- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03083431
Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity (RoProp)
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
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
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Dirk Bassler, M.D.
- Phone Number: +41 44 255 53 40
- Email: dirk.bassler@usz.ch
Study Contact Backup
- Name: Christoph Rüegger, M.D.
- Phone Number: +41 43 253 98 10
- Email: christoph.rueegger@usz.ch
Study Locations
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Baden-Württemberg
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Tübingen, Baden-Württemberg, Germany, 72076
- Recruiting
- University Hospital Tübingen
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Contact:
- Axel R Franz, Prof.
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Zurich
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Zürich, Zurich, Switzerland, 8091
- Recruiting
- University Hospital Zurich
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Contact:
- Christoph M Rüegger
- Phone Number: +41432539810
- Email: christoph.rueegger@usz.ch
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Contact:
- Claudia Knoepfli
- Email: claudia.knoepfli@usz.ch
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Principal Investigator:
- Christoph Rüegger
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Sub-Investigator:
- David Glauser
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Ankara, Turkey, 06590
- Recruiting
- Ankara University School of Medicine Children's Hospital
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Contact:
- Ömer Erdeve, Prof.
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
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
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)
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Oral propranolol (1.6 mg propranolol-hydrochloride/kg/d in 4 divided dosages)
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Placebo Comparator: Placebo
Placebo (same duration as oral propranolol solution)
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Oral solution containing the same excipients as propranolol solution
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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
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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.
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48 weeks postmenstrual age
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to adverse ophthalmological outcome in days
Time Frame: 48 weeks postmenstrual age
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Time to adverse ophthalmological outcome in days (alternative to primary endpoint to account for the timing, considering death as a competing risk)
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48 weeks postmenstrual age
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Survival without adverse ophthalmological outcome
Time Frame: 48 weeks postmenstrual age
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Survival without adverse ophthalmological outcome (as defined for the primary outcome)
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48 weeks postmenstrual age
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Survival with adverse ophthalmological outcome
Time Frame: 48 weeks postmenstrual age
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Survival with adverse ophthalmological outcome (as defined for the primary outcome)
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48 weeks postmenstrual age
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Survival without local treatment for ROP
Time Frame: 48 weeks postmenstrual age
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Survival without local treatment for ROP (ablative laser surgery or intravitreal injections of anti-VEGF agents).
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48 weeks postmenstrual age
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Death until discharge
Time Frame: 48 weeks postmenstrual age
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Death until discharge
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48 weeks postmenstrual age
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Death until 48 weeks postmenstrual age
Time Frame: 48 weeks postmenstrual age
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Death until 48 weeks postmenstrual age
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48 weeks postmenstrual age
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Recurrence of ROP in infants treated with anti-VEGF-antagonists
Time Frame: 70 (+/- 2 weeks) postmenstrual age
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Recurrence of ROP in infants treated with anti-VEGF-antagonists
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70 (+/- 2 weeks) postmenstrual age
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Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists
Time Frame: 70 (+/- 2 weeks) postmenstrual age
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Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists
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70 (+/- 2 weeks) postmenstrual age
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Intraventricular haemorrhages (all grades)
Time Frame: 48 weeks postmenstrual age
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Intraventricular haemorrhage (all grades)
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48 weeks postmenstrual age
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Posthaemorrhagic hydrocephalus requiring intervention
Time Frame: 48 weeks postmenstrual age
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Posthaemorrhagic hydrocephalus requiring intervention
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48 weeks postmenstrual age
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Cystic leukomalacia
Time Frame: 48 weeks postmenstrual age
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Cystic leukomalacia
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48 weeks postmenstrual age
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Persistent ductus arteriosus requiring treatment
Time Frame: 48 weeks postmenstrual age
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Persistent ductus arteriosus requiring treatment
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48 weeks postmenstrual age
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Bronchopulmonary dysplasia
Time Frame: 48 weeks postmenstrual age
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Bronchopulmonary dysplasia (mild, moderate, severe), defined and graded according to the consensus statement of the national institutes of health
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48 weeks postmenstrual age
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Duration of subsequent hospitalisation
Time Frame: 48 weeks postmenstrual age
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Number of days of subsequent hospitalisations
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48 weeks postmenstrual age
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Duration of primary hospitalisation
Time Frame: 48 weeks postmenstrual age
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Number of days of primary hospitalisation
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48 weeks postmenstrual age
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Z-scores for weight
Time Frame: 48 weeks postmenstrual age
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Z-scores for weight at the beginning and end of IMP administration
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48 weeks postmenstrual age
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Z-scores for head circumference
Time Frame: 48 weeks postmenstrual age
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Z-scores for head circumference at the beginning and end of IMP administration
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48 weeks postmenstrual age
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Duration of supplemental oxygen
Time Frame: 48 weeks postmenstrual age
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Number of days on supplemental oxygen
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48 weeks postmenstrual age
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Necrotizing enterocolitis
Time Frame: 48 weeks postmenstrual age
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Necrotizing enterocolitis (requiring surgery)
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48 weeks postmenstrual age
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Safety: Culture-proven sepsis or meningitis during IMP administration
Time Frame: 48 weeks postmenstrual age
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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)
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48 weeks postmenstrual age
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Safety: Symptomatic hypoglycemia during IMP administration
Time Frame: 48 weeks postmenstrual age
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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)
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48 weeks postmenstrual age
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Safety: Emergency endotracheal intubation during IMP administration
Time Frame: 48 weeks postmenstrual age
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Emergency endotracheal intubation attributable to obstructive airway disease during IMP administration (excluding elective intubation for surgery)
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48 weeks postmenstrual age
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Dirk Bassler, M.D., University of Zurich
Publications and helpful links
General Publications
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Eye Diseases
- Infant, Newborn, Diseases
- Pregnancy Complications
- Obstetric Labor Complications
- Obstetric Labor, Premature
- Infant, Premature, Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Retinal Diseases
- Premature Birth
- Retinopathy of Prematurity
- Physiological Effects of Drugs
- Adrenergic beta-Antagonists
- Adrenergic Antagonists
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Antihypertensive Agents
- Vasodilator Agents
- Propranolol
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)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
- CSR
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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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