Clinical trial NCT04306393: Nitric Oxide Gas Inhalation in Severe Acute Respiratory Syndrome in COVID-19
Official title: Nitric Oxide Gas Inhalation Therapy for Mechanically Ventilated Patients With Severe Acute Respiratory Syndrome Caused by SARS-CoV2: a Randomized Clinical Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: SARS (Severe Acute Respiratory Syndrome)
Coronavirus
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Xijing Hospital
name: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
name: Niguarda Hospital
First posted: 2020-03-12
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Severe acute respiratory syndrome (SARS-CoV2) due to novel Coronavirus (2019-nCoV) related infection (COVID-19) is characterized by severe ventilation perfusion mismatch leading to refractory hypoxemia. To date, there is no specific treatment available for 2019-nCoV. Nitric oxide is a selective pulmonary vasodilator gas used in as a rescue therapy in refractory hypoxemia due to acute respiratory distress syndrome (ARDS). In-vitro and clinical evidence indicate that inhaled nitric oxide gas (iNO) has also antiviral activity against other strains of coronavirus. The primary aim of this study is to determine whether inhaled NO improves oxygenation in patients with hypoxic SARS-CoV2. This is a multicenter single-blinded randomized controlled trial with 1:1 individual allocation

Detailed description: Severe acute respiratory syndrome (SARS-CoV-2) due to novel Coronavirus (2019-nCoV) related infection (COVID-19) is characterized by severe ventilation perfusion mismatch leading to refractory hypoxemia. To date, there is no specific treatment available for 2019-nCoV. Nitric oxide is a selective pulmonary vasodilator gas used as a rescue therapy in refractory hypoxemia due to acute respiratory distress syndrome (ARDS). In has also shown in-vitro and clinical evidence that inhaled nitric oxide gas (iNO) has antiviral activity against other strains of coronavirus.

The primary aim of this study is to determine whether inhaled NO improves oxygenation in patients with hypoxic SARS-CoV2.

This is a multicenter randomized controlled trial with 1:1 individual allocation. Patients will be blinded to the treatment.

Intubated patients admitted to the intensive care unit with confirmed SARS-CoV-2 infection and severe hypoxemia will be randomized to receive inhalation of NO (treatment group) or not (control group). Treatment will be stopped when patients are free from hypoxemia for more than 24 hours.

Eligibility criteria: Inclusion criteria: (1) Adult patients, \>/= 18 year-old; (2) Patients admitted to the ICU; (3) Patients who are intubated and mechanically ventilated; (4) Confirmed diagnosis of SARS-CoV2 by positive rt-PCR.

Exclusion criteria: (1) Patients intubated for more than 72 hours from initiation of the treatment gas; (2) Subjects enrolled in another interventional research study; (3) Physician of record opposed to enrolling the patient due to perceived safety concerns; or any condition that does not allow the protocol to be followed safely; (4) Subjects with past medical history of lung malignancy or pneumonectomy or lung transplant; (5) Subjects receiving a tidal volume \< 3 cc/kg of ideal body weight at the time of enrollment; (6) Subjects with severe burns involving more than 40% of Total Body Surface Area; (7) Subjects that have experienced cardiac arrest with CPR for longer than 30 minutes; (8) Subjects with a presumed severe deficit in cerebral function with fixed dilated pupil; (9) Subjects receiving renal replacement therapy at the time of enrollment; (10) Subjects who have an impaired ability to ventilate without assistance; (11) Subjects who have a history of malignancy or other irreversible disease/conditions with a 6-month mortality \> 50%; (12) Subjects not fully committed to full support at the time of enrollment; (13) Subject receiving inhaled nitric oxide gas prior to enrollment; (14) Subject's hospital admission unrelated to COVID-19.

Primary outcomes:
measure: Change of arterial oxygenation at 48 hours from enrollment
timeFrame: 48 hours
Secondary outcomes:
measure: Time to reach normoxemia during the first 28 days after enrollment
timeFrame: 28 days
measure: Proportion of SARS-nCoV-2 free patients during the first 28 days after enrollment
timeFrame: 28 days
measure: Survival at 28 days from enrollment
timeFrame: 28 days
measure: Survival at 90 days from enrollment
timeFrame: 90 days
Other outcomes:
measure: Daily oxygenation in the two groups until day 28
timeFrame: 28 days
measure: Need for new renal replacement therapy during the first 28 days
timeFrame: 28 days
measure: Mechanical support of circulation during the first 28 days
timeFrame: 28 days
measure: Days free of vasopressors during the first 28 days
timeFrame: 28 days
measure: Ventilator-free days at 28 days
timeFrame: 28 days
measure: Time to SARS-CoV-2 rt-PCR negative in upper respiratory tract specimen
timeFrame: 28 days
measure: ICU-free days at 28 days
timeFrame: 28 days
measure: ICU length of stay
timeFrame: 90 days
measure: SARS-CoV-2 Viral Load in Sputum
timeFrame: 28 days
measure: SARS-CoV-2 Viral Load in Plasma
timeFrame: 28 days
measure: Acute Kidney Injury at 28 days
timeFrame: 28 days
measure: Daily Vasoactive Inotropic Score
timeFrame: 28 days
measure: Requirement for VV-ECMO
timeFrame: 28 days
measure: Daily Sequential Organ Failure Assessment
timeFrame: 28 days
measure: Hospital-free days at 28 days
timeFrame: 28 days
measure: Hospital length of stay
timeFrame: 90 days
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Shreveport
country: United States
facility: Louisiana State University Health Shreveport
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Danderyd
country: Sweden
facility: Danderyd Sjukhus AB
state: Stockholm
Study officials:
affiliation: Massachusetts General Hospital
name: Lorenzo Berra, MD
role: STUDY_DIRECTOR
References:
citation: Gibson LE, Fenza RD, Lang M, Capriles MI, Li MD, Kalpathy-Cramer J, Little BP, Arora P, Mueller AL, Ichinose F, Bittner EA, Berra L, G Chang M. Right Ventricular Strain Is Common in Intubated COVID-19 Patients and Does Not Reflect Severity of Respiratory Illness. J Intensive Care Med. 2021 Aug;36(8):900-909. doi: 10.1177/08850666211006335. Epub 2021 Mar 30.
citation: Lei C, Su B, Dong H, Bellavia A, Fenza RD, Fakhr BS, Gianni S, Grassi LG, Kacmarek R, Morais CCA, Pinciroli R, Vassena E, Berra L. Protocol of a randomized controlled trial testing inhaled Nitric Oxide in mechanically ventilated patients with severe acute respiratory syndrome in COVID-19 (SARS-CoV-2). medRxiv [Preprint]. 2020 May 24:2020.03.09.20033530. doi: 10.1101/2020.03.09.20033530.