iNO300 Therapy in Critically Ill Patients With Pneumonia

Official title

High Dose Inhaled Nitric Oxide Therapy in Critically Ill Patients With Pneumonia: a Pilot, Double-blinded, Randomized, Controlled Trial

Overview

The goal of this clinical trial is to learn the formation and recovery rate of methemoglobin (MetHb) in severely sick patients with pneumonia who receive high doses of inhaled nitric oxide (iNO) therapy at 250 parts per million (ppm), not exceeding 300 ppm. Meanwhile, the benefits of the therapy to treat severely sick patients with pneumonia will be explored. Patients who are 18 years or older, newly diagnosed with pneumonia, and severely sick with requirement of a breathing machine could be included. The main questions it aims to answer are: How does methemoglobin change through the iNO treatment? Does iNO therapy increase the number of patients recovering from pneumonia? Researchers will compare iNO treatment to placebo, which means using the same device as the treatment group without delivering the study drug. Participants will: * Receive iNO treatment starting at 250 ppm, not exceeding 300 ppm, 40 min, every 6 hours, from day 1 to day 5 * Be followed up for 60 days

Detailed description

This study is designed as a pilot, double-blinded, randomized controlled trial to investigate levels of methemoglobin in the treatment group versus the control group and efficacy of high dose inhaled NO among critically ill patients with pneumonia. We will enroll 34 adult patients with newly diagnosed pneumonia and invasive mechanical ventilation who are admitted to the ICUs at Massachusetts General Hospital.

After enrollment, participants will be randomized in 1:1 ratio to intervention group or control group. Baseline characteristics will be collected.

During treatment period, patients allocated to the intervention group will receive high dose inhaled NO starting at 250 ppm (not exceeding 300 ppm), 40min, 4 times daily, for 5 days. The control group will receive sham intervention. Both groups will receive standard therapy.

During follow-up period, we will follow participants for a total duration of 60 days. Methemoglobin kinetic levels and efficacy outcomes will be collected.

Interventions

• Drug High dose inhaled nitric oxide
  Inhaled nitric oxide starting at 250-300 ppm, 40min, every 6 hours, from day 1 to day 5. Nitric oxide is delivered using a gas cylinder containing nitric oxide and nitrogen.
• Other Sham treatment
  Sham intervention with the nitric oxide gas cylinder replaced by that containing only nitrogen and all other delivery procedures identical to the intervention group
• Other standard therapy
  Standard therapy pneumonia and critical illness

Primary outcome measures

• Peaks of methomoglobin [Time frame: From Day 1 to Day 5]

Secondary outcome measures (12)

• Nitrogen dioxide level [Time frame: From Day 1 to Day 5]
• Feasibility [Time frame: From enrollment to Day 60]
• Clinical cure rate of pneumonia [Time frame: From enrollment to test of cure day (4 -11 days post end of treatment)]
• Clinical improvement rate of pneumonia [Time frame: Day 5]
• Microbiologic eradication rate [Time frame: From enrollment to test of cure day (4 -11 days post end of treatment)]
• 28-day all cause mortality [Time frame: From enrollment to Day 28]
• 60-day all cause mortality [Time frame: From enrollment to Day 60]
• 28-day ventilator free days [Time frame: From enrollment to Day 28]
• Days free from organ support in 28 days [Time frame: From enrollment to Day 28]
• Blood stream infection [Time frame: From enrollment to Day 28]
• Days free from antibiotics during hospitalization [Time frame: From enrollment to the day of hospital discharge or death, whichever comes earlier, assessed up to 60 days]
• Acquisition of multidrug-resistant (MDR) infection or colonization [Time frame: From enrollment to Day 28]

Eligibility criteria

Inclusion criteria

• 18 years or older
• Intubated and mechanically ventilated
• Within 72h of diagnosis of community- or hospital-acquired pneumonia
• Written informed consent obtained from patients or legally authorized representatives

Exclusion criteria

• Baseline methemoglobin 3% or higher
• Genetic diseases including glucose-6-phosphate dehydrogenase deficiency, cytochrome b5 reductase deficiency, sickle cell disease
• Oxygen saturation < 88% on 100% inspired fraction of oxygen
• Anemia with hemoglobin < 7.0 g/dl
• Acute cardiogenic shock requiring inotropic or mechanical support with an ejection fraction less than 20%
• Receiving inhaled NO therapy or decision to initiate inhaled NO therapy within 24 hours post randomization
• A decision to do-not-resuscitate (DNR)
• Enrollment in another experimental antimicrobial treatment protocol
• Patients for whom follow-up is expected to be impossible

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Massachusetts General Hospital — Boston

Publications

• Tal A, Greenberg D, Av-Gay Y, Golan-Tripto I, Feinstein Y, Ben-Shimol S, Dagan R, Goldbart AD. Nitric oxide inhalations in bronchiolitis: A pilot, randomized, double-blinded, controlled trial. Pediatr Pulmonol. 2018 Jan;53(1):95-102. doi: 10.1002/ppul.23905. Epub 2017 Nov 27. PMID 29178284
• Wolak T, Dicker D, Shifer Y, Grossman A, Rokach A, Shitrit M, Tal A. A safety evaluation of intermittent high-dose inhaled nitric oxide in viral pneumonia due to COVID-19: a randomised clinical study. Sci Rep. 2024 Jul 26;14(1):17201. doi: 10.1038/s41598-024-68055-w. PMID 39060420
• Miller C, Miller M, McMullin B, Regev G, Serghides L, Kain K, Road J, Av-Gay Y. A phase I clinical study of inhaled nitric oxide in healthy adults. J Cyst Fibros. 2012 Jul;11(4):324-31. doi: 10.1016/j.jcf.2012.01.003. Epub 2012 Apr 18. PMID 22520076
• Wiegand SB, Safaee Fakhr B, Carroll RW, Zapol WM, Kacmarek RM, Berra L. Rescue Treatment With High-Dose Gaseous Nitric Oxide in Spontaneously Breathing Patients With Severe Coronavirus Disease 2019. Crit Care Explor. 2020 Nov 16;2(11):e0277. doi: 10.1097/CCE.0000000000000277. eCollection 2020 Nov. PMID 33225304
• Strickland B, Albala L, Coffey EC, Carroll RW, Zapol WM, Ichinose F, Berra L, Harris NS. Safety and practicality of high dose inhaled nitric oxide in emergency department COVID-19 patients. Am J Emerg Med. 2022 Aug;58:5-8. doi: 10.1016/j.ajem.2022.04.052. Epub 2022 May 4. PMID 35623183
• Safaee Fakhr B, Di Fenza R, Gianni S, Wiegand SB, Miyazaki Y, Araujo Morais CC, Gibson LE, Chang MG, Mueller AL, Rodriguez-Lopez JM, Ackman JB, Arora P, Scott LK, Bloch DB, Zapol WM, Carroll RW, Ichinose F, Berra L; Nitric Oxide Study Investigators. Inhaled high dose nitric oxide is a safe and effective respiratory treatment in spontaneous breathing hospitalized patients with COVID-19 pneumonia. N PMID 34400339
• Wiegand SB, Traeger L, Nguyen HK, Rouillard KR, Fischbach A, Zadek F, Ichinose F, Schoenfisch MH, Carroll RW, Bloch DB, Zapol WM. Antimicrobial effects of nitric oxide in murine models of Klebsiella pneumonia. Redox Biol. 2021 Feb;39:101826. doi: 10.1016/j.redox.2020.101826. Epub 2020 Dec 11. PMID 33352464
• Valsecchi C, Winterton D, Safaee Fakhr B, Collier AY, Nozari A, Ortoleva J, Mukerji S, Gibson LE, Carroll RW, Shaefi S, Pinciroli R, La Vita C, Ackman JB, Hohmann E, Arora P, Barth WH Jr, Kaimal A, Ichinose F, Berra L; DELiverly oF iNO (DELFiNO) Network Collaborators. High-Dose Inhaled Nitric Oxide for the Treatment of Spontaneously Breathing Pregnant Patients With Severe Coronavirus Disease 2019 PMID 35852269

Identifiers

NCT: NCT06950294 · 2025P000909

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