Clinical trial NCT04619680: The Study of the Use of Nintedanib in Slowing Lung Disease in Patients With Fibrotic or Non-Fibrotic Interstitial Lung Disease Related to COVID-19
Official title: Early Nintedanib Deployment in COVID-19 Interstitial Lung Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Fibrosis
Interstitial Lung Disease
Respiratory Disease
Keywords: COVID-19
Infiltrates
SARS CoV-2
lung
scarring
fibrosis
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2020-11-06
Enrollment: 121
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a collaborative study between Icahn School of Medicine at Mount Sinai, Boehringer Ingelheim Pharmaceuticals and up to 9 other clinical centers across the US to determine the effect of nintedanib on slowing the rate of lung disease in patients who have been diagnosed with COVID-19, and have ongoing lung injury more than 30 days out from their diagnosis. 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 or a history of desaturation below 90%.

Detailed description: The purpose of this study is to determine the efficacy of the study drug, nintedanib, on slowing the rate of lung disease in patients who are noted to have infiltrates, or ongoing lung injury, on chest x-ray/CT 30 days 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 studied in patients with post COVID 19 lung disease.

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, the study doctor will travel to the hospital room. There will also be a follow-up phone call 30 days after finishing study drug.
* Undergo a HRCT (High-resolution computed tomography) scan of the chest within 6 weeks 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 a six-minute walk test at baseline, day 90 and day 180 after enrollment.
* Have blood drawn routinely while participating in this study (within 14 days of randomization, 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
6. Kidney disease resulting in protein/and or albumin being lost through urine

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.

Eligibility criteria: 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
* Have findings consistent with interstitial lung disease found on CT scan (these may include ground glass opacities, 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 or a history of desaturation below 90%
* Are at least 30 days from onset of initial SARS-CoV-2 symptoms
* Forced Vital Capacity less than or equal to 90% predicted based on ATS/ERS criteria or DLCO less than or equal to 70%
* 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 or immunosuppressive therapy or disease modifying agents
* 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)
* Patients who are in the intensive care unit (ICU) or in the step-down unit on invasive or non-invasive mechanical ventilation, ECMO, or high flow nasal cannula oxygen, will not be included.
* Any condition that in the opinion of the Investigator, constitute a risk or a contraindication for the participation of the patient into the study or that could interfere with the study objectives, conduct or evaluation.
* Patients with known hypersensitivity to nintedanib, peanut, soy, or to any of the excipients.

Primary outcomes:
measure: Change in Forced Vital Capacity (FVC)
timeFrame: Baseline and 180 days
Secondary outcomes:
measure: Number of deaths due to respiratory cause
timeFrame: within 90-180 days
measure: Chest CT visual score
timeFrame: 180 days
measure: St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Day 90
measure: St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Day 180
measure: King's Brief Interstitial Lung Disease Questionnaire (KBILD)
timeFrame: Day 90
measure: King's Brief Interstitial Lung Disease Questionnaire(KBILD)
timeFrame: Day 180
measure: Leicester Cough Questionnaire (LCQ)
timeFrame: Day 90
measure: Leicester Cough Questionnaire (LCQ)
timeFrame: Day 180
measure: Short Form (SF) 36 Health Survey
timeFrame: Day 90
measure: Short Form (SF) 36 Health Survey
timeFrame: Day 180
measure: Hospital Anxiety and Depression Scale (HADS)
timeFrame: Day 90
measure: Hospital Anxiety and Depression Scale (HADS)
timeFrame: Day 180
measure: Number of participants with Increase in liver transaminases (AST and ALT) > 3 times the upper limit of normal
timeFrame: day 90
measure: Number of participants with Increase in liver transaminases (AST and ALT) > 3 times the upper limit of normal
timeFrame: day 180
measure: Number of participants with Thrombotic events
timeFrame: day 90
measure: Number of participants with Thrombotic events
timeFrame: day 180
measure: Number of participants with 10% weight loss over 90 days
timeFrame: day 90
measure: Number of participants with 10% weight loss over 90 days
timeFrame: day 180
measure: Number of participants with GI events
timeFrame: day 90
measure: Number of participants with GI events
timeFrame: day 180
measure: Change in 6 minute walk test
timeFrame: Baseline and day 180
measure: Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F)
timeFrame: Day 90
measure: Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F)
timeFrame: Day 180
measure: Change in Forced Vital Capacity (FVC)
timeFrame: Baseline and Day 90
measure: Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)
timeFrame: Baseline and Day 180
measure: Number of deaths due to any cause
timeFrame: within 90-180 days
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Healthcare Network
state: Georgia
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: New York
country: United States
facility: Mount Sinai Beth Israel
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Dallas
country: United States
facility: Baylor University Medical Center Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Maria Padilla, MD
role: PRINCIPAL_INVESTIGATOR
References: