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Nitric Oxide During Bypass for Arterial Switch Operation (NASO)

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ClinicalTrials.gov Identifier: NCT03661385
Recruitment Status : Recruiting
First Posted : September 7, 2018
Last Update Posted : September 2, 2020
Sponsor:
Information provided by (Responsible Party):
Warwick Butt, Murdoch Childrens Research Institute

Brief Summary:

This trial will test if adding nitric oxide (NO) gas to the cardiopulmonary bypass (CPB) circuit in infants undergoing an arterial switch operation (ASO) for Transposition of the Great Arteries (TGA) changes the incidence of major postoperative adverse events (AEs).

Major postoperative AEs include cardiac arrest, emergency chest opening, use of ECMO (machine that acts as an artificial heart and lung during surgery), and death.

Participants will be randomised to receive oxygen plus nitric oxide (intervention arm) or oxygen without nitric oxide (control arm) during CPB.


Condition or disease Intervention/treatment Phase
Low Cardiac Output Syndrome Transposition of Great Vessels Drug: Nitric Oxide Phase 3

Detailed Description:

The incidence of congenital heart disease (CHD) is approximately 1/100 live born children, of which up to 50% require cardiac surgery to correct the underlying abnormality at some stage during their life. (Centre for Disease Control and Prevention, USA). Despite major improvements in CPB devices, the exposure of host blood to large artificial organ surfaces, combined with myocardial injury during planned myocardial ischemia, results in a significant systemic inflammatory response. CPB-triggered systemic inflammatory syndrome is responsible for the most serious and potentially life-threatening side effects associated with cardiac surgery. It is characterized by endotoxin release, leukocyte and complement activation, and widespread activation of inflammatory mediators, resulting in endothelial leak, increased oxygen consumption, and organ dysfunction.

NO is an endogenous anti-inflammatory mediator that helps to protect endothelial beds and immunologically active cells. NO has a myocardial protective effect by reducing reperfusion injury. NO generation is essential for regulation of endothelial function and microvascular inflammation. However, dysregulation of endogenous NO during CPB may aggravate the subsequent inflammatory response.

A randomized controlled study adding NO into the bypass circuit was conducted by the Royal Children's Hospital in Melbourne on 198 children. This pilot study confirmed the positive effects of gaseous NO reported in the U.S. trial, as well as a reduction in the incidence of low cardiac output syndrome (LCOS). Other improved patient outcomes included a reduced need for extracorporeal life support (ECLS), trends towards a reduced length of stay, and shorter duration of ventilation. In light of these promising preliminary results from these two separate studies, a large multicentre trial to test these findings in children requiring cardiac surgery is needed.

The NASO study is running concurrently with the Nitric Oxide during Cardio Pulmonary Bypass during surgery for congenital heart defects: A Randomised Controlled Trial study (ANZCTR Trial Registry ID: ACTRN12617000821392) within Australia (run by Lady Cilento, Brisbane). This study is aiming to look at the effects of Nitric Oxide on all children under the age of 2 years undergoing bypass surgery for CHD.

TGA presents in 5-7% of all patients with congenital heart disease and isolated TGA is managed in a similar manner all over the world. The surgical treatment for this is the ASO. Hence this single operation and diagnosis provides an appropriate setting to evaluate the efficacy of NO in the CPB circuit. By allowing each centre to have their own protocols of care (pre, intra and postoperatively) and only collecting 'routine clinical data", the investigators anticipate each centre having high rates of screening and consent.

Patients will be stratified by centre and by age at time of surgery. Participants will be randomized into one of two arms:

  • Intervention arm will receive NO 20 parts per million (ppm) into the oxygenator of a cardio-pulmonary bypass circuit
  • Control arm will not receive NO

At the end of CPB, the participants will return to the Intensive Care Unit where normal care will continue.

A total of 800 participants will be enrolled in the study and will be stratified by centre and age at time of surgery.

Study aims to investigate whether exposure to gaseous NO reduces the incidence of postoperative major adverse events in infants on cardiopulmonary bypass.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double blinded, randomised controlled, parallel study comparing an intervention with a control.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Perfusionist (operating bypass) is unblinded to randomisation. They will randomize patient in a computer base (REDcap).Randomization is blinded to all other staff and the nitric oxide container is draped. Nitric oxide container will be attached in all cases.
Primary Purpose: Prevention
Official Title: A Randomised Controlled Trial of Nitric Oxide Administration During Cardiopulmonary Bypass in Infants Undergoing Arterial Switch Operation for Repair of Transposition of the Great Arteries
Actual Study Start Date : July 11, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Active Comparator: Intervention arm
• Intervention arm will receive nitric oxide 20 parts per million (ppm) into the oxygenator of a cardio-pulmonary bypass circuit
Drug: Nitric Oxide
Addition of nitric oxide 20ppm into bypass circuit

No Intervention: Control arm
Control arm will not receive nitric oxide, they will receive standard bypass as per local policy



Primary Outcome Measures :
  1. Major adverse events [ Time Frame: 28 days post intervention ]
    The primary outcome is the number of participants with major adverse events (MAEs) within 28 days post-operatively. MAEs include cardiac arrest, emergency chest opening, use of ECMO, and death.


