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Nitric OxidePhase 2INORDINATENCT05721144

Inhaled NO in Surgical Patients With Recent COVID-19 Infection

A Phase 2 study testing Nitric Oxide Gas in people with Nitric Oxide and COVID-19, run by Xijing Hospital at 1 site in China.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The aim of this study is to evaluate the effect of perioperative inhalation of NO on reducing the incidence of postoperative pulmonary complications in patients with recent COVID-19 infection, and to evaluate whether inhaled NO can improve the prognosis of patients. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Nitric Oxide, COVID-19, Surgery
What is being tested?
Nitric Oxide Gas
Could I receive a placebo?
No, everyone receives an active treatment
How many people
660 participants
Where
1 siteChina
Study dates
17 Feb 2023to 7 May 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥ 18 years old
  • Planned for surgery under general anesthesia
  • With a history of COVID-19 infection within 7 weeks prior to surgery.

Who cannot join

  • Physician makes a decision that trial involvement is not in the patient's best interest or any condition that does not allow the protocol to be followed safely
  • ASA ≥ IV, life expectancy< 24 h.
  • Pregnant or lactating women.
  • Severe liver disease (Child-Pugh score ≥ 12).
  • Patients with severe respiratory failure need mechanical ventilation support or ECMO life support before the operation.
  • Severe renal dysfunction (eGFRC≤30 ml/min/1.73m2) or receiving continuous renal replacement therapy, hemodialysis, and peritoneal dialysis.
  • Having received or participated in other clinical trials within the previous month.

Trial locations and contacts

1 site in 1 country.

China1 site

  • Xijing Hospital

    Xi'an, Shaanxi, 710032

Other trials in China

About this study

Official title: Inhaled NO ReDuce postoperatIve pulmoNAry complicATions in patiEnts With Recent COVID-19 Infection

The aim of this study is to evaluate the effect of perioperative inhalation of NO on reducing the incidence of postoperative pulmonary complications in patients with recent COVID-19 infection, and to evaluate whether inhaled NO can improve the prognosis of patients.

The investigators will enroll 660 surgical patients who was infected with SARS-CoV-2 within 42days (7 weeks ) prior to planed surgery under general anesthesia. Patients will be randomized to receive either inhaled nitric oxide (per protocol) or a placebo. Perioperative standards of care will be the institution's own protocols (such as ventilation strategies and use and dose of anesthetics, analgesia and fluid management, etc).

Read the detailed description

The outbreak of COVID-19 and its global pandemic has posed a threat to public health. On December 7, 2022, the National Health Commission (NHC) of China issued an announcement on further optimization of public health control measures. Since then, the rapid spread and breakthrough of SARS-CoV-2 infections have been observed in the majority of China, caused by the more infectious and less virulent Omicron variant of SARS-Cov-2. Consequently, the proportion of surgical patients with current or previous SARS-CoV-2 infections will inevitably increase within a relatively narrow time window.

It has been reported that a history of SARS-CoV-2 infection is associated with a transiently elevated risk of postoperative complications. The longer the time interval between infection and surgery, the lower the risk of postoperative complications. An updated recommendation suggested postponing surgery for at least seven weeks following SARS-CoV-2 infection, thereby reducing the risk of postoperative complications and 30-day mortality to baseline levels (similar to those without a history of SARS-CoV-2 infection).

COVID-19 infection significantly affects respiratory functions by massively disrupting pulmonary oxygenation and activating the synthesis of proinflammatory cytokines, inducing severe oxidative stress, enhanced vascular permeability, and endothelial dysfunction which has rendered researchers and clinicians to depend on prophylactic treatment due to the unavailability of proper disease management approaches. Inhaled nitric oxide gas (NO) has shown antiviral activity against Coronavirus during the 2003 SARS outbreak. Previous studies have indicated that nitric oxide (NO) application appears to be significant concerning the antiviral activities, antioxidant, and anti-inflammatory properties in relieving disease-related symptoms. Inhaled nitric oxide had been widely used during the Covid-19 pandemic. In the scoping and systemic reviews, it was demonstrated that nitric oxide inhalation was effective in improving oxygenation, cardiopulmonary function, and fastening virus clearance. The investigators designed this study to assess whether inhaled NO reduces postoperative pulmonary complications in patients with a COVID-19 infection history 7 weeks prior to surgery.

Here, the investigators propose a randomized clinical trial aimed to improve postoperative outcomes in patients with an increased risk of postoperative pulmonary complications after COVID-19 infection.

