Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity

Retinopathy of Prematurity Clinical Trial

— RoProp  

Official title:

Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03083431
• Other study ID #: RoProp
• Secondary ID: 2017-002124-2432
• Status: Recruiting
• Phase: Phase 2
• Start date: September 22, 2022
• Est. completion date: July 2026

Study information

• Verified date: April 2024
• Source: University of Zurich
• Contact: Dirk Bassler, M.D.
• Phone: +41 44 255 53 40
• Email: dirk.bassler[@]usz.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 276
• Est. completion date: July 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Weeks to 15 Weeks

Eligibility

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)

Related Conditions & MeSH terms

• Premature Birth
• Retinal Diseases
• Retinopathy of Prematurity

Intervention

Drug:
• Propranolol
Oral propranolol (1.6 mg propranolol-hydrochloride/kg/d in 4 divided dosages)
• Placebo
Oral solution containing the same excipients as propranolol solution

Locations

Country	Name	City	State
Germany	University Hospital Tübingen	Tübingen	Baden-Württemberg
Switzerland	University Hospital Zurich	Zürich	Zurich
Turkey	Ankara University School of Medicine Children's Hospital	Ankara

Sponsors (3)

Lead Sponsor	Collaborator
University of Zurich	Ankara University, University Hospital Tuebingen

Countries where clinical trial is conducted

Germany,  Switzerland,  Turkey, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Intraventricular haemorrhages (all grades)	Intraventricular haemorrhage (all grades)	48 weeks postmenstrual age
Other	Posthaemorrhagic hydrocephalus requiring intervention	Posthaemorrhagic hydrocephalus requiring intervention	48 weeks postmenstrual age
Other	Cystic leukomalacia	Cystic leukomalacia	48 weeks postmenstrual age
Other	Persistent ductus arteriosus requiring treatment	Persistent ductus arteriosus requiring treatment	48 weeks postmenstrual age
Other	Bronchopulmonary dysplasia	Bronchopulmonary dysplasia (mild, moderate, severe), defined and graded according to the consensus statement of the national institutes of health	48 weeks postmenstrual age
Other	Duration of subsequent hospitalisation	Number of days of subsequent hospitalisations	48 weeks postmenstrual age
Other	Duration of primary hospitalisation	Number of days of primary hospitalisation	48 weeks postmenstrual age
Other	Z-scores for weight	Z-scores for weight at the beginning and end of IMP administration	48 weeks postmenstrual age
Other	Z-scores for head circumference	Z-scores for head circumference at the beginning and end of IMP administration	48 weeks postmenstrual age
Other	Duration of supplemental oxygen	Number of days on supplemental oxygen	48 weeks postmenstrual age
Other	Necrotizing enterocolitis	Necrotizing enterocolitis (requiring surgery)	48 weeks postmenstrual age
Other	Safety: Culture-proven sepsis or meningitis during IMP administration	Culture-proven sepsis or meningitis during IMP administration (defined as growth of a recognized pathogen not counting coagulase-negative staphylococci in blood or cerebrospinal fluid in an infant treated for at least 5 d with intravenous antibiotics and a rise of C-reactive protein to more than 10 mg/l during the first 72 h of antibiotic treatment)	48 weeks postmenstrual age
Other	Safety: Symptomatic hypoglycemia during IMP administration	Symptomatic hypoglycemia during IMP administration (blood glucose < 30 mg/dl requiring intravenous glucose administration for 48 h or more), not counting glucose administration "to keep-vein-open" (e.g. at rates of = 1 mL/h)	48 weeks postmenstrual age
Other	Safety: Emergency endotracheal intubation during IMP administration	Emergency endotracheal intubation attributable to obstructive airway disease during IMP administration (excluding elective intubation for surgery)	48 weeks postmenstrual age
Primary	Survival without adverse ophthalmological outcome (stage = 3, AP-ROP, or any ROP treatment)	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.	48 weeks postmenstrual age
Secondary	Time to adverse ophthalmological outcome in days	Time to adverse ophthalmological outcome in days (alternative to primary endpoint to account for the timing, considering death as a competing risk)	48 weeks postmenstrual age
Secondary	Survival without adverse ophthalmological outcome	Survival without adverse ophthalmological outcome (as defined for the primary outcome)	48 weeks postmenstrual age
Secondary	Survival with adverse ophthalmological outcome	Survival with adverse ophthalmological outcome (as defined for the primary outcome)	48 weeks postmenstrual age
Secondary	Survival without local treatment for ROP	Survival without local treatment for ROP (ablative laser surgery or intravitreal injections of anti-VEGF agents).	48 weeks postmenstrual age
Secondary	Death until discharge	Death until discharge	48 weeks postmenstrual age
Secondary	Death until 48 weeks postmenstrual age	Death until 48 weeks postmenstrual age	48 weeks postmenstrual age
Secondary	Recurrence of ROP in infants treated with anti-VEGF-antagonists	Recurrence of ROP in infants treated with anti-VEGF-antagonists	70 (+/- 2 weeks) postmenstrual age
Secondary	Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists	Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists	70 (+/- 2 weeks) postmenstrual age