Secondary Outcome Measures :
  1. Length of stay in ICU (hours) [ Time Frame: This will be calculated from date and time of admission to ICU to date and time of discharge from ICU in hours up to 28 days ]
    Length of stay in ICU (hours) will be calculated from date and time of admission to ICU date and time of discharge to ICU.

  2. Length of stay in hospital (days) [ Time Frame: 28 days (or until hospital discharge) ]
    Length of stay in hospital (days) will be calculated from date and time of admission to hospital to date and time of discharge to hospital.

  3. Ventilator-free days [ Time Frame: 28 days (or until ICU discharge) ]
    Ventilator-free days will be calculated from date and time of intubation to date and time of extubation. Each day (or part of a day) will be counted as a day.

  4. Inotrope hours [ Time Frame: Number of hours inotropes have been administered during first 28 days post operatively ]
    Inotrope hours will be calculated from data input into REDCAP.

  5. Dialysis-free days [ Time Frame: 28 days (or until ICU discharge) ]
    Dialysis-free days will be calculated from date and time of start of dialysis to date and time of stopping dialysis. Each day (or part of a day) will be counted as a day.

  6. Inhaled NO hours [ Time Frame: Number of hours inhaled NO have been administered during first 28 days post operatively ]
    Inhaled NO hours will be calculated from data input into REDCAP.

  7. ECMO-free days [ Time Frame: 28 days (or until ICU discharge) ]
    ECMO-free days will be calculated from date and time of start of ECMO to date and time of stopping ECMO. Each day (or part of a day) will be counted as a day.

  8. Closed sternum days [ Time Frame: 28 days (or until ICU discharge) ]
    Closed sternum days will be calculated from date and time of start of chest opening (or return to ICU time if delayed chest closure) to date and time of chest closure. Each day (or part of a day) will be counted as a day.

  9. Composite free-day score [ Time Frame: 28 days (or until hospital discharge) ]
    This score is a combination of scores 1-8 to create a composite free-day score. Composite free-day score is a score highlighting the number of days free from post-operative complications including free of hospitalization within the first 28 days post operatively. For each score, the days free of complication will be calculated to create an individual free from score these will be then added together to create an overall free-from score. Higher scores suggest a better outcome (free from hospital and complications).



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria;

Each participant must meet all of the following criteria to be enrolled in this study:

  • Infant aged greater than or equal to 36 weeks gestation
  • Infants less than 2 years
  • Diagnosed with TGA and requiring Arterial Switch Operation
  • Consent of parents/guardian.

Exclusion criteria

Potential participants will be excluded if they meet any of the following criteria:

  • They have multiple major congenital anomalies (anomalies which affect the infant's life expectancy or health status)
  • They have multiple other cardiac abnormalities (with the exception of ASD, VSD or PDA)
  • They weigh less than 2.2kgs.
  • Prior surgical exposure to cardio-pulmonary bypass

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03661385


Contacts
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Contact: Kate L Masterson, Research Nurse PICU +61 3 93455522 ext 56492 kate.masterson@rch.org.au
Contact: Warwick Butt, Prof warwick.butt@rch.org.au

Locations
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United States, Texas
Texas Children's Hospital Not yet recruiting
Houston, Texas, United States, 77030
Contact: Paul Checcia         
Australia, Victoria
Royal Children's Hospital Recruiting
Melbourne, Victoria, Australia, 3050
Contact: Kate L Masterson, Research Nurse       kate.masterson@rch.org.au   
Contact: Warwick Butt, MD       warwick.butt@rch.org.au   
Indonesia
Harapan Kita Children and Women's Hospital Recruiting
Jakarta, Indonesia
Contact: Eva Marwali       evamarwali@yahoo.com   
Israel
Schneider Children's medical center Recruiting
Petach Tikvah, Israel
Contact: Ofer Schiller, MD       Schillero@clalit.org.il   
Malaysia
Institut Jantung Negara Recruiting
Kuala Lumpur, Malaysia, 50400
Contact: Soo Kok Wai         
United Kingdom
Alder Hey Hospital Not yet recruiting
Liverpool, United Kingdom, L12 21ap
Contact: Attilio Lotto         
Sponsors and Collaborators
Warwick Butt
Investigators
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Principal Investigator: Warwick Butt MRCI
  Study Documents (Full-Text)

Documents provided by Warwick Butt, Murdoch Childrens Research Institute:
Informed Consent Form  [PDF] August 14, 2018
Study Protocol  [PDF] January 25, 2019

Publications of Results:
Other Publications:
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Responsible Party: Warwick Butt, Director of Paediatric Intensive Care, Murdoch Childrens Research Institute
ClinicalTrials.gov Identifier: NCT03661385    
Other Study ID Numbers: 38017
ACTRN12618000089235p ( Registry Identifier: ANZCTR )
First Posted: September 7, 2018    Key Record Dates
Last Update Posted: September 2, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Warwick Butt, Murdoch Childrens Research Institute:
Cardiopulmonary bypass
Congenital heart disease
Low cardiac output syndrome
Nitric oxide
Transposition of Great Arteries
Arterial switch operation
Additional relevant MeSH terms:
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Cardiac Output, Low
Transposition of Great Vessels
Situs Inversus
Congenital Abnormalities
Heart Diseases
Cardiovascular Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents