What side effects are associated with this type of intervention?

Common treatments for Atrial Septal Defect (ASD) include surgical repair and catheter-based procedures, which generally have risks such as infection, bleeding, and arrhythmias. For managing associated pulmonary hypertension, treatments like inhaled nitric oxide and prostacyclin are used. Inhaled nitric oxide can increase the risk of renal impairment but rarely causes methemoglobinemia or bleeding. Prostacyclin, while improving oxygenation and reducing pulmonary arterial pressure, may cause side effects like headache, nausea, and flushing. Both treatments aim to improve blood flow and reduce pulmonary hypertension, similar to the effects of L-citrulline.

What prior FDA approvals exist?

The FDA has approved several treatments for conditions related to Atrial Septal Defect (ASD) that aim to improve blood flow and reduce pulmonary hypertension. One such treatment is sildenafil, a phosphodiesterase-5 inhibitor, which has been shown to improve pulmonary hemodynamics and exercise capacity in patients with pulmonary arterial hypertension (PAH). Another related drug is tadalafil, which also increases nitric oxide availability and has similar benefits in PAH patients. These treatments are relevant as they share a mechanism of action with L-citrulline, which increases nitric oxide production to potentially improve blood flow and reduce pulmonary hypertension.

What other types of research exist?

Promising alternatives to L-citrulline for ASD patients include soluble guanylate cyclase stimulators like riociguat, which have shown potential benefits in improving quality of life and exercise capacity. Additionally, phosphodiesterase-5 inhibitors (PDE5Is) such as sildenafil may also be considered, although their combination with guanylate cyclase stimulators is not recommended due to increased risk of hypotension.

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Amino Acid

L-Citrulline for Congenital Heart Defects

Phase 3

Waitlist Available

Led By Christopher Mastropietro, MD, FCCM

Research Sponsored by Asklepion Pharmaceuticals, LLC

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Male and female subjects aged ≤18 years of age (females of child-bearing potential willing to practice an acceptable form of birth control)

Patients undergoing cardiopulmonary bypass for repair of a large unrestrictive ventricular septal defect, an ostium primum/secundum atrial septal defect, or a partial or complete atrioventricular septal defect

Must not have

Evidence of pulmonary artery or vein abnormalities that will not be addressed surgically. Specific abnormalities excluded include: significant pulmonary artery narrowing not amenable to surgical correction, previous pulmonary artery stent placement, significant left sided AV valve regurgitation not amenable to surgical correction, pulmonary venous return abnormalities not amenable to surgical correction, pulmonary vein stenosis not amenable to surgical correction

Preoperative requirement for mechanical ventilation or IV inotrope support

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 1, 2, 4, 12, 24, and 48 hours post-dose

Awards & highlights

Pivotal Trial

Summary

This trial tests L-citrulline in patients with specific congenital heart defects undergoing surgery. L-citrulline helps improve blood flow by widening blood vessels, which may reduce complications during and after surgery. L-citrulline is an amino acid that has been shown to improve blood flow and vascular function by increasing nitric oxide availability.

Who is the study for?

This trial is for children under 18 with certain heart defects needing surgery, who can have a guardian sign consent. It's not for those with conditions affecting the study, pregnant girls or sexually active ones not using birth control, patients in other trials recently, on pulmonary hypertension meds, or with specific uncorrectable lung blood vessel issues.

What is being tested?

The study tests if L-citrulline can prevent lung injury after heart defect surgery in kids. Patients are randomly chosen to get either L-citrulline or a placebo without knowing which one they receive. The safety and effectiveness of both treatments are compared.

What are the potential side effects?

While the trial document does not specify side effects of L-citrulline, common ones may include stomach pain, heartburn, changes in urination patterns and possible allergic reactions. Side effects will be closely monitored throughout the trial.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 or younger and, if female, willing to use birth control.

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I am having heart surgery to fix a hole in my heart.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have lung blood vessel issues that cannot be fixed with surgery.

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I need a machine to help me breathe or IV medication to support my heart function before surgery.

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I have a type of high blood pressure in the lungs called pulmonary hypertension.

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I am taking medication for high blood pressure in my lungs before surgery.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 1, 2, 4, 12, 24, and 48 hours post-dose

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~1, 2, 4, 12, 24, and 48 hours post-dose

This trial's timeline: 3 weeks for screening, Varies for treatment, and 1, 2, 4, 12, 24, and 48 hours post-dose for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Post-operative need for mechanical ventilation

Secondary study objectives

Adverse events

Arterial blood gasses (HCO3)

Arterial blood gasses (PaCO2)

+29 more

Side effects data

From 2019 Phase 3 trial • 189 Patients • NCT02891837

18%

Pyrexia

14%

Pain

13%

Hypertension

12%

Tachycardia

12%

Hypokalaemia

11%

Constipation

11%

Restlessness

Haemoglobin decreased

Pleural effusion

Hypocalcaemia

Tachypnoea

Vomiting

Electrolyte imbalance

Cough

Pulmonary congestion

Hypotension

Metabolic acidosis

Hypomagnesaemia

Stridor

Oligurea

Atelectasis

Leukocytosis

Anaemia

Sinus bradycardia

Diarrhoea

Post procedural haemorrhage

Blood pressure decreased

Coagulation time prolonged

Pulmonary oedema

Haematocrit decreased

Ventricular tachycardia

Arrhythmia

Staphylococcal infection

Cardiac tamponade

Ventricular fibrillation

Leukopenia

Thrombocytopenia

Aortic valve incompetence

Atrioventricular block complete

Nausea

Peripheral swelling

Blood lactic acid increased

C-reactive protein increased

Chylothorax

100%

80%

60%

40%

20%

Study treatment Arm

L-citrulline - All Patients on Mechanical Ventilation for ≤48 Hours

L-citrulline - All Patients

L-citrulline - US Patients on Mechanical Ventilation for >48 Hours

Placebo - All Patients

L-citrulline - US Patients on Mechanical Ventilation for ≤48 Hours

L-citrulline - All Patients on Mechanical Ventilation for >48 Hours

Placebo - All Patients on Mechanical Ventilation for ≤48 Hours

Placebo - US Patients on Mechanical Ventilation for ≤48 Hours

Placebo - All Patients on Mechanical Ventilation for >48 Hours

Placebo - US Patients on Mechanical Ventilation for >48 Hours

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: ActiveExperimental Treatment1 Intervention

Patients will receive: 1. an L-citrulline bolus of 150 mg/kg at the initiation of cardiopulmonary bypass 2. the addition L-citrulline to maintain a steady state target concentration of approximately 100 μmol/L of L-citrulline during cardiopulmonary bypass 3. an L-citrulline bolus of 10 mg/kg 30 minutes after decannulation from cardiopulmonary bypass, followed immediately by a 9 mg/kg/hour continuous L-citrulline infusion or placebo for up to 48 hours post-first dose. The infusion rate will be adjusted (up or down titration of drug infusion) to achieve a target steady state concentration of 100 μmol/L. Infusion will be discontinued once invasive arterial blood pressure monitoring is discontinued or at 48 hours, whichever occurs first.

Group II: PlaceboPlacebo Group1 Intervention

Plasmalyte A administered to the same schedule as the active treatment arm.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

L-citrulline

2010

Completed Phase 3

~530

0 / 6Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Atrial Septal Defect (ASD) often focus on improving blood flow and reducing pulmonary hypertension. L-citrulline and L-arginine are precursors to nitric oxide (NO), a molecule that helps dilate blood vessels, thereby improving blood flow and reducing the pressure in the pulmonary arteries. This is particularly important for ASD patients, as they are at risk for increased pulmonary blood flow and subsequent pulmonary hypertension. By enhancing NO production, these treatments can alleviate some of the hemodynamic stresses associated with ASD, potentially improving patient outcomes. Other treatments may include surgical or catheter-based interventions to close the defect, but the use of NO precursors offers a non-invasive option to manage symptoms and improve quality of life.

The effects of L-arginine on neointimal formation and vascular function following balloon injury in heritable hyperlipidaemic rabbits.L-arginine augments endothelium-dependent vasodilation in cholesterol-fed rabbits.Sodium nitroprusside inhibits lactate formation in rat atria: is cyclic GMP involved?