<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/NCT02977000</url>
  </required_header>
  <id_info>
    <org_study_id>ROP-PROP</org_study_id>
    <nct_id>NCT02977000</nct_id>
  </id_info>
  <brief_title>Oral Propranolol Improve Retinopathy of Prematurity Outcomes in Very Preterm Infants</brief_title>
  <official_title>Department of Neonatology, Children's Hospital of Zhengzhou</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Huiqing Sun</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Zhengzhou Children's Hospital, China</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Retinopathy of prematurity (ROP) is a major cause of blindness and visual impairment in&#xD;
      children in both developing and developed countries around the world. ROP is a multifactorial&#xD;
      disease characterized by perturbation of normal vascular development in the retina. The&#xD;
      pathogenesis of ROP is hypothesized to consist of two distinct phases of which the second&#xD;
      phase is characterized by hypoxia-induced up-regulation of vascular endothelial growth factor&#xD;
      (VEGF) and retinal neovascularization.&#xD;
&#xD;
      Recent studies have shown a relationship between the β-adrenergic system and angiogenesis.&#xD;
      This relationship has been observed in several diseases, like infantile hemangiomas, ROP, and&#xD;
      neoplasias. Studies in animal models have shown that norepinephrine stimulates VEGF&#xD;
      expression and secretion in retinal cells. In oxygen induced retinopathy, blockage