
MUC5B at risk allele detection at inclusion
Time Frame
at inclusion
Title
safety of nintedanib
Description
Incidence of clinical or biological adverse events with nintedanib versus placebo over 12 months
Time Frame
over 12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
89 Years
Accepts Healthy Volunteers
No
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:
Previous clinical or echocardiographic evidence of significant right heart failure
History of right heart catheterisation showing a cardiac index ≤2 L/min/m²
PAH requiring parenteral therapy with epoprostenol/treprostinil.
History of cardiovascular diseases, any of the following:
Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 months of Visit 1
Myocardial infarction within 6 months of Visit 1
Unstable cardiac angina within 6 months of Visit 1.
Bleeding risk, any of the following:
Known genetic predisposition to bleeding.
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bruno Crestani, MD,PHD
Phone
01 40 25 68 00
Email
bruno.crestani@aphp.fr
Facility Information:
Facility Name
Pneumologie
City
Paris
ZIP/Postal Code
95018
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Crestani Bruno, MD
Phone
0140256863
Email
bruno.crestani@aphp.fr
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
Nintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis
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