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a Prospective Cohort Study for Propranolol Treatment in Retinopathy of Prematurity

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ClinicalTrials.gov Identifier: NCT03038295
Recruitment Status : Not yet recruiting
First Posted : January 31, 2017
Last Update Posted : February 3, 2017
Sponsor:
Information provided by (Responsible Party):
Nie Chuan, Guangdong Women and Children Hospital

Brief Summary:
The purpose of this study is to evaluate the safety and efficacy of oral/local propranolol in preterm newborns who diagnosed as early phase of retinopathy of prematurity (ROP).

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

Detailed Description:

The incidence of Retinopathy of Prematurity (ROP) in preterm newborns less than 1500g is about 60% in the developed countries around the world, while there are much more preterm newborns more than 1500g and 32 weeks gestational age with Retinopathy of Prematurity (ROP) had to be treated in the developing countries. ROP has listed top of the five causes lead to blindness in children, which seriously threated children's vision and quality of life.

The ablation of the retina with photocoagulation by laser or cryotherapy reduces the incidence of blindness by suppressing the neovascular phase of ROP. However, those Surgeries require anesthesia and some of them may result in complications such as apnea, neonatal necrotizing enterocolitis, sepsis, and hemorrhage of digestive tract. As a result, it's important to study an alternative non-surgical treatment method.

The development of ROP depends largely from vascular endothelial growth factor (VEGF). The reduction of VEGF expression in the neovascular phase might prevent destructive neovascularization in ROP.

Propranolol is a kind of beta-adrenergic receptor (β-AR) which can inhibit the expression of VEGF and has been first choice of treating infantile hemangioma, the most common tumor of infancy. There are some pilot studies suggesting that the administration of oral propranolol is effective in counteracting the progression of ROP in patients without operation indication. Nevertheless that safety is a concern, for oral propranolol may result in associated complications and side effects such as bradycardia, hypotension, injury of cerebrum growth and olfactory.

Recently a research of eye drop propranolol in a mouse model of oxygen-induced retinopathy (OIR) has shown that propranolol was still effective in inhibiting angiogenic processes, indicating that local administration is equally effective.

The purpose of this study is to evaluate safety and efficacy of oral/local propranolol in preterm newborns with early phase of retinopathy of prematurity (ROP).The study will be followed up for a period of time, observing the development of optic and nerve system complications to further confirm the efficacy of propranolol to ROP treatment, which can provide theoretical basis for the futher clinical application of the drug in ROP.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Propranolol Treatment in Newborns With Retinopathy of Prematurity:a Prospective Cohort Study
Estimated Study Start Date : March 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: oral propranol group

Enrolled preterm newborns will receive oral propranolol 0.25mg/kg daily(every 24 hours).

The treatment will be started as soon as the diagnosis of stage 1 or 2 ROP without plus is made and will be continue until the development of retinal vascularization is completed, but no more than 90 days.

Drug: Propranolol
Oral propranolol:0.25mg/kg daily(every 24 hours);Eye drop propranolol(0.2%):3 microdrops,in each eye, four times daily (every 6 hours) .Both administration routes will be discontinued until retinal vascularization will be completed, but no more than 90 days.The study will be discontinued immediately in the presence of serious adverse effects attributable to the pharmacological actions of propranolol (severe hypotension, bradycardia or bronchospasm).In case of surgery or induction of anesthesia during the administration of propranolol, the drug should be discontinued at least 24 hours before surgery.In cases of severe hypotension or bradycardia may be administered one or more of the following drugs:Atropine.Isoproterenol hydrochloride (isoprenaline).Terlipressin.Glucagon In case of severe bronchospasm may be used salbutamol aerosol or salbutamol + ipratropium bromide. Betamethasone could be used for aerosol or systemic (intravenous or intramuscular).

Placebo Comparator: oral placebo group
Enrolled preterm newborns will receive oral normal saline 0.25mg/kg daily(every 24 hours) and other disposals will be done similarily to the oral propranol group.
Drug: placebo
Oral/eye drop placebo will be taken in enrolled newborns. Other treatment will follow the standard treatment schedule of Early Treatment For Retinopathy Of Prematurity Cooperative Group.
Other Name: normal saline

Experimental: eye drop propranol group

Enrolled preterm newborns will receive propranolol as ophthalmic solution (0.2%). 3 microdrops of 6 microliters (μL) propranolol solution (= 6 μg propranolol/microdrop) will be topically applied with a calibrated pipette,in each eye, four times daily (every 6 hours) .

