Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity

NCT03083431 | Recruiting Phase 2 DMC

• 3 other identifiers: RoProp32ER30_1736772017-002124-24
• Study Type: interventional
• Target: 276
• Locations: 3 countries
• Sites: 3

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.

Conditions

Retinopathy of Prematurity

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Time to adverse ophthalmological outcome in days

  48 weeks postmenstrual age

• Survival without adverse ophthalmological outcome

  48 weeks postmenstrual age

• Survival with adverse ophthalmological outcome

  48 weeks postmenstrual age

• Survival without local treatment for ROP

  48 weeks postmenstrual age

• Death until discharge

  48 weeks postmenstrual age

Other Outcomes (14)

• Intraventricular haemorrhages (all grades)

  48 weeks postmenstrual age

• Posthaemorrhagic hydrocephalus requiring intervention

  48 weeks postmenstrual age

• Cystic leukomalacia

  48 weeks postmenstrual age

Study Arms (2)

Propranolol

EXPERIMENTAL

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)

Drug: Propranolol

Placebo

PLACEBO COMPARATOR

Placebo (same duration as oral propranolol solution)

Drug: Placebo

Interventions

Propranolol DRUG

Oral propranolol (1.6 mg propranolol-hydrochloride/kg/d in 4 divided dosages)

Propranolol

Placebo DRUG

Oral solution containing the same excipients as propranolol solution

Placebo

Eligibility Criteria

• Age: 5 Weeks - 15 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Zurich: lead
• Ankara University: collaborator
• University Hospital Tuebingen: collaborator

Study Sites (3)

University Hospital Tübingen

Tübingen, Baden-Wurttemberg, 72076, Germany

RECRUITING

University Hospital Zurich

Zurich, Canton of Zurich, 8091, Switzerland

RECRUITING

Ankara University School of Medicine Children's Hospital

Ankara, Ankara, 06590, Turkey (Türkiye)

RECRUITING

Related 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.

  PMID: 25968340 BACKGROUND

• 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.

  PMID: 29982217 BACKGROUND

MeSH Terms

Conditions

Retinopathy of Prematurity

Interventions

Propranolol

Condition Hierarchy (Ancestors)

Retinal Diseases; Eye Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Study Officials

• Dirk Bassler, M.D.

  University of Zurich

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dirk Bassler, M.D.

CONTACT

+41 44 255 53 40; dirk.bassler@usz.ch

Christoph Rüegger, M.D.

CONTACT

+41 43 253 98 10; christoph.rueegger@usz.ch

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind Placebo-controlled
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 13, 2017
• First Posted: March 20, 2017
• Study Start: September 22, 2022
• Primary Completion: December 1, 2025
• Study Completion (Estimated): July 1, 2026
• Last Updated: December 12, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: 6 months - 5 years after publication of the results in a peer-reviewed journal
• Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee (learned intermediary)

Locations

DE (1); CH (1); TU (1)