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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether nitric oxide can prevent kidney problems after heart surgery in newborns with congenital heart defects. Researchers believe that administering nitric oxide during surgery might reduce the risk of acute kidney injury (AKI), a serious issue affecting many children post-operation. The trial compares the effects of nitric oxide with standard treatment without it. Newborns undergoing heart surgery without existing kidney issues or other specific conditions may be eligible. As a Phase 3 trial, this study represents the final step before FDA approval, offering a chance to contribute to a potentially groundbreaking treatment.

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.

Is there any evidence suggesting that nitric oxide is likely to be safe for humans?

Research has shown that nitric oxide is generally safe in various medical situations. Studies have found that using nitric oxide for adult patients with heart problems and high blood pressure in the lungs after surgery is both safe and effective. One study showed that inhaling nitric oxide did not increase the need for blood or platelet transfusions, indicating it was well-tolerated. This suggests that nitric oxide is usually safe for medical treatments. However, using nitric oxide for children undergoing heart surgery remains under investigation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for congenital heart disease?

Unlike the standard treatments for congenital heart disease, which often focus on surgical interventions and medication management, nitric oxide offers a unique approach by being administered intraoperatively through the oxygenator of the cardiopulmonary bypass (CPB) circuit. This method allows for direct delivery at a precise concentration, potentially enhancing the surgical outcome by improving blood flow and reducing inflammation during the procedure. Researchers are excited about nitric oxide because it targets the underlying physiological processes in a novel way, which could lead to better recovery and outcomes for patients with this challenging condition.

What evidence suggests that nitric oxide might be an effective treatment for acute kidney injury?

In this trial, some participants will receive Nitric Oxide. Research has shown that it can help children recover faster after heart surgery by reducing the time on breathing machines and decreasing the need for blood transfusions. Nitric Oxide widens blood vessels, improving blood flow and reducing swelling during surgery. One study found that adding Nitric Oxide to the machine supplying oxygen during surgery helped patients come off breathing support more quickly. Although not yet widely used to prevent kidney problems after surgery, its ability to improve blood flow and reduce swelling makes it a promising option. Meanwhile, other participants in this trial will receive standard care without Nitric Oxide as a placebo comparator. ^{1 3 5 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40681972/

Innovative nitric oxide delivery technology for postoperative ... This study evaluated the safety and efficacy of a novel electrochemical nitric oxide generator (ENG) for administering iNO to adult patients ...

2. ahajournals.org ahajournals.org/doi/10.1161/circ.150.suppl_1.4142086

Abstract 4142086: Efficacy And Safety Of Inhaled Nitric ... Our review and meta-analysis highlights the potential benefits of iNO in reducing ventilation time and FFP transfusion in pediatric patients undergoing cardiac ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1053077025007323

Efficacy and Safety of Pulmonary Vasodilator and Inodilator ... The use of vasodilators or inodilators did not significantly reduce perioperative mortality in paediatric patients undergoing surgical repair of ...

4. bmccardiovascdisord.biomedcentral.com bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-025-04967-3

Innovative nitric oxide delivery technology for postoperative ... This device has proven to be safe and effective for use in adult patients with congenital heart disease and pulmonary hypertension post-surgery.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9237803/

Effect of Nitric Oxide via Cardiopulmonary Bypass on ... This clinical trial compares the efficacy of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT07099144

Inhaled Nitric Oxide for the Treatment of Neonatal Hypoxic ... This is a prospective, open-label, single-arm, multicenter Phase IV clinical study to evaluate the safety of INOmax for the treatment of ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1441277223002892

Statistical analysis plan for the NITric oxide during ... The statistical analysis plan for the NITRIC trial establishes detailed pre-planned analyses alongside Stata scripts to analyse the largest trial in the field ...