Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity

Study Overview
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Brief Summary
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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
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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.

Official Title
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Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity

Conditions
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Retinopathy of Prematurity

Intervention / Treatment
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* Drug: Propranolol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 5 Weeks
Maximum Age: 15 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 48 weeks postmenstrual age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 48 weeks postmenstrual age | 
| Safety: Death until discharge | Death until discharge home from the hospital. | At 48 weeks postmenstrual age | 
| Safety: Death until 48 weeks postmenstrual age. | Until 48 weeks postmenstrual age. | At 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. | At 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). | At 48 weeks postmenstrual age | 
| 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). | At 48 weeks postmenstrual age | 
| 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). | At 48 weeks postmenstrual age | 
| Safety: duration of supplemental oxygen | Number of days with supplemental oxygen | At 48 weeks postmenstrual age | 
| Safety: Duration of primary hospitalisation | Number of days of primary hospitalisation | 48 weeks postmenstrual age | 
| Safety: Duration of subsequent hospitalisation | Number of days of subsequent hospitalisation | 48 weeks postmenstrual age | 
| 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 | At final cessation of investigational medicinal product (IMP) administration (up to 70 days post-allocation) | 
| 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 | At final cessation of investigational medicinal product (IMP) administration (up to 70 days post-allocation) |