Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity (RoProp)

April 4, 2024 updated by: University of Zurich

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

276

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Germany
    • Baden-Württemberg
      • Tübingen, Baden-Württemberg, Germany, 72076
        • Recruiting
        • University Hospital Tübingen
        • Contact:
          • Axel R Franz, Prof.
  • Switzerland
    • Zurich
      • Zürich, Zurich, Switzerland, 8091
        • Recruiting
        • University Hospital Zurich
        • Contact:
        • Contact:
        • Principal Investigator:
          • Christoph Rüegger
        • Sub-Investigator:
          • David Glauser
  • Turkey
      • Ankara, Turkey, 06590
        • Recruiting
        • Ankara University School of Medicine Children's Hospital
        • Contact:
          • Ömer Erdeve, Prof.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 month to 3 months (Child)

Accepts Healthy Volunteers

No

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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)
Drug: Propranolol
Oral propranolol (1.6 mg propranolol-hydrochloride/kg/d in 4 divided dosages)
Placebo Comparator: Placebo
Placebo (same duration as oral propranolol solution)
Drug: Placebo
Oral solution containing the same excipients as propranolol solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival without adverse ophthalmological outcome (stage ≥ 3, AP-ROP, or any ROP treatment)
Time Frame: 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.
48 weeks postmenstrual age

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to adverse ophthalmological outcome in days
Time Frame: 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)
48 weeks postmenstrual age
Survival without adverse ophthalmological outcome
Time Frame: 48 weeks postmenstrual age
Survival without adverse ophthalmological outcome (as defined for the primary outcome)
48 weeks postmenstrual age
Survival with adverse ophthalmological outcome
Time Frame: 48 weeks postmenstrual age
Survival with adverse ophthalmological outcome (as defined for the primary outcome)
48 weeks postmenstrual age
Survival without local treatment for ROP
Time Frame: 48 weeks postmenstrual age
Survival without local treatment for ROP (ablative laser surgery or intravitreal injections of anti-VEGF agents).
48 weeks postmenstrual age
Death until discharge
Time Frame: 48 weeks postmenstrual age
Death until discharge
48 weeks postmenstrual age
Death until 48 weeks postmenstrual age
Time Frame: 48 weeks postmenstrual age
Death until 48 weeks postmenstrual age
48 weeks postmenstrual age
Recurrence of ROP in infants treated with anti-VEGF-antagonists
Time Frame: 70 (+/- 2 weeks) postmenstrual age
Recurrence of ROP in infants treated with anti-VEGF-antagonists
70 (+/- 2 weeks) postmenstrual age
Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists
Time Frame: 70 (+/- 2 weeks) postmenstrual age
Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists
70 (+/- 2 weeks) postmenstrual age

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intraventricular haemorrhages (all grades)
Time Frame: 48 weeks postmenstrual age
Intraventricular haemorrhage (all grades)
48 weeks postmenstrual age
Posthaemorrhagic hydrocephalus requiring intervention
Time Frame: 48 weeks postmenstrual age
Posthaemorrhagic hydrocephalus requiring intervention
48 weeks postmenstrual age
Cystic leukomalacia
Time Frame: 48 weeks postmenstrual age
Cystic leukomalacia
48 weeks postmenstrual age
Persistent ductus arteriosus requiring treatment
Time Frame: 48 weeks postmenstrual age
Persistent ductus arteriosus requiring treatment
48 weeks postmenstrual age
Bronchopulmonary dysplasia
Time Frame: 48 weeks postmenstrual age
Bronchopulmonary dysplasia (mild, moderate, severe), defined and graded according to the consensus statement of the national institutes of health
48 weeks postmenstrual age
Duration of subsequent hospitalisation
Time Frame: 48 weeks postmenstrual age
Number of days of subsequent hospitalisations
48 weeks postmenstrual age
Duration of primary hospitalisation
Time Frame: 48 weeks postmenstrual age
Number of days of primary hospitalisation
48 weeks postmenstrual age
Z-scores for weight
Time Frame: 48 weeks postmenstrual age
Z-scores for weight at the beginning and end of IMP administration
48 weeks postmenstrual age
Z-scores for head circumference
Time Frame: 48 weeks postmenstrual age
Z-scores for head circumference at the beginning and end of IMP administration
48 weeks postmenstrual age
Duration of supplemental oxygen
Time Frame: 48 weeks postmenstrual age
Number of days on supplemental oxygen
48 weeks postmenstrual age
Necrotizing enterocolitis
Time Frame: 48 weeks postmenstrual age
Necrotizing enterocolitis (requiring surgery)
48 weeks postmenstrual age
Safety: Culture-proven sepsis or meningitis during IMP administration
Time Frame: 48 weeks postmenstrual age
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
Safety: Symptomatic hypoglycemia during IMP administration
Time Frame: 48 weeks postmenstrual age
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
Safety: Emergency endotracheal intubation during IMP administration
Time Frame: 48 weeks postmenstrual age
Emergency endotracheal intubation attributable to obstructive airway disease during IMP administration (excluding elective intubation for surgery)
48 weeks postmenstrual age

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Zurich

Collaborators

University Hospital Tuebingen
Ankara University

Investigators

  • Principal Investigator: Dirk Bassler, M.D., University of Zurich

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 22, 2022

Primary Completion (Estimated)

December 1, 2025

Study Completion (Estimated)

July 1, 2026

Study Registration Dates

First Submitted

March 13, 2017

First Submitted That Met QC Criteria

March 13, 2017

First Posted (Actual)

March 20, 2017

Study Record Updates

Last Update Posted (Actual)

April 8, 2024

Last Update Submitted That Met QC Criteria

April 4, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RoProp
  • 2017-002124-24 (EudraCT Number)
  • 32ER30_173677 (Other Grant/Funding Number: Swiss National Science Foundation (SNSF))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Anonymized data set containing gestational age (only weeks), birth weight (in 100g categories), year of birth, country, gender, intervention (propranolol or placebo), outcome (retinopathy of prematurity, maximum stage), date and type of treatment for retinopathy if any

IPD Sharing Time Frame

6 months - 5 years after publication of the results in a peer-reviewed journal

IPD Sharing Access Criteria

Investigators whose proposed use of the data has been approved by an independent review committee (learned intermediary)

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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