Evaluation of Oral Propranolol Hydrochloride for the Prevention of Threshold Retinopathy of Prematurity in Extremely Preterm Infants

Trial ID: 2024-511338-10-01
Protocol: ROPROP
Sponsor: Universitaetsklinikum Tuebingen AöR

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Diseases & Conditions

Retinopathy of prematurity

Objectives

The primary objective of this study is to evaluate the **safety** and **efficacy** of orally administered **propranolol** in reducing the risk of threshold **retinopathy of prematurity** in extremely preterm infants. This is clinically relevant as retinopathy of prematurity is a significant cause of visual impairment in this vulnerable population, and effective prevention strategies are crucial for improving long-term visual outcomes.

Secondary objectives include assessing the safety and efficacy of orally administered propranolol in reducing the rate of extremely preterm infants requiring local interventions for severe retinopathy of prematurity. This further evaluation is important to determine the potential of propranolol in minimizing the need for invasive treatments, thereby reducing associated risks and healthcare burdens.

Participants

The clinical trial involves a total of **176 participants** who are extremely preterm infants. The study population includes both male and female subjects, specifically preterm infants born before 28 weeks of gestation with a birth weight below 1250 grams. Participants are required to be alive at 5 weeks of age and have a postmenstrual age between 31 0/7 and 36 6/7 weeks. The infants must exhibit ophthalmoscopic evidence of incipient **retinopathy of prematurity** (stage 1 or 2, with or without plus disease). The trial population was selected based on these criteria, and written informed consent was obtained from parents or legal guardians, including the agreement to save and propagate pseudonymous medical data for study purposes. The study does not specify any particular lifestyle considerations such as diet or physical activity, as the participants are a vulnerable population of preterm infants. The trial aims to assess the safety and efficacy of orally administered propranolol to reduce the risk of threshold retinopathy of prematurity in this specific group.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and **efficacy** of orally administered **propranolol hydrochloride** in reducing the risk of threshold **retinopathy of prematurity** in extremely preterm infants. This is a Phase IV, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on July 1, 2024, and conclude by December 31, 2025. Participants will be randomly assigned to receive either the active treatment or a placebo, with the active treatment being propranolol hydrochloride administered as an oral solution. The maximum daily dose is 1.6 mg/kg, with a total maximum dose of 112 mg over a treatment period of up to 10 days.

The study will include several key visits: an initial screening visit, follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be assessed based on criteria such as gestational age, birth weight, and evidence of incipient retinopathy of prematurity. Written informed consent from parents or legal guardians is required. Follow-up visits will monitor the infant's response to treatment and any adverse events. The primary endpoint is survival without threshold retinopathy of prematurity, while secondary endpoints include survival without the need for ablative laser surgery or intravitreal VEGF antagonists.

Participant involvement is expected to last until the end of the treatment period, with regular follow-up visits to assess outcomes. Conditions that may lead to early termination from the study include significant adverse reactions or withdrawal of consent by the parents or guardians. The trial aims to provide valuable data on the potential benefits of propranolol hydrochloride in preventing severe retinopathy of prematurity, contributing to improved clinical outcomes for this vulnerable population.

Treatment

The clinical trial involves the administration of **PROPRANOLOL HYDROCHLORIDE**, an experimental medication, to assess its safety and efficacy in reducing the risk of threshold retinopathy of prematurity in extremely preterm infants. **PROPRANOLOL HYDROCHLORIDE** is provided in the form of an oral solution. The active substance, **PROPRANOLOL HYDROCHLORIDE**, is chemically derived and administered via oral use. The dosing regimen involves a maximum daily dose of 1.6 mg/kg, with a total maximum dose of 112 mg/kg over a treatment period not exceeding 10 days. The medication is not formulated specifically for pediatric use, and participant compliance with the dosing schedule is monitored throughout the trial.

In addition to the experimental treatment, a placebo is utilized in the study. The placebo is compositionally identical to the investigational medicinal product (IMP) apart from the active substance. The placebo is administered in the same pharmaceutical form and route as the experimental medication, ensuring blinding and maintaining the integrity of the trial. The placebo serves as a comparator to evaluate the true efficacy of **PROPRANOLOL HYDROCHLORIDE** in the prevention of threshold retinopathy of prematurity.

Efficacy

The clinical trial aims to assess the efficacy of orally administered **propranolol hydrochloride** in reducing the risk of threshold retinopathy of prematurity (ROP) in extremely preterm infants. Efficacy will be primarily evaluated by the endpoint of survival without threshold ROP, defined as stage 3 or more severe ROP, including aggressive posterior ROP. A secondary endpoint will assess survival without ROP treated with ablative laser surgery or intravitreal VEGF antagonists. These endpoints will be measured through clinical assessments of the infants' ophthalmologic status, specifically looking for the presence or progression of ROP.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Preterm infant born before 28 weeks gestation
Birth weight below 1250 g
Alive at 5 weeks of age
Postmenstrual age 31 0/7 – 36 6/7 weeks
Ophthalmoscopic evidence of incipient ROP (stage 1 or 2, with or without plus disease)
Written informed consent by parents or legal guardian, including saving and propagation of pseudonymous medical data for study purposes, according to national requirements

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Exclusion Criteria

ROP stage ≥ 3, AP-ROP or suspected AP-ROP, or any other ROP requiring an intervention (study endpoint already reached)
PHACE syndrome (posterior fossa anomalies, large infantile hemangiomas of the face, neck, and/or scalp, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies) (risk of cerebrovascular complications)
Very large hemangioma (risk of hyperkalemia), as judged by the attending physician
Heart rate consistently (>1 h) < 100/min
Noninvasive mean arterial pressure consistently (>1 h) <40 mmHg
Medication of the infant or the mother if breastfeeding with clonidine, reserpine, angiotensin-converting enzyme inhibitors, angiotensinreceptor antagonists, or antiarrhythmic drugs including amiodarone, propafenone, lidocaine, digoxin/digitoxin, quinidine, verapamil, diltiazem, or bepridil (pharmacodynamic interaction)
Medication of the infant with rifampicin or phenobarbitone (enhanced metabolic clearance), clonidine, antiarrhythmic drugs (amiodarone, propafenone, lidocaine, digoxin/digitoxin, quinidine), verapamil, diltiazem, bepridil), antihypertensive agents (reserpine, angiotensinconverting enzyme inhibitors, angiotensin-receptor antagonists, (pharmacodynamic drug interaction)
Concurrent treatment with insulin (risk of hypoglycemia)
Severe liver dysfunction (GPT > 900 U/l)
Chronic kidney impairment (creatinine > 1.3 mg/dl [100 μM])
Persistent hypoglycemia (blood glucose < 36 mg/dl [2.0 mM] in 3 consecutive samples immediately preceding enrollment)
Thyrotoxicosis, arterial hypertension or congenital heart diseases requiring open-label propranolol treatment (such as tetralogy of Fallot, paroxysmal supraventricular tachycardia, or long QT syndrome)
Persistent hyperkalemia (venous serum potassium > 5.9 mM in 3 consecutive samples immediately preceding enrollment)
Persistent neutropenia (absolute neutrophil counts <1,000/μL in 3 consecutive samples immediately preceding enrollment)
Known hypersensitivity to propranolol or any of the excipients
Prinzmetal's angina, Raynaud's phenomenon (severe peripheral arterial circulatory disturbance), or pheochromocytoma (contraindications for propranolol in adults, not occurring in newborn infants)
Participation in another pharmacological interventional clinical trial
Any circumstances that make the investigator believe that in the infant’s own interest, he/she should no longer receive the study medication
Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial
Atrio-ventricular block grade 2 or 3 (contraindication for propranolol)
Sinuatrial block (contraindication for propranolol)
Uncontrolled heart failure or cardiogenic shock (contraindication for propranolol)
Acute severe infection (inclusion may be postponed until infection has resolved)
Bronchial asthma
Major congenital malformations or known chromosomal anomalies
Colobomas and other eye malformations
> 7 days after first ROP diagnosis (day 1 = first ROP diagnosis)
Previous or current conditions that indicated/indicate beta-blocker therapy, open label propranolol such as: thyrotoxicosis, arterial hypertension or certain heart diseases (such as tetralogy of Fallot, paroxysmal supraventricular tachycardia long QT syndrome, or hypertrophic cardiomyopathy)