Nitric Oxide for Congenital Heart Disease

Overseen By David S Cooepr, MD

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Steroids, Inhaled NO, others

Disqualifiers: Preoperative AKI, Cardiac arrest, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Intraoperative

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have recently been treated with steroids or are using inhaled nitric oxide (iNO) before surgery.

What evidence supports the effectiveness of the drug nitric oxide for congenital heart disease?

Inhaled nitric oxide is shown to be beneficial as a selective pulmonary vasodilator (a drug that widens blood vessels in the lungs) for treating pulmonary hypertension (high blood pressure in the lungs) in newborns with congenital heart disease, providing hemodynamic benefits (improvements in blood flow and pressure). However, these benefits have not been confirmed in randomized, placebo-controlled studies. ^{1 2 3 4 5}

Is nitric oxide generally safe for use in humans?

Nitric oxide is involved in many body processes and has been studied for various conditions. It can cause side effects like headaches and low blood pressure due to its ability to widen blood vessels. However, it is generally considered safe when used appropriately, although targeting its effects to specific tissues remains a challenge. ^{1 4 5 6 7}

How is the drug nitric oxide unique in treating congenital heart disease?

Nitric oxide is unique because it is inhaled and acts as a selective pulmonary vasodilator, meaning it specifically relaxes the blood vessels in the lungs, which can help manage pulmonary hypertension (high blood pressure in the lungs) in patients with congenital heart disease. This targeted action helps improve blood flow and oxygen delivery without affecting the rest of the body, unlike some other treatments. ^{3 4 5 8 9}

What is the purpose of this trial?

Acute kidney injury (AKI) following cardiac surgery for congenital heart defects (CHD) in children affects up to 60% of high risk-patients and is a major cause of both short- and long-term morbidity and mortality. Despite effort, to date, no successful therapeutic agent has gained widespread success in preventing this postoperative decline in renal function. Nitric oxide is an intricate regulator of acute inflammation and coagulation and is a potent vasodilator. The investigators hypothesize that nitric oxide, administered during cardiopulmonary bypass (CPB), may reduce the incidence of AKI.

Eligibility Criteria

This trial is for newborns (up to 31 days old) who need heart surgery with cardiopulmonary bypass for congenital heart defects. They must weigh over 2 kg and be at least 36 weeks gestational age. Babies can't join if they've had a recent cardiac arrest, preoperative AKI, certain lung or kidney conditions, steroid treatments, or are on other trials.

Inclusion Criteria

My newborn is having heart surgery with CPB for congenital heart disease.

Exclusion Criteria

Non-English speakers

My kidney ultrasound showed structural abnormalities.

I need surgery urgently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Nitric oxide is administered during cardiopulmonary bypass (CPB) to reduce the incidence of AKI

Intraoperative

1 visit (in-person, surgical procedure)

Follow-up

Participants are monitored for AKI and other outcomes postoperatively

72 hours

Continuous monitoring during hospital stay

Extended Follow-up

Participants are monitored for long-term kidney function and recovery

4 weeks

Treatment Details

Interventions

• Nitric Oxide

Trial Overview The study tests whether nitric oxide given during heart surgery can lower the risk of acute kidney injury in newborns with congenital heart defects. It's exploring if this gas helps protect the kidneys by reducing inflammation and improving blood flow during surgery.

Participant Groups

Group I: Nitric Oxide Experimental Treatment 1 Intervention

Intraoperative NO entrained at 20 ppm into the oxygenator of the CPB circuit with standard care

Group II: Oxygen Placebo Group 1 Intervention

Standard CPB without NO administered at any point intraoperatively

Nitric Oxide is already approved in United States for the following indications:

Approved in United States as Inomax for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Approved in United States as Noxivent for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Approved in United States as GeNOsyl for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Mallinckrodt

Industry Sponsor

Trials

202

Recruited

15,700+

Mario Saltarelli

Mallinckrodt

Chief Medical Officer

MD

Siggi Olafsson

Mallinckrodt

Chief Executive Officer

PhD in Pharmacy

Indiana University

Collaborator

Trials

1,063

Recruited

1,182,000+

Findings from Research

Nitric oxide (NO) is identified as a key endothelium-derived relaxing factor (EDRF) that regulates smooth muscle tone and platelet behavior, with its release being significantly inhibited by N omega-Monomethylarginine (N-MeArg), suggesting its crucial role in vascular relaxation.

The study demonstrated that the relaxation effect induced by histamine and acetylcholine in the guinea pig pulmonary artery is dependent on EDRF, and that this effect can be reversed by L-arginine, indicating that EDRF likely originates from arginine metabolism in the endothelium.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of arginine as a precursor of endothelium-derived relaxing factor. Sakuma, I., Stuehr, DJ., Gross, SS., et al.[2022]

Nitric oxide (NO) has a complex role in cardiac health, showing both cardioprotective effects during myocardial ischemia-reperfusion and potential to worsen reperfusion injury by producing harmful peroxynitrite.

Exogenous supplementation of NO, particularly through agents like protamine sulfate, may enhance NO production and provide therapeutic benefits in conditions like pulmonary hypertension and atherosclerotic coronary heart disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of nitric oxide in cardiac surgery. Nonami, Y.[2022]

Inhaled nitric oxide is an effective treatment for pulmonary hypertension in patients with congenital heart disease, particularly benefiting newborns, who made up 37% of the 400 patients treated at the center.

While it helps in diagnosing and managing conditions like total anomalous pulmonary venous connection and congenital mitral stenosis, the efficacy of inhaled nitric oxide has not been rigorously tested in randomized, placebo-controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide in the neonate with cardiac disease. Atz, AM., Wessel, DL.[2022]

Endothelium-derived nitric oxide (EDNO) plays a crucial role in vascular smooth muscle relaxation and is responsible for activating soluble guanylate cyclase, leading to increased cyclic GMP levels and inhibition of platelet aggregation.

EDNO has a very short half-life of 3-5 seconds, which limits its biological activity, but it is synthesized from L-arginine and may be involved in regulating blood flow and platelet function in both healthy and disease states.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelium-derived nitric oxide: actions and properties. Ignarro, LJ.[2022]

Both endothelium-derived relaxing factor (EDRF) and nitric oxide (NO) effectively relax smooth muscle, but arterial smooth muscle is significantly more sensitive to these relaxants compared to nonvascular smooth muscle, as shown in a study using various muscle preparations.

The study identified EDRF from human umbilical vein as nitric oxide or a related nitroso compound, confirming that NO is a key mediator in vascular relaxation and suggesting its potential therapeutic role in managing vascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelium-derived nitric oxide relaxes nonvascular smooth muscle. Buga, GM., Gold, ME., Wood, KS., et al.[2019]

Nitric oxide (NO) plays a crucial role in various physiological and pathological processes, leading to the development of NO donor drugs that can treat conditions like atherosclerosis, hypertension, and inflammatory diseases.

Current NO donor drugs face challenges such as tolerance and side effects, but new classes like S-nitrosothiols and diazeniumdiolates are being researched to improve targeting and efficacy while minimizing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitric oxide donor drugs: an update on pathophysiology and therapeutic potential. Scatena, R., Bottoni, P., Martorana, GE., et al.[2019]

Endothelium-derived nitric oxide (EDNO) plays a crucial role in vascular smooth muscle relaxation by activating guanylate cyclase, leading to increased cyclic GMP levels, which promotes muscle relaxation and inhibits platelet aggregation.

Nitroglycerin and other organic nitrates mimic the action of EDNO by converting to nitric oxide within vascular smooth muscle cells, providing a similar therapeutic effect in promoting blood flow and reducing platelet adhesion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelium-derived nitric oxide: pharmacology and relationship to the actions of organic nitrate esters. Ignarro, LJ.[2019]

Inhalation of low levels of nitric oxide (80 ppm) significantly reduced mean pulmonary artery pressure and pulmonary vascular resistance in 10 pediatric patients with congenital heart disease and pulmonary hypertension, demonstrating its efficacy as a selective pulmonary vasodilator.

Breathing nitric oxide did not affect systemic blood pressure or vascular resistance, indicating its safety and potential for targeted treatment without systemic side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide in congenital heart disease. Roberts, JD., Lang, P., Bigatello, LM., et al.[2019]

Nitrates, as nitrovasodilators, effectively reduce cardiac workload and improve oxygen delivery to ischemic heart areas by relaxing blood vessels, which is crucial for treating conditions like angina.

The mechanism of action involves the activation of soluble guanylyl cyclase by nitric oxide (NO), leading to increased levels of cyclic guanosine monophosphate (cGMP) that lower calcium concentrations in cells, enhancing vascular relaxation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrates in different vascular beds, nitrate tolerance, and interactions with endothelial function. Bassenge, E., Zanzinger, J.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Identification of arginine as a precursor of endothelium-derived relaxing factor. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

The role of nitric oxide in cardiac surgery. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide in the neonate with cardiac disease. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Endothelium-derived nitric oxide: actions and properties. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Endothelium-derived nitric oxide relaxes nonvascular smooth muscle. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Nitric oxide donor drugs: an update on pathophysiology and therapeutic potential. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Endothelium-derived nitric oxide: pharmacology and relationship to the actions of organic nitrate esters. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide in congenital heart disease. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Nitrates in different vascular beds, nitrate tolerance, and interactions with endothelial function. [2019]