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

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ClinicalTrials.gov Identifier: NCT03083431
Recruitment Status : Not yet recruiting
First Posted : March 20, 2017
Last Update Posted : July 23, 2019
Sponsor:
Collaborators:
Ankara University
University Hospital, Zürich
Hadassah Medical Organization
Information provided by (Responsible Party):
Christoph Bührer, Charite University, Berlin, Germany

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 two 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 hemangiomas in the European Union, Switzerland and the United States. 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.

Condition or disease Intervention/treatment Phase
Retinopathy of Prematurity Drug: Propranolol Drug: Placebo Phase 2

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 two 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 hemangiomas 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 276 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind Placebo-controlled
Primary Purpose: Prevention
Official Title: Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity
Estimated Study Start Date : September 3, 2019
Estimated Primary Completion Date : November 3, 2021
Estimated Study Completion Date : July 3, 2022


Arm Intervention/treatment
Experimental: Propranolol
Oral propranolol (1.6 mg propranolol-HCl/kg·d in 3-4 divided dosages) given for 4 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




Primary Outcome Measures :
  1. Survival without threshold ROP (stage 3 or more) [ Time Frame: 48 weeks p.m. gestational age ]
    The primary endpoint for efficacy is survival until 48 weeks postmenstrual age without ROP stage 3 (any zone), as diagnosed according to the International Committee for the Classification of Retinopathy of Prematurity Revisited


Secondary Outcome Measures :
  1. Survival without ROP treated with ablative laser surgery or intravitreal antagonists of VEGF (vascular endothelial growth factor) [ Time Frame: 48 weeks p.m. gestational age ]
    The secondary endpoint for efficacy is survival until 48 weeks postmenstrual age without local treatment for ROP (ablative laser surgery or intravitreal injections of anti-VEGF agents such as bevacizumab or ranibizumab)



Information from the National Library of Medicine

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Ages Eligible for Study:   5 Weeks to 15 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Preterm infant born before 28 weeks gestation
  • Birth weight below 1250 g
  • Alive at 5 weeks of age
  • Postmenstrual age 310/7 - 36 6/7 weeks
  • Ophthalmoscopic evidence of incipient ROP (stage 1 or 2, with or without plus disease)
  • Written informed consent by parents or legal guardian, including saving and propagation of pseudonymous medical data for study purposes, according to national requirements

Exclusion criteria

  • ROP stage 3 at time of inclusion (endpoint already reached)
  • Thyrotoxicosis, arterial hypertension or congenital heart diseases requiring open-label propranolol treatment (such as tetralogy of Fallot, paroxysmal supraventricular tachycardia, or long QT syndrome)
  • Atrio-ventricular block grade 2 or 3 (contraindication for propranolol)
  • Sinuatrial block (contraindication for propranolol)
  • Uncontrolled heart failure or cardiogenic shock (contraindication for propranolol)
  • Acute severe infection (inclusion may be postponed until infection has resolved)
  • Bronchial asthma
  • 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
  • Heart rate consistently (>1 h) < 100/min
  • Noninvasive mean arterial pressure consistently (>1 h) <40 mmHg
  • Medication of the infant or the mother if breastfeeding with clonidine, reserpine, angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists, antiarrhythmic drugs including amiodarone, propafenone, lidocaine, digoxin/digitoxin, quinidine, verapamil, diltiazem, or bepridil (pharmacodynamic interaction)
  • Medication of the infant with rifampicin or phenobarbitone (enhanced metabolic clearance)
  • Concurrent treatment with insulin (risk of hypoglycemia)
  • Severe liver dysfunction (GPT > 900 U/L)
  • Chronic kidney impairment (creatinine > 1.3 mg/dl [100 µM])
  • Persistent hypoglycemia (blood glucose < 36 mg/dl [2.0 mM] in 3 consecutive samples immediately preceding enrollment)
  • Persistent hyperkalemia (venous serum potassium > 5.9 mM in 3 consecutive samples immediately preceding enrollment)
  • Persistent neutropenia (absolute neutrophil counts <1,000/µL in 3 consecutive samples immediately preceding enrollment)
  • Known hypersensitivity to propranolol or any of the excipients
  • Prinzmetal's angina, Raynaud's phenomenon severe peripheral arterial circulatory disturbance), or pheochromocytoma (contraindications for propranolol in adults, not occurring in newborn infants)
  • Participation in another pharmacological interventional clinical trial
  • Any circumstances that make the investigator believe that participation in the study leads to exceptional medical or organizational problems for the patient.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03083431


Contacts
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Contact: Christoph Bührer, M.D. +49-30-450 566122 christoph.buehrer@charite.de
Contact: Slavica Dimitrovska, M.S. +49-30-450 516058 rop-rop@charite.de

Sponsors and Collaborators
Charite University, Berlin, Germany
Ankara University
University Hospital, Zürich
Hadassah Medical Organization
Investigators
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Principal Investigator: Christoph Bührer, M.D. Charite University, Berlin, Germany

Publications of Results:
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Responsible Party: Christoph Bührer, M.D., Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT03083431     History of Changes
Other Study ID Numbers: ROPROP
2017‐002124‐24 ( EudraCT Number )
01GM1703 ( Other Grant/Funding Number: BMBF )
First Posted: March 20, 2017    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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)

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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
Additional relevant MeSH terms:
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Propranolol
Retinal Diseases
Retinopathy of Prematurity
Premature Birth
Eye Diseases
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Infant, Premature, Diseases
Infant, Newborn, Diseases
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents