Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity
- Registration Number
- NCT03083431
- Lead Sponsor
- University of Zurich
- Brief 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 small studies. 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.
- Detailed Description
Threshold Retinopathy of Prematurity (ROP), observed in a fraction of extremely premature infants, is characterized by retinal vessel proliferation that threatens vision secondary to retinal detachment. Currently available treatments (ablative laser surgery or intravitreal anti-VEGF injections) may prevent most but not all cases of permanent ROP-mediated blindness and are associated with significant costs and side effects.
Orally administered propranolol, a commonly used drug to treat hypertension, may be effective in halting progression of ROP to severe stages, as suggested by preliminary data from 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 hemangioma in the European Union, Switzerland and the United States. This multicenter randomized placebo-controlled trial aims to assess whether oral propranolol given to extremely premature infants below 28 weeks gestational age reduces the rates of threshold ROP.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 276
Not provided
- ROP stage ≥ 3, AP-ROP or suspected AP-ROP, or any other ROP requiring an intervention (study endpoint already reached).
- Conditions that indicate open label propranolol such as: thyrotoxicosis, arterial hypertension or certain heart diseases (such as tetralogy of Fallot, paroxysmal supraventricular tachycardia, or long QT syndrome) etc.
- 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
- Medication of the infant with rifampicin or phenobarbitone (enhanced metabolic clearance)
- Chronic kidney impairment (serum creatinine > 1.3 mg/dl [115 μmol/L])
- Severe liver dysfunction (ALT (GPT) > 900 U/L)
- Known hypersensitivity to propranolol or any of the excipients (see 6.3.1.)
- Prinzmetal's angina, Raynaud's phenomenon (severe peripheral arterial circulatory disturbance), or pheochromocytoma (contraindications for propranolol in adults, not occurring in newborn infants)
- Any circumstances that make the investigator believe that participation in the study leads to exceptional medical or organizational problems for the patient
- Conditions that prohibit propranolol therapy such as: Atrio-ventricular block grade 2 or 3 hypertrophic cardiomyopathy, sinoatrial block, uncontrolled heart failure or cardiogenic shock, bronchial asthma
- Medication of the infant or the mother if breastfeeding with clonidine, reserpine, angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists (contraindicated in preterm infants) or antiarrhythmic drugs including amiodarone, propafenone, lidocaine, digoxin/digitoxin, quinidine, verapamil, diltiazem, bepridil (pharmacodynamic interaction)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Placebo (same duration as oral propranolol solution) Propranolol Propranolol Oral propranolol (1.6 mg propranolol-HCl/kg/d in 3-4 divided dosages) given for a maximum of 10 weeks (depending on postmenstrual gestational age at birth)
- Primary Outcome Measures
Name Time Method Survival without adverse ophthalmological outcome (stage ≥ 3, AP-ROP, or any ROP treatment) 48 weeks postmenstrual age The primary endpoint for efficacy is survival until 48 weeks postmenstrual age without adverse ophthalmological outcome (stage ≥ 3, AP-ROP, or any ROP treatment) diagnosed according to the International Committee for the Classification of Retinopathy of Prematurity Revisited.
- Secondary Outcome Measures
Name Time Method Time to adverse ophthalmological outcome in days 48 weeks postmenstrual age Time to adverse ophthalmological outcome in days (alternative to primary endpoint to account for the timing, considering death as a competing risk)
Survival without local treatment for ROP 48 weeks postmenstrual age Survival without local treatment for ROP (ablative laser surgery or intravitreal injections of anti-VEGF agents).
Survival with adverse ophthalmological outcome 48 weeks postmenstrual age Survival with adverse ophthalmological outcome (as defined for the primary outcome)
Recurrence of ROP in infants treated with anti-VEGF-antagonists 70 (+/- 2 weeks) postmenstrual age Recurrence of ROP in infants treated with anti-VEGF-antagonists
Death until discharge 48 weeks postmenstrual age Death until discharge
Death until 48 weeks postmenstrual age 48 weeks postmenstrual age Death until 48 weeks postmenstrual age
Survival without adverse ophthalmological outcome 48 weeks postmenstrual age Survival without adverse ophthalmological outcome (as defined for the primary outcome)
Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists 70 (+/- 2 weeks) postmenstrual age Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists
Trial Locations
- Locations (3)
University Hospital Tübingen
🇩🇪Tübingen, Baden-Württemberg, Germany
University Hospital Zurich
🇨🇭Zürich, Zurich, Switzerland
Ankara University School of Medicine Children's Hospital
🇹🇷Ankara, Turkey