Control group: the institutional standard of care will be delivered. Treatment group: In addition to standard therapy, the subjects will receive inhalation of NO. Inspired NO/N2 will be delivered at 80 parts per million (ppm) after anesthesia induction and intubation and last until the end of surgery and leave the operating room. The physician will follow their own institutional weaning protocols. In the absence of institutional protocols, NO will be reduced in a step-wise fashion starting from 40 ppm to 20, 10, 5, 3, 2, and 1 ppm. If hypoxemia (SpO2 < 93%) or acute hypotension (systolic blood pressure < 90 mmHg) occurs during weaning, NO should be increased to a prior higher concentration.

Safety: prolonged treatment with inhaled NO can lead to increased methemoglobin levels. Blood levels of methemoglobin will be monitored via a non-invasive CO-oximeter or MetHb levels in the blood. If methemoglobin levels rise above 5% at any point in the study, inhaled NO concentration will be halved.

Being tested
Nitric Oxide Gas
Keywords
Nitric Oxide Inhalation, Postoperative Pulmonary Complications, Surgery, COVID-19
Medical subject headings
COVID-19, Postoperative Complications

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nitric Oxide GasDrug

    Also called Nitric Oxide inhalation

    Inspired NO/N2 will be delivered at 80 parts per million (ppm) after anesthesia induction and intubation and lasted until the end of surgery and leave the operating room.

Study groups in NCT05721144
Study groupRoleWhat they receive
Experimental: Treatment GroupExperimentalInspired NO/N2 will be delivered at 80 parts per million (ppm) after anesthesia induction and intubation and lasted until the end of surgery and leave the operating room. The physician will follow their own institutional weaning protocols.
Receives: Drug: Nitric Oxide Gas
Sham Comparator: Control GroupNo interventionThe delivery system will be set up anyway without studying gas administration

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. postoperative pulmonary complications

    It is composite outcome including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis

    Measured: within 7 days after operation

Secondary outcomes (7)

  1. mortality within 30 days postoperatively

    All-cause mortality

    Measured: within 30 days after operation

  2. Classification of pulmonary complications (Clavien-Dindo)

    Evaluation of the severity of pulmonary complications according to Clavien-Dindo classification. It consists of 7 grades (I, II, IIIa, IIIb, IVa, IVb and V).

    Measured: within 7 days after operation

  3. the rate of unplanned ICU admission

    Percentage of patients admitted into ICU after surgery, which is not expected before surgery

    Measured: within 7 days after operation

  4. postoperative length of hospital stay

    duration between end of surgery and discharge from hospital

    Measured: From the date of surgery until the date patient discharge from hospital, assessed up to 30 days

  5. Incidence of thrombotic events

    including DVT and pulmonary embolism

    Measured: From the date of surgery until the date patient discharge from hospital, assessed up to 30 days

  6. incidence of nonpulmonary complications

    including acute kidney injury, Stroke and myocardial infarction

    Measured: From the date of surgery until the date patient discharge from hospital, assessed up to 30 days

  7. postoperative comprehensive complication index (CCI)

    Ranging from 0 (no complication) to 100 (death) was computed based on the Clavien-Dindo classification

    Measured: within 7 days after operation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Feb 2023
  2. Study start17 Feb 2023
  3. Primary completion14 Apr 2024
  4. Study completion7 May 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
660 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05721144
Sponsor's protocol ID
KY-20230079
Acronym
INORDINATE
Status last verified
May 2024
First submitted
7 Feb 2023
Last updated
10 May 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Individual participant data that underline the results reported in this article, after deidentification.

Publications

  • Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.

    PubMed 32031570

  • Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24.

    PubMed 31978945

  • Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18. No abstract available.

    PubMed 32085846

  • Chen L, Liu P, Gao H, Sun B, Chao D, Wang F, Zhu Y, Hedenstierna G, Wang CG. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin Infect Dis. 2004 Nov 15;39(10):1531-5. doi: 10.1086/425357. Epub 2004 Oct 22.

    PubMed 15546092

  • Keyaerts E, Vijgen L, Chen L, Maes P, Hedenstierna G, Van Ranst M. Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound. Int J Infect Dis. 2004 Jul;8(4):223-6. doi: 10.1016/j.ijid.2004.04.012.

    PubMed 15234326

  • 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 (COVID-19) Pneumonia. Obstet Gynecol. 2022 Aug 1;140(2):195-203. doi: 10.1097/AOG.0000000000004847. Epub 2022 Jul 6.

    PubMed 35852269

  • Fang W, Jiang J, Su L, Shu T, Liu H, Lai S, Ghiladi RA, Wang J. The role of NO in COVID-19 and potential therapeutic strategies. Free Radic Biol Med. 2021 Feb 1;163:153-162. doi: 10.1016/j.freeradbiomed.2020.12.008. Epub 2020 Dec 22.

    PubMed 33347987

  • Al Sulaiman K, Korayem GB, Altebainawi AF, Al Harbi S, Alissa A, Alharthi A, Kensara R, Alfahed A, Vishwakarma R, Al Haji H, Almohaimid N, Al Zumai O, Alrubayan F, Asiri A, Alkahtani N, Alolayan A, Alsohimi S, Melibari N, Almagthali A, Aljahdali S, Alenazi AA, Alsaeedi AS, Al Ghamdi G, Al Faris O, Alqahtani J, Al Qahtani J, Alshammari KA, Alshammari KI, Aljuhani O. Evaluation of inhaled nitric oxide (iNO) treatment for moderate-to-severe ARDS in critically ill patients with COVID-19: a multicenter cohort study. Crit Care. 2022 Oct 3;26(1):304. doi: 10.1186/s13054-022-04158-y.

    PubMed 36192801

  • Garfield B, McFadyen C, Briar C, Bleakley C, Vlachou A, Baldwin M, Lees N, Price S, Ledot S, McCabe C, Wort SJ, Patel BV, Price LC. Potential for personalised application of inhaled nitric oxide in COVID-19 pneumonia. Br J Anaesth. 2021 Feb;126(2):e72-e75. doi: 10.1016/j.bja.2020.11.006. Epub 2020 Nov 14. No abstract available.

    PubMed 33288208

  • Ghosh A, Joseph B, Anil S. Nitric Oxide in the Management of Respiratory Consequences in COVID-19: A Scoping Review of a Different Treatment Approach. Cureus. 2022 Apr 5;14(4):e23852. doi: 10.7759/cureus.23852. eCollection 2022 Apr.

    PubMed 35530860

  • Bunch CM, Moore EE, Moore HB, Neal MD, Thomas AV, Zackariya N, Zhao J, Zackariya S, Brenner TJ, Berquist M, Buckner H, Wiarda G, Fulkerson D, Huff W, Kwaan HC, Lankowicz G, Laubscher GJ, Lourens PJ, Pretorius E, Kotze MJ, Moolla MS, Sithole S, Maponga TG, Kell DB, Fox MD, Gillespie L, Khan RZ, Mamczak CN, March R, Macias R, Bull BS, Walsh MM. Immuno-Thrombotic Complications of COVID-19: Implications for Timing of Surgery and Anticoagulation. Front Surg. 2022 May 4;9:889999. doi: 10.3389/fsurg.2022.889999. eCollection 2022.

    PubMed 35599794

  • COVIDSurg Collaborative; GlobalSurg Collaborative. SARS-CoV-2 infection and venous thromboembolism after surgery: an international prospective cohort study. Anaesthesia. 2022 Jan;77(1):28-39. doi: 10.1111/anae.15563. Epub 2021 Aug 24.

    PubMed 34428858

  • COVIDSurg Collaborative. Outcomes and Their State-level Variation in Patients Undergoing Surgery With Perioperative SARS-CoV-2 Infection in the USA: A Prospective Multicenter Study. Ann Surg. 2022 Feb 1;275(2):247-251. doi: 10.1097/SLA.0000000000005310.

    PubMed 34793350

  • Abbott TEF, Fowler AJ, Dobbs TD, Gibson J, Shahid T, Dias P, Akbari A, Whitaker IS, Pearse RM. Mortality after surgery with SARS-CoV-2 infection in England: a population-wide epidemiological study. Br J Anaesth. 2021 Aug;127(2):205-214. doi: 10.1016/j.bja.2021.05.018. Epub 2021 Jun 11.

    PubMed 34148733

  • COVIDSurg Collaborative and GlobalSurg Collaborative. Timing of surgery following SARS-CoV-2 infection: an international prospective cohort study. Anaesthesia. 2021 Jun;76(6):748-758. doi: 10.1111/anae.15458. Epub 2021 Mar 9.

    PubMed 33690889

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nitric Oxide Gas in people with Nitric Oxide and COVID-19, run by Xijing Hospital at 1 site in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

postoperative pulmonary complications (time frame: within 7 days after operation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05721144, which also lists 21 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 May 2024.

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