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

Primary Purpose

Retinopathy of Prematurity

Status
Recruiting
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Propranolol
Placebo
Sponsored by
University of Zurich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Retinopathy of Prematurity

Eligibility Criteria

5 Weeks - 15 Weeks (Child)All SexesDoes not accept healthy volunteers

Inclusion criteria:

  • Preterm infant born before 28 weeks gestation
  • Birth weight below 1250 g
  • 5 weeks of age (at randomisation)
  • Postmenstrual age 31 0/7 - 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:

Patients will be screened for the presence of exclusion criteria in a two-step process: (1) once all inclusion criteria have met, and (2) once informed consent has been obtained.

  1. st screening:

    • ROP stage 3, AP-ROP or suspected AP-ROP (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 organisational problems for the patient

    Inclusion may be postponed in the presence of the following acute and transient conditions:

    • Acute severe infection
    • Arterial hypotension requiring therapeutic intervention by local standards
    • Heart rate consistently (> 1h) < 100/min
    • Concurrent treatment with insulin (risk of hypoglycaemia)
    • Discontinuation of enteral feeding
    • Persistent hypoglycaemia (blood glucose < 36 mg/dl [2.0 mmol/L] in 3 consecutive samples immediately preceding enrolment)
    • Persistent hyperkalemia (venous serum potassium > 5.9 mmol/L in 3 consecutive samples immediately preceding enrolment)
    • Persistent neutropenia (absolute neutrophil counts <1,000/μL in 3 consecutive samples immediately preceding enrolment)

  2. nd screening (re-screening):

    • 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)

Sites / Locations

  • University Hospital ZurichRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Propranolol

Placebo

Arm Description

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)

Placebo (same duration as oral propranolol solution)

Outcomes

Primary Outcome Measures

Survival without threshold ROP (stage ≥ 3, AP-ROP, or any therapy for ROP)
The primary endpoint for efficacy is survival until 48 weeks postmenstrual age without any threshold ROP (defined as ROP stage 3 in any zone or more severe ROP [including AP-ROP] or any therapy for ROP) diagnosed according to the International Committee for the Classification of Retinopathy of Prematurity Revisited.

Secondary Outcome Measures

Efficacy: Survival without local treatment for ROP
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).
Safety: Death until discharge
Death until discharge home from the hospital.
Safety: Death until 48 weeks postmenstrual age.
Until 48 weeks postmenstrual age.
Safety: culture-proven sepsis or meningitis
Number of sepsis or meningitis episodes between the beginning of investigational medicinal product (IMP) administration and 48 weeks postmenstrual age.
Safety: symptomatic hypoglycaemia requiring intravenous glucose administration
Symptomatic hypoglycaemia requiring intravenous glucose administration between the beginning of investigational medicinal product (IMP) administration and 48 weeks postmenstrual age (adverse event of special interest).
Safety: emergency endotracheal intubation attributable to obstructive airway disease
Endotracheal intubation attributable to obstructive airway disease between the beginning of investigational medicinal product (IMP) administration and 48 weeks postmenstrual age (adverse event of special interest).
Safety: necrotising enterocolitis (surgically treated)
Surgically treated necrotising enterocolitis between the beginning of investigational medicinal product (IMP) administration and 48 weeks postmenstrual age (adverse event of special interest).
Safety: duration of supplemental oxygen
Number of days with supplemental oxygen
Safety: Duration of primary hospitalisation
Number of days of primary hospitalisation
Safety: Duration of subsequent hospitalisation
Number of days of subsequent hospitalisation
Safety: Weight gain during the administration of the investigational medicinal product (IMP)
Standard deviation score for gain in weight between the beginning and end of investigational medicinal product (IMP) administration
Safety: Gain in head circumference during the administration of the investigational medicinal product (IMP)
Standard deviation score for gain in head circumference between the beginning and end of investigational medicinal product (IMP) administration

Full Information

First Posted
March 13, 2017
Last Updated
October 3, 2022
Sponsor
University of Zurich
Collaborators
Ankara University, University Hospital Tuebingen
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1. Study Identification

Unique Protocol Identification Number
NCT03083431
Brief Title
Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity
Acronym
RoProp
Official Title
Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 22, 2022 (Actual)
Primary Completion Date
August 2024 (Anticipated)
Study Completion Date
November 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Zurich
Collaborators
Ankara University, University Hospital Tuebingen

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Retinopathy of Prematurity

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-blind Placebo-controlled
Allocation
Randomized
Enrollment
276 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Propranolol
Arm Type
Experimental
Arm Description
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)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo (same duration as oral propranolol solution)
Intervention Type
Drug
Intervention Name(s)
Propranolol
Intervention Description
Oral propranolol (1.6 mg propranolol-hydrochloride/kg/d in 4 divided dosages)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Oral solution containing the same excipients as propranolol solution
Primary Outcome Measure Information:
Title
Survival without threshold ROP (stage ≥ 3, AP-ROP, or any therapy for ROP)
Description
The primary endpoint for efficacy is survival until 48 weeks postmenstrual age without any threshold ROP (defined as ROP stage 3 in any zone or more severe ROP [including AP-ROP] or any therapy for ROP) diagnosed according to the International Committee for the Classification of Retinopathy of Prematurity Revisited.
Time Frame
48 weeks postmenstrual age
Secondary Outcome Measure Information:
Title
Efficacy: Survival without local treatment for ROP
Description
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).
Time Frame
48 weeks postmenstrual age
Title
Safety: Death until discharge
Description
Death until discharge home from the hospital.
Time Frame
At 48 weeks postmenstrual age
Title
Safety: Death until 48 weeks postmenstrual age.
Description
Until 48 weeks postmenstrual age.
Time Frame
At 48 weeks postmenstrual age
Title
Safety: culture-proven sepsis or meningitis
Description
Number of sepsis or meningitis episodes between the beginning of investigational medicinal product (IMP) administration and 48 weeks postmenstrual age.
Time Frame
At 48 weeks postmenstrual age
Title
Safety: symptomatic hypoglycaemia requiring intravenous glucose administration
Description
Symptomatic hypoglycaemia requiring intravenous glucose administration between the beginning of investigational medicinal product (IMP) administration and 48 weeks postmenstrual age (adverse event of special interest).
Time Frame
At 48 weeks postmenstrual age
Title
Safety: emergency endotracheal intubation attributable to obstructive airway disease
Description
Endotracheal intubation attributable to obstructive airway disease between the beginning of investigational medicinal product (IMP) administration and 48 weeks postmenstrual age (adverse event of special interest).
Time Frame
At 48 weeks postmenstrual age
Title
Safety: necrotising enterocolitis (surgically treated)
Description
Surgically treated necrotising enterocolitis between the beginning of investigational medicinal product (IMP) administration and 48 weeks postmenstrual age (adverse event of special interest).
Time Frame
At 48 weeks postmenstrual age
Title
Safety: duration of supplemental oxygen
Description
Number of days with supplemental oxygen
Time Frame
At 48 weeks postmenstrual age
Title
Safety: Duration of primary hospitalisation
Description
Number of days of primary hospitalisation
Time Frame
48 weeks postmenstrual age
Title
Safety: Duration of subsequent hospitalisation
Description
Number of days of subsequent hospitalisation
Time Frame
48 weeks postmenstrual age
Title
Safety: Weight gain during the administration of the investigational medicinal product (IMP)
Description
Standard deviation score for gain in weight between the beginning and end of investigational medicinal product (IMP) administration
Time Frame
At final cessation of investigational medicinal product (IMP) administration (up to 70 days post-allocation)
Title
Safety: Gain in head circumference during the administration of the investigational medicinal product (IMP)
Description
Standard deviation score for gain in head circumference between the beginning and end of investigational medicinal product (IMP) administration
Time Frame
At final cessation of investigational medicinal product (IMP) administration (up to 70 days post-allocation)
Other Pre-specified Outcome Measures:
Title
Intraventricular haemorrhages (all grades)
Description
Newly diagnosed intraventricular haemorrhage after the beginning of investigational medicinal product (IMP) administration.
Time Frame
At 48 weeks postmenstrual age
Title
Posthaemorrhagic hydrocephalus requiring intervention
Description
Newly diagnosed posthaemorrhagic hydrocephalus requiring intervention after the beginning of investigational medicinal product (IMP) administration.
Time Frame
At 48 weeks postmenstrual age
Title
Cystic leukomalacia
Description
Newly diagnosed cystic leukomalacia after the beginning of investigational medicinal product (IMP) administration.
Time Frame
At 48 weeks postmenstrual age
Title
Persistent ductus arteriosus requiring treatment
Description
Newly diagnosed persistent ductus arteriosus requiring treatment after the beginning of investigational medicinal product (IMP) administration.
Time Frame
At 48 weeks postmenstrual age
Title
Bronchopulmonary dysplasia
Description
Defined and graded according to the consensus statement of the national institutes of health
Time Frame
At 48 weeks postmenstrual age

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Weeks
Maximum Age & Unit of Time
15 Weeks
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Preterm infant born before 28 weeks gestation Birth weight below 1250 g 5 weeks of age (at randomisation) Postmenstrual age 31 0/7 - 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: Patients will be screened for the presence of exclusion criteria in a two-step process: (1) once all inclusion criteria have met, and (2) once informed consent has been obtained. st screening: ROP stage 3, AP-ROP or suspected AP-ROP (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 organisational problems for the patient Inclusion may be postponed in the presence of the following acute and transient conditions: Acute severe infection Arterial hypotension requiring therapeutic intervention by local standards Heart rate consistently (> 1h) < 100/min Concurrent treatment with insulin (risk of hypoglycaemia) Discontinuation of enteral feeding Persistent hypoglycaemia (blood glucose < 36 mg/dl [2.0 mmol/L] in 3 consecutive samples immediately preceding enrolment) Persistent hyperkalemia (venous serum potassium > 5.9 mmol/L in 3 consecutive samples immediately preceding enrolment) Persistent neutropenia (absolute neutrophil counts <1,000/μL in 3 consecutive samples immediately preceding enrolment) nd screening (re-screening): 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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dirk Bassler, M.D.
Phone
+41 44 255 53 40
Email
dirk.bassler@usz.ch
First Name & Middle Initial & Last Name or Official Title & Degree
Christoph Rüegger, M.D.
Phone
+41 43 253 98 10
Email
christoph.rueegger@usz.ch
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dirk Bassler, M.D.
Organizational Affiliation
University of Zurich
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Zurich
City
Zürich
State/Province
Zurich
ZIP/Postal Code
8091
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christoph M Rüegger
Phone
+41432539810
Email
christoph.rueegger@usz.ch
First Name & Middle Initial & Last Name & Degree
Claudia Knoepfli
Email
claudia.knoepfli@usz.ch
First Name & Middle Initial & Last Name & Degree
Christoph Rüegger
First Name & Middle Initial & Last Name & Degree
David Glauser

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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)
Citations:
PubMed Identifier
25968340
Citation
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.
Results Reference
result
PubMed Identifier
29982217
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.
Results Reference
result

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Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity

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