<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03038295</url>
  </required_header>
  <id_info>
    <org_study_id>lqiong</org_study_id>
    <nct_id>NCT03038295</nct_id>
  </id_info>
  <brief_title>a Prospective Cohort Study for Propranolol Treatment in Retinopathy of Prematurity</brief_title>
  <official_title>Safety and Efficacy of Propranolol Treatment in Newborns With Retinopathy of Prematurity:a Prospective Cohort Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Guangdong Women and Children Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Guangdong Women and Children Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and efficacy of oral/local propranolol in&#xD;
      preterm newborns who diagnosed as early phase of retinopathy of prematurity (ROP).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The incidence of Retinopathy of Prematurity (ROP) in preterm newborns less than 1500g is&#xD;
      about 60% in the developed countries around the world, while there are much more preterm&#xD;
      newborns more than 1500g and 32 weeks gestational age with Retinopathy of Prematurity (ROP)&#xD;
      had to be treated in the developing countries. ROP has listed top of the five causes lead to&#xD;
      blindness in children, which seriously threated children's vision and quality of life.&#xD;
&#xD;
      The ablation of the retina with photocoagulation by laser or cryotherapy reduces the&#xD;
      incidence of blindness by suppressing the neovascular phase of ROP. However, those Surgeries&#xD;
      require anesthesia and some of them may result in complications such as apnea, neonatal&#xD;
      necrotizing enterocolitis, sepsis, and hemorrhage of digestive tract. As a result, it's&#xD;
      important to study an alternative non-surgical treatment method.&#xD;
&#xD;
      The development of ROP depends largely from vascular endothelial growth factor (VEGF). The&#xD;
      reduction of VEGF expression in the neovascular phase might prevent destructive&#xD;
      neovascularization in ROP.&#xD;
&#xD;
      Propranolol is a kind of beta-adrenergic receptor (β-AR) which can inhibit the expression of&#xD;
      VEGF and has been first choice of treating infantile hemangioma, the most common tumor of&#xD;
      infancy. There are some pilot studies suggesting that the administration of oral propranolol&#xD;
      is effective in counteracting the progression of ROP in patients without operation&#xD;
      indication. Nevertheless that safety is a concern, for oral propranolol may result in&#xD;
      associated complications and side effects such as bradycardia, hypotension, injury of&#xD;
      cerebrum growth and olfactory.&#xD;
&#xD;
      Recently a research of eye drop propranolol in a mouse model of oxygen-induced retinopathy&#xD;
      (OIR) has shown that propranolol was still effective in inhibiting angiogenic processes,&#xD;
      indicating that local administration is equally effective.&#xD;
&#xD;
      The purpose of this study is to evaluate safety and efficacy of oral/local propranolol in&#xD;
      preterm newborns with early phase of retinopathy of prematurity (ROP).The study will be&#xD;
      followed up for a period of time, observing the development of optic and nerve system&#xD;
      complications to further confirm the efficacy of propranolol to ROP treatment, which can&#xD;
      provide theoretical basis for the futher clinical application of the drug in ROP.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">March 2017</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">December 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of newborns who have ROP progression</measure>
    <time_frame>participants will be followed for the duration of hospital stay, an expected average of 2 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of newborns who need surgical treatment</measure>
    <time_frame>participants will be followed for the duration of hospital stay, an expected average of 2 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of newborns who have side effects</measure>
    <time_frame>participants will be followed for the duration of hospital stay, an expected average of 2 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Plasma concentrations of propranolol at the steady state measured by dried blood spots</measure>
    <time_frame>10th day of treatment</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>visual assessment of enrolled newborns</measure>
    <time_frame>about 12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Scores of Gesell development scale of enrolled newborns</measure>
    <time_frame>about 12 months</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Retinopathy of Prematurity</condition>
  <arm_group>
    <arm_group_label>oral propranol group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enrolled preterm newborns will receive oral propranolol 0.25mg/kg daily(every 24 hours).&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>oral placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>eye drop propranol group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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) .&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>eye drop placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propranolol</intervention_name>
    <description>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).</description>
    <arm_group_label>eye drop propranol group</arm_group_label>
    <arm_group_label>oral propranol group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>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.</description>
    <arm_group_label>eye drop placebo group</arm_group_label>
    <arm_group_label>oral placebo group</arm_group_label>
    <other_name>normal saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Preterm newborns (birth weight less than 1500g) with stage 1/2 ROP in Zone 2 or 3&#xD;
             without plus&#xD;
&#xD;
          -  A signed parental informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Newborns with heart failure&#xD;
&#xD;
          -  Newborns with recurrent bradycardia (heart rate &lt; 90 beat per minute)&#xD;
&#xD;
          -  Newborns with second or third degree atrioventricular block&#xD;
&#xD;
          -  Newborns with congenital cardiovascular anomalies, except for persistent ductus&#xD;
             arteriosus, patent foramen ovale and small ventricular septal defects&#xD;
&#xD;
          -  Newborns with hypotension&#xD;
&#xD;
          -  Newborns with renal failure&#xD;
&#xD;
          -  Newborns with actual cerebral haemorrhage&#xD;
&#xD;
          -  Newborns with other diseases which contraindicate the use of beta-adrenoreceptor&#xD;
             blockers.&#xD;
&#xD;
          -  Newborns with a more severe stage of ROP than stage 2 or in Zone 1&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>8 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chuan Nie, Doctor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Guangdong Women and Children Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Chuan Nie, Doctor</last_name>
    <phone>+86-136-8227-0294</phone>
    <email>chuannie@sina.com</email>
  </overall_contact>
  <link>
    <url>https://druginfo.nlm.nih.gov/drugportal/name/propranolol</url>
    <description>Drug Information</description>
  </link>
  <reference>
    <citation>Zin A, Gole GA. Retinopathy of prematurity-incidence today. Clin Perinatol. 2013 Jun;40(2):185-200. doi: 10.1016/j.clp.2013.02.001.</citation>
    <PMID>23719304</PMID>
  </reference>
  <reference>
    <citation>Fierson WM; American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2013 Jan;131(1):189-95. doi: 10.1542/peds.2012-2996. Epub 2012 Dec 31.</citation>
    <PMID>23277315</PMID>
  </reference>
  <reference>
    <citation>Filippi L, Cavallaro G, Bagnoli P, Dal Monte M, Fiorini P, Donzelli G, Tinelli F, Araimo G, Cristofori G, la Marca G, Della Bona ML, La Torre A, Fortunato P, Furlanetto S, Osnaghi S, Mosca F. Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives. J Pediatr. 2013 Dec;163(6):1570-1577.e6. doi: 10.1016/j.jpeds.2013.07.049. Epub 2013 Sep 18.</citation>
    <PMID>24054431</PMID>
  </reference>
  <reference>
    <citation>Dal Monte M, Casini G, la Marca G, Isacchi B, Filippi L, Bagnoli P. Eye drop propranolol administration promotes the recovery of oxygen-induced retinopathy in mice. Exp Eye Res. 2013 Jun;111:27-35. doi: 10.1016/j.exer.2013.03.013. Epub 2013 Mar 23.</citation>
    <PMID>23528535</PMID>
  </reference>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>January 19, 2017</study_first_submitted>
  <study_first_submitted_qc>January 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 31, 2017</study_first_posted>
  <last_update_submitted>February 1, 2017</last_update_submitted>
  <last_update_submitted_qc>February 1, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 3, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Guangdong Women and Children Hospital</investigator_affiliation>
    <investigator_full_name>Nie Chuan</investigator_full_name>
    <investigator_title>Vice director of Department of Neonatology</investigator_title>
  </responsible_party>
  <keyword>Retinopathy of Prematurity</keyword>
  <keyword>propranolol</keyword>
  <keyword>ROP</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Retinal Diseases</mesh_term>
    <mesh_term>Retinopathy of Prematurity</mesh_term>
    <mesh_term>Premature Birth</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Propranolol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03038295
org study id: lqiong
nct id: NCT03038295
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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).
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: 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
measure: 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
measure: 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
measure: Plasma concentrations of propranolol at the steady state measured by dried blood spots
time frame: 10th day of treatment
measure: visual assessment of enrolled newborns
time frame: about 12 months
measure: Scores of Gesell development scale of enrolled newborns
time frame: about 12 months
arm group label: oral propranol group
arm group type: Experimental
description: 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.
arm group label: oral placebo group
arm group type: Placebo Comparator
description: 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.
arm group label: eye drop propranol group
arm group type: Experimental
description: 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.
arm group label: eye drop placebo group
arm group type: Placebo Comparator
description: 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.
intervention type: Drug
intervention name: Propranolol
description: 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).
arm group label: eye drop propranol group
arm group label: oral propranol group
intervention type: Drug
intervention name: placebo
description: 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.
arm group label: eye drop placebo group
arm group label: oral placebo group
other name: normal saline
criteria: 
gender: All
minimum age: N/A
maximum age: 8 Weeks
healthy volunteers: No
last name: Chuan Nie, Doctor
role: Principal Investigator
affiliation: Guangdong Women and Children Hospital
last name: Chuan Nie, Doctor
phone: +86-136-8227-0294
email: chuannie@sina.com
url: https://druginfo.nlm.nih.gov/drugportal/name/propranolol
description: Drug Information
citation: Zin A, Gole GA. Retinopathy of prematurity-incidence today. Clin Perinatol. 2013 Jun;40(2):185-200. doi: 10.1016/j.clp.2013.02.001.
PMID: 23719304
citation: Fierson WM; American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2013 Jan;131(1):189-95. doi: 10.1542/peds.2012-2996. Epub 2012 Dec 31.
PMID: 23277315
citation: Filippi L, Cavallaro G, Bagnoli P, Dal Monte M, Fiorini P, Donzelli G, Tinelli F, Araimo G, Cristofori G, la Marca G, Della Bona ML, La Torre A, Fortunato P, Furlanetto S, Osnaghi S, Mosca F. Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives. J Pediatr. 2013 Dec;163(6):1570-1577.e6. doi: 10.1016/j.jpeds.2013.07.049. Epub 2013 Sep 18.
PMID: 24054431
citation: Dal Monte M, Casini G, la Marca G, Isacchi B, Filippi L, Bagnoli P. Eye drop propranolol administration promotes the recovery of oxygen-induced retinopathy in mice. Exp Eye Res. 2013 Jun;111:27-35. doi: 10.1016/j.exer.2013.03.013. Epub 2013 Mar 23.
PMID: 23528535
responsible party type: Principal Investigator
investigator affiliation: Guangdong Women and Children Hospital
investigator full name: Nie Chuan
investigator title: Vice director of Department of Neonatology
mesh term: Retinal Diseases
mesh term: Retinopathy of Prematurity
mesh term: Premature Birth
mesh term: Propranolol
sharing ipd: No