Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity

• Status: Withdrawn
• Trial end date: 2023-11-03
• Target enrollment: 0
• Participant gender: All

Summary

Extremely premature infants are at risk of developing a potentially blinding eye disease, called retinopathy of prematurity (ROP). Currently available treatment, consisting of laser surgery or injection of drugs into the eye balls, may prevent most but not all cases of permanent ROP-mediated blindness. Both types of treatment are associated with significant costs and side effects. An orally administered drug commonly used to treat hypertension, propranolol, may be effective in halting progression of ROP to severe stages, as suggested by preliminary data from two small studies. Propranolol has been used for decades not only in adult patients but also in newborn infants with heart diseases. Moreover, it has been licensed in 2014 for the use in newborn infants with hemangiomas in the European Union, Switzerland and the United States. As severe (threshold) ROP is an overall rare disease, the effectiveness of propranolol in combating ROP can only be assessed in a large, multicenter randomized controlled trial involving hospitals caring for extremely preterm infants of diverse origin.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Charite University, Berlin, Germany
• Collaborators: Ankara University; Hadassah Medical Organization; University Hospital, Zürich
• Treatments: Propranolol

Criteria

Inclusion criteria:

• Preterm infant born before 28 weeks gestation

• Birth weight below 1250 g

• Alive at 5 weeks of age

• Postmenstrual age 310/7 - 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

Exclusion criteria

• ROP stage 3 at time of inclusion (endpoint already reached)

• Thyrotoxicosis, arterial hypertension or congenital heart diseases requiring open-label propranolol treatment (such as tetralogy of Fallot, paroxysmal supraventricular tachycardia, or long QT syndrome)

• 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

• 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, angiotensin-receptor antagonists, 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)

• 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)

• 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 participation in the study leads to exceptional medical or organizational problems for the patient.