Clinical trial NCT03083431: Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity
Official title: Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Retinopathy of Prematurity
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Ankara University
name: University Hospital Tuebingen
First posted: 2017-03-20
Enrollment: 276
Sex: ALL
Minimum age (years): 5
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: Inclusion criteria:

* Preterm infant born before 28 week's gestation
* Birth weight below 1250 g
* At least 5 weeks of age (at randomisation)
* PMA 310/7 - 36 6/7 weeks
* Ophthalmoscopic evidence of incipient ROP (stage 1 or 2, with or without plus disease in any zone)
* Written informed consent by parents or legal guardian, according to national requirements

Exclusion Criteria:

* 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)

Primary outcomes:
measure: Survival without adverse ophthalmological outcome (stage ≥ 3, AP-ROP, or any ROP treatment)
timeFrame: 48 weeks postmenstrual age
Secondary outcomes:
measure: Time to adverse ophthalmological outcome in days
timeFrame: 48 weeks postmenstrual age
measure: Survival without adverse ophthalmological outcome
timeFrame: 48 weeks postmenstrual age
measure: Survival with adverse ophthalmological outcome
timeFrame: 48 weeks postmenstrual age
measure: Survival without local treatment for ROP
timeFrame: 48 weeks postmenstrual age
measure: Death until discharge
timeFrame: 48 weeks postmenstrual age
measure: Death until 48 weeks postmenstrual age
timeFrame: 48 weeks postmenstrual age
measure: Recurrence of ROP in infants treated with anti-VEGF-antagonists
timeFrame: 70 (+/- 2 weeks) postmenstrual age
measure: Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists
timeFrame: 70 (+/- 2 weeks) postmenstrual age
Other outcomes:
measure: Intraventricular haemorrhages (all grades)
timeFrame: 48 weeks postmenstrual age
measure: Posthaemorrhagic hydrocephalus requiring intervention
timeFrame: 48 weeks postmenstrual age
measure: Cystic leukomalacia
timeFrame: 48 weeks postmenstrual age
measure: Persistent ductus arteriosus requiring treatment
timeFrame: 48 weeks postmenstrual age
measure: Bronchopulmonary dysplasia
timeFrame: 48 weeks postmenstrual age
measure: Duration of subsequent hospitalisation
timeFrame: 48 weeks postmenstrual age
measure: Duration of primary hospitalisation
timeFrame: 48 weeks postmenstrual age
measure: Z-scores for weight
timeFrame: 48 weeks postmenstrual age
measure: Z-scores for head circumference
timeFrame: 48 weeks postmenstrual age
measure: Duration of supplemental oxygen
timeFrame: 48 weeks postmenstrual age
measure: Necrotizing enterocolitis
timeFrame: 48 weeks postmenstrual age
measure: Safety: Culture-proven sepsis or meningitis during IMP administration
timeFrame: 48 weeks postmenstrual age
measure: Safety: Symptomatic hypoglycemia during IMP administration
timeFrame: 48 weeks postmenstrual age
measure: Safety: Emergency endotracheal intubation during IMP administration
timeFrame: 48 weeks postmenstrual age
Locations:
city: Tübingen
country: Germany
facility: University Hospital Tübingen
state: Baden-Württemberg
city: Zürich
country: Switzerland
facility: University Hospital Zurich
state: Zurich
city: Ankara
country: Turkey
facility: Ankara University School of Medicine Children's Hospital
Study officials:
affiliation: University of Zurich
name: Dirk Bassler, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buhrer C, Bassler D. Oral Propranolol: A New Treatment for Infants with Retinopathy of Prematurity? Neonatology. 2015;108(1):49-52. doi: 10.1159/000381659. Epub 2015 May 9.
citation: Buhrer C, Erdeve O, Bassler D, Bar-Oz B. Oral propranolol for prevention of threshold retinopathy of prematurity (ROPROP): protocol of a randomised controlled trial. BMJ Open. 2018 Jul 6;8(7):e021749. doi: 10.1136/bmjopen-2018-021749.