Melatonin for Pulmonary Hypertension in Full Term Neonates

Melatonin as an Adjunct Therapy to Milrinone for Pulmonary Hypertension in Full Term Neonates

Published evidence has provided a possible role of melatonin and the treatment of pulmonary hypertension through its strong antioxidant properties and improving vascular function in animals.

This study will test the hypothesis of the possible use of melatonin as an adjunct therapy to milrinone for neonatal pulmonary hypertension.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension; Neonatal Mortality; Neonatal Diseases and Abnormalities; Pulmonary Arterial Hypertension, Children
• Intervention / Treatment: Drug: Melatonin; Other: Placebo

Detailed Description

Normal pulmonary artery pressure shows a gradual declining trend after birth, and pulmonary artery pressure of 72 h after birth is still higher than that of normal adults Infants born after 34 weeks of gestation with primary findings on physical examination reveals tachypnoea, retractions, grunting, desaturation unresponsive to supplemental O2, cyanosis and pulmonary arterial pressure (PAP) > 25 mm Hg measured by echocardiography, within 72 h of birth, are considered to have pulmonary hypertension Pulmonary hypertension in neonates (PPHN) is a syndrome characterized by failure in the mechanisms that decrease pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) after birth Persistent pulmonary hypertension of newborn (PPHN) develops when pulmonary vascular resistance (PVR) remains elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. The PVR may remain elevated due to pulmonary hypoplasia, like that seen with congenital diaphragmatic hernia, and maladaptation of the pulmonary vascular bed as occurs with perinatal asphyxia It has been shown that one of the mechanisms involved in the pathophysiology of PPHN is oxidative stress, which results in an imbalance between an increase in free radicals generation and decreased antioxidant capacity Currently, the treatment for PHN considers timely and precise interventions such as intravenous milrinone, oral pulmonary vasodilators such as endothelin receptor antagonist, phosphodiesterase-5 inhibitors such as sildenafil, inhaled nitric oxideand are used both during acute and chronic phases of PPHN, controlled oxygen administration, and even extracorporeal membrane oxygenation.

However, these therapeutic strategies do not markedly reduce the mortality and the long-term neonatal outcomes remain poor Melatonin, more commonly known as the sleep hormone, has been highlighted by experimental evidence, to have significant effects as a direct scavenger of oxygen free radicals and induces antioxidant enzymatic It has been shown that melatonin has vasodilator properties and may modulate pro-oxidant sources in the neonatal lung which is proposed to treat PHN in the first days of neonatal life.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Ain Shams University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• full term neonates ≥37 weeks diagnosed with pulmonary hypertension, with Pulmonary arterial pressure (PAP) > 25 mm Hg measured by echocardiography, within 72 h of birth (Chetan et al., 2022).

Exclusion Criteria:

• Neonates with major congenital anomalies like congenital heart diseases

  • NPO or any contraindications to oral intake
  • Neonates with suspected inborn error of metabolism

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group melatonin group; Intervention group : will receive oral melatonin (Kids Daily Vit Sleep syrup) 3 mg/kg/day divided in 3 doses , after enteral feeding, for 3 consecutive days, as combined therapy to milrinone (Garofoli et al., 2021). Human studies documented that short-term use of melatonin is safe, even in extreme doses (Andersen et al., 2016).	Drug: Melatonin; oral melatonin 3 mg/kg/day divided in 3 doses , after enteral feeding, for 3 consecutive days, as combined therapy to milrinone
Placebo Comparator: Control group; Control group: will receive the treatment of PHN as our NICU protocol in the form of loading dose of milrinone (50 μg/kg) over 60 mins followed by a maintenance infusion (0.33-0.99 μg/kg/min) for 72 hrs. (McNamara et al., 2013) And equivalent amout of distilled water as a placebogive at same time intervals as melatoni	Other: Placebo; Equivalent amount of distilled water will be given every hours as combined therapy to milrinone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary arterial pressure	Measuring pulmonary artery pressure by echocardiography	After 72 hours of the start of the drug
FiO2	FiO2 needs to maintain oxygen saturation monitored non invasively	Hourly for 3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital stay	Duration of hospital stay	One month

Collaborators and Investigators

• Sponsor: Ain Shams University

Publications and helpful links

General Publications

• Chetan C, Suryawanshi P, Patnaik S, Soni NB, Rath C, Pareek P, Gupta B, Garegrat R, Verma A, Singh Y. Oral versus intravenous sildenafil for pulmonary hypertension in neonates: a randomized trial. BMC Pediatr. 2022 May 27;22(1):311. doi: 10.1186/s12887-022-03366-3.
• 1- Andersen LPH., Gögenur I, Rosenberg J, Reiter RJ. The safety of melatonin in humans. Clin Drug Investig. 2016 Mar. 36(3), 169-175. 2- Ballard JL, Khoury JC, Wedig K, Wang L, Eilers-Walsman BL and Lipp R. New Ballard Score, expanded to include extremely premature infants. J pediatr. 1991 sep. 119(3), 417-423. 3- Chetan C, Suryawanshi P, Patnaik S, Soni NB, Rath C, Pareek P,et al. Oral versus intravenous sildenafil for pulmonary hypertension in neonates: a randomized trial. BMC pediatr . 2022 May . 22(1), 1-7. 4- D'Angelo, G., Chimenz, R., Reiter, R. J., & Gitto, E. Use of melatonin in oxidative stress related neonatal diseases. Antioxidants. 2020, 9(6), 477

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2024
• Primary Completion (Actual): December 15, 2024
• Study Completion (Actual): March 15, 2025

Study Registration Dates

• First Submitted: November 11, 2024
• First Submitted That Met QC Criteria: November 11, 2024
• First Posted (Actual): November 12, 2024

Study Record Updates

• Last Update Posted (Actual): July 10, 2025
• Last Update Submitted That Met QC Criteria: July 6, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Melatonin; Pulmonary hypertension; Neonate; Milrinon
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Pulmonary Arterial Hypertension; Hypertension; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Infant, Newborn, Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antioxidants; Protective Agents; Melatonin
• Other Study ID Numbers: Melatonin in pulmonary hyperte

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Information can be shared upon accepted request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No