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The Study Will Evaluate the Use of Nintedanib in Slowing Lung Fibrosis in Patients With Pulmonary Infiltrates Related to COVID-19 (ENDCOV-I)

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ClinicalTrials.gov Identifier: NCT04619680
Recruitment Status : Recruiting
First Posted : November 6, 2020
Last Update Posted : December 17, 2020
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Maria L Padilla, Icahn School of Medicine at Mount Sinai

Tracking Information
First Submitted Date  ICMJE November 5, 2020
First Posted Date  ICMJE November 6, 2020
Last Update Posted Date December 17, 2020
Actual Study Start Date  ICMJE November 18, 2020
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 5, 2020)
Change in Forced Vital Capacity (FVC) [ Time Frame: Baseline and 180 days ]
Change in Forced Vital Capacity (FVC) at 180 days as compared to baseline. Forced vital capacity (FVC) is the amount of air that can be forcibly exhaled from your lungs after taking the deepest breath possible, as measured by spirometry.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2020)
  • Number of deaths due to respiratory cause [ Time Frame: within 90-180 days ]
    Death within 90 days and 180 days from enrollment due to a respiratory cause
  • Chest CT visual score [ Time Frame: 180 days ]
    Quantitative Change in chest CT visual score graded by blinded chest radiologists. Data driven texture analysis (DTA) is a patented deep learning method to quantify lung fibrosis. DTA score is reported in percentage ranging from 0% to 100%. A minimally clinical important difference when comparing CT scans from the same subject is 4%. A higher percentage suggests worsening lung injury.
  • St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: Day 90 ]
    The Saint George's Respiratory Questionnaire (SGRQ) is a self-reported disease-specific, health-related quality of life (QOL) questionnaire. 50-item instrument. Scores range from 0 to 100, with higher scores indicating more limitations.
  • St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: Day 180 ]
    The Saint George's Respiratory Questionnaire (SGRQ) is a self-reported disease-specific, health-related quality of life (QOL) questionnaire. 50-item instrument. Scores range from 0 to 100, with higher scores indicating more limitations.
  • King's Brief Interstitial Lung Disease (KBILD) [ Time Frame: Day 90 ]
    The King's Brief Interstitial Lung Disease (KBILD) questionnaire is a self-administered, ILD-specific measure of health-related quality of life, comprising 15 items with three domains (Psychological (KBILD-P), Breathlessness and activities (KBILD-B), and Chest symptoms (KBILD-C)) combined in a total score (KBILD-T). The KBILD domain and total score ranges are 0-100; 100 represents best health status.
  • King's Brief ILD (KBILD) [ Time Frame: Day 180 ]
    The King's Brief Interstitial Lung Disease (KBILD) questionnaire is a self-administered, ILD-specific measure of health-related quality of life, comprising 15 items with three domains (Psychological (KBILD-P), Breathlessness and activities (KBILD-B), and Chest symptoms (KBILD-C)) combined in a total score (KBILD-T). The KBILD domain and total score ranges are 0-100; 100 represents best health status.
  • Leicester Cough Questionnaire (LCQ) [ Time Frame: Day 90 ]
    The LCQ is a 19 item questionnaire that assesses cough-related QOL. It has 3 domains (physical, psychological and social). The domain scores range from 1-7 and total score range is 3-21 with a higher score indicating a better quality of life.
  • Leicester Cough Questionnaire [ Time Frame: Day 180 ]
    The LCQ is a 19 item questionnaire that assesses cough-related QOL. It has 3 domains (physical, psychological and social). The domain scores range from 1-7 and total score range is 3-21 with a higher score indicating a better quality of life.
  • Short Form (SF) 36 Health Survey [ Time Frame: Day 90 ]
    The (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status. Scores range from 0 - 100, with higher scores indicating less disability.
  • SF 36 Health Survey [ Time Frame: Day 180 ]
    The (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status. Scores range from 0 - 100, with higher scores indicating less disability.
  • Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Day 90 ]
    Questionnaire with 7 items for anxiety and 7 items for depression, each item is scored on a 4 point response 0 - 3, with full range from 0 to 42, with higher score indicating more severe anxiety or depression. 14-items scale with responses scored from 0-3, scores for each subscale from 0 (normal) to 21 (severe symptoms). Scores for the entire scale is 0 to 42, with higher score indicating more distress.
  • Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Day 180 ]
    Questionnaire with 7 items for anxiety and 7 items for depression, each item is scored on a 4 point response 0 - 3, with full range from 0 to 42, with higher score indicating more severe anxiety or depression. 14-items scale with responses scored from 0-3, scores for each subscale from 0 (normal) to 21 (severe symptoms). Scores for the entire scale is 0 to 42, with higher score indicating more distress.
  • Number of participants with Increase in liver transaminases (AST and ALT) > 3 times the upper limit of normal [ Time Frame: day 90 ]
    Number of participants with Increase in liver transaminases
  • Number of participants with Increase in liver transaminases (AST and ALT) > 3 times the upper limit of normal [ Time Frame: day 180 ]
    Number of participants with Increase in liver transaminases
  • Number of participants with Thrombotic events [ Time Frame: day 90 ]
    Number of participants with Thrombotic events: venous or arterial thrombosis
  • Number of participants with Thrombotic events [ Time Frame: day 180 ]
    Number of participants with Thrombotic events: venous or arterial thrombosis
  • Number of participants with 10% weight loss over 90 days [ Time Frame: day 90 ]
    Number of participants with 10% weight loss
  • Number of participants with 10% weight loss over 90 days [ Time Frame: day 180 ]
    Number of participants with 10% weight loss
  • Number of participants with GI events [ Time Frame: day 90 ]
    Number of participants with Nausea/emesis/diarrhea not responsive to anti-emetics and anti-motility agents
  • Number of participants with GI events [ Time Frame: day 180 ]
    Number of participants with Nausea/emesis/diarrhea not responsive to anti-emetics and anti-motility agents
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Study Will Evaluate the Use of Nintedanib in Slowing Lung Fibrosis in Patients With Pulmonary Infiltrates Related to COVID-19
Official Title  ICMJE Early Nintedanib Deployment in COVID-19 Interstitial Fibrosis
Brief Summary This is a collaborative study between Icahn School of Medicine at Mount Sinai and Boehringer Ingelheim Pharmaceuticals to determine the effect of Nintedanib on slowing the rate of lung fibrosis in patients who have been diagnosed with COVID-19, and have ongoing lung injury more than 4 weeks out from their diagnosis.
Detailed Description

The purpose of this study is to determine the efficacy of the study drug, Nintedanib, on slowing the rate of lung fibrosis in patients who are noted to have infiltrates, or ongoing lung injury, on chest x-ray/CT 4 weeks or longer from their initial symptoms. In addition, the study will also investigate patient reported outcomes using questionnaires, and the safety and tolerability of the study drug. Blood specimens will be collected to assess biomarkers and monitor drug safety.

The trial will be randomized 1:1 between Nintedanib and placebo.

Nintedanib has been approved by the FDA for the treatment of chronic fibrosing ILD with a progressive phenotype, but has not been studies in patients with post COVID 19 lung fibrosis.

Subjects participating in this study will:

  • Attend in person visits to the study doctor's office on the date of enrollment, 15 days after enrollment, 45 days after enrollment, 90 days after enrollment, 135 days after enrollment, and 180 days after enrollment. If the participant is being enrolled in the study while hospitalized at Mount Sinai, the study doctor will travel to the hospital room.
  • Undergo a HRCT (High-resolution computed tomography) scan of the chest within 14 days of enrollment, and then again at 180 days after enrollment.
  • Have Pulmonary Function Tests within 14 days of enrollment, and then again 45, 90, 135 and 180 days after enrollment.
  • Have blood drawn routinely while participating in this study (15 days after starting medication, then again on day 45, 90, 135 and 180).
  • Participants will not pay for physician visits, blood draws, breathing tests, CT scans or the medication for this study. Participants will receive a stipend to cover the transportation costs for your visits.

The main risks to participants are:

  1. Common side effects include: nausea, vomiting, diarrhea, stomach discomfort
  2. Loss of appetite and weight loss
  3. Liver function abnormalities (blood work will be monitored periodic intervals at scheduled blood draws as listed above)
  4. Slightly higher risk of bleeding
  5. Slightly higher risk of blood clots that can form in the blood vessels that supply oxygen to vital organs such as the brain and heart

Benefits from participation in this research include the possibility that Nintedanib may slow down/prevent progression of lung fibrosis. If the lungs can heal without fibrosis, this may result in fewer symptoms of shortness of breath, cough and need for added oxygen.

Instead of participating in this research, subjects may choose to monitor their lung condition with their doctor or participate in another research study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
  • The study compares the effects of the active study drug, Nintedanib with an inactive substance (placebo).
  • Patients will be assigned to Nintedanib or placebo by random chance in a 1:1 allocation. There is 50% chance to receive the study drug and a 50% chance to receive the placebo.
  • The study will be double blinded. No one (including the patient or the study team) will know who is receiving the study drug or the placebo. This way, the results of the study will not be favored one way or another. If it becomes urgently necessary for a patient's care, the study doctor will be able to find out whether the patient is taking the placebo or the study drug, Nintedanib.
  • Patients will be told whether they received the study drug, Nintedanib, or the placebo once the study is finished.
Primary Purpose: Treatment
Condition  ICMJE
  • Pulmonary Fibrosis
  • Interstitial Lung Disease
  • Respiratory Disease
Intervention  ICMJE
  • Drug: Nintedanib
    150 mg PO twice a day, taken with food
  • Drug: Placebo
    placebo equivalent given twice a day
Study Arms  ICMJE
  • Experimental: Nintedanib
    150 mg po twice a day
    Intervention: Drug: Nintedanib
  • Placebo Comparator: Placebo
    placebo equivalent po twice a day
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 5, 2020)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Willing and able to provide written informed consent
  • Subjects Age > 18
  • Initial SARS-CoV-2 infection confirmed by PCR test or positive serologies within or > 12 weeks of enrollment. SARS CoV-2 serologies will be confirmed by Mount Sinai Lab prior to enrollment.
  • Have findings consistent with fibrosis found on CT scan (these may include reticulations, traction bronchiectasis, septal thickening, and early honeycombing)
  • Required one of the following after diagnosis with SARS-CoV-2: supplemental oxygen by nasal cannula, high flow oxygen, non invasive ventilation such as CPAP or BIPAP, or mechanical ventilation
  • Are 30 days from onset of initial SARS-CoV-2 symptoms
  • Forced Vital Capacity less than 80% predicted based on ATS/ERS criteria
  • Women of childbearing potential who agree to use of highly effective contraception during treatment and for three months following the last dose of nintedanib

Exclusion Criteria:

Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of the Screening Visit (prior to randomization):

  • Co-administration of other investigational agents against COVID-19
  • Active SARS-CoV-2 infection based on clinical judgment
  • Currently Pregnant or Breast Feeding
  • Current Use of Prednisone or equivalent > 10 mg/daily
  • Use of full dose anticoagulation therapy or high dose anti platelet drug therapy at screening (at the discretion of the investigator, anticoagulation therapy may be added if clinically indicated)
  • History of myocardial infarction within past 90 days
  • Life threatening bleed
  • Hemodynamic instability or shock
  • Superimposed pulmonary bacterial infection
  • Pre-existing interstitial lung disease
  • Active Hep A/B/C hepatitis as measured with PCR for viral load and/or serologies
  • Pre-existing liver disease: Including Abnormal Laboratory Liver Function: Childs Pugh B/C, AST/ALT > 3 times the upper limit of normal (ULN). If Child Pugh A, can participate on Nintedanib 100 mg by mouth twice daily.
  • Subjects with a Creatinine clearance <30 ml/min or currently on hemodialysis
  • Inability to tolerate orally administered medication (medication must be taken with meals)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Maria Padilla, MD 212-241-5656 Maria.Padilla@mssm.edu
Contact: Alona Lansky 212-824-8404 Alona.Lansky@mssm.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04619680
Other Study ID Numbers  ICMJE GCO 20-2147
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All of the individual participant data collected during the trial, after deidentification.
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Beginning 3 months and ending 5 years following article publication.
Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose. Proposals should be directed to Maria.Padilla@mssm.edu. To gain access, data requestors will need to sign a data access agreement. Data are available for 5 years at a third party website
Responsible Party Maria L Padilla, Icahn School of Medicine at Mount Sinai
Study Sponsor  ICMJE Icahn School of Medicine at Mount Sinai
Collaborators  ICMJE Boehringer Ingelheim
Investigators  ICMJE
Principal Investigator: Maria Padilla, MD Icahn School of Medicine at Mount Sinai
PRS Account Icahn School of Medicine at Mount Sinai
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP