Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 276
- 试验地点
- 6
- 主要终点
- Survival without adverse ophthalmological outcome (stage ≥ 3, AP-ROP, or any ROP treatment)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind Placebo-controlled
入排标准
- 年龄范围
- 5 Weeks 至 15 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
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)
干预措施: Propranolol (Drug)
Placebo
Placebo (same duration as oral propranolol solution)
干预措施: Placebo (Drug)
结局指标
主要结局
Survival without adverse ophthalmological outcome (stage ≥ 3, AP-ROP, or any ROP treatment)
时间窗: 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.
次要结局
- Time to adverse ophthalmological outcome in days(48 weeks postmenstrual age)
- Survival without local treatment for ROP(48 weeks postmenstrual age)
- Survival with adverse ophthalmological outcome(48 weeks postmenstrual age)
- Recurrence of ROP in infants treated with anti-VEGF-antagonists(70 (+/- 2 weeks) postmenstrual age)
- Death until discharge(48 weeks postmenstrual age)
- Death until 48 weeks postmenstrual age(48 weeks postmenstrual age)
- Survival without adverse ophthalmological outcome(48 weeks postmenstrual age)
- Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists(70 (+/- 2 weeks) postmenstrual age)