The treatment will be started as soon as the diagnosis of stage 1 or 2 ROP without plus is made and will be continue until the development of retinal vascularization is completed, but no more than 90 days.

Drug: Propranolol
Oral propranolol:0.25mg/kg daily(every 24 hours);Eye drop propranolol(0.2%):3 microdrops,in each eye, four times daily (every 6 hours) .Both administration routes will be discontinued until retinal vascularization will be completed, but no more than 90 days.The study will be discontinued immediately in the presence of serious adverse effects attributable to the pharmacological actions of propranolol (severe hypotension, bradycardia or bronchospasm).In case of surgery or induction of anesthesia during the administration of propranolol, the drug should be discontinued at least 24 hours before surgery.In cases of severe hypotension or bradycardia may be administered one or more of the following drugs:Atropine.Isoproterenol hydrochloride (isoprenaline).Terlipressin.Glucagon In case of severe bronchospasm may be used salbutamol aerosol or salbutamol + ipratropium bromide. Betamethasone could be used for aerosol or systemic (intravenous or intramuscular).

Placebo Comparator: eye drop placebo group
Enrolled preterm newborns will receive placebo as ophthalmic solution in the same way of eye drop propranolol and other disposals will be done similarily to the eye drop propranol group.
Drug: placebo
Oral/eye drop placebo will be taken in enrolled newborns. Other treatment will follow the standard treatment schedule of Early Treatment For Retinopathy Of Prematurity Cooperative Group.
Other Name: normal saline




Primary Outcome Measures :
  1. Number of newborns who have ROP progression [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 2 months ]
  2. Number of newborns who need surgical treatment [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 2 months ]
  3. Number of newborns who have side effects [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 2 months ]
  4. Plasma concentrations of propranolol at the steady state measured by dried blood spots [ Time Frame: 10th day of treatment ]

Secondary Outcome Measures :
  1. visual assessment of enrolled newborns [ Time Frame: about 12 months ]
  2. Scores of Gesell development scale of enrolled newborns [ Time Frame: about 12 months ]


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Ages Eligible for Study:   up to 8 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Preterm newborns (birth weight less than 1500g) with stage 1/2 ROP in Zone 2 or 3 without plus
  • A signed parental informed consent

Exclusion Criteria:

  • Newborns with heart failure
  • Newborns with recurrent bradycardia (heart rate < 90 beat per minute)
  • Newborns with second or third degree atrioventricular block
  • Newborns with congenital cardiovascular anomalies, except for persistent ductus arteriosus, patent foramen ovale and small ventricular septal defects
  • Newborns with hypotension
  • Newborns with renal failure
  • Newborns with actual cerebral haemorrhage
  • Newborns with other diseases which contraindicate the use of beta-adrenoreceptor blockers.
  • Newborns with a more severe stage of ROP than stage 2 or in Zone 1

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): NCT03038295


Contacts
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Contact: Chuan Nie, Doctor +86-136-8227-0294 chuannie@sina.com

Sponsors and Collaborators
Guangdong Women and Children Hospital
Investigators
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Principal Investigator: Chuan Nie, Doctor Guangdong Women and Children Hospital

Additional Information:
Publications:
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Responsible Party: Nie Chuan, Vice director of Department of Neonatology, Guangdong Women and Children Hospital
ClinicalTrials.gov Identifier: NCT03038295     History of Changes
Other Study ID Numbers: lqiong
First Posted: January 31, 2017    Key Record Dates
Last Update Posted: February 3, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nie Chuan, Guangdong Women and Children Hospital:
Retinopathy of Prematurity
propranolol
ROP

Additional relevant MeSH terms:
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Propranolol
Retinal Diseases
Premature Birth
Retinopathy of Prematurity
Eye Diseases
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Infant, Premature, Diseases
Infant, Newborn, Diseases
Ophthalmic Solutions
Pharmaceutical Solutions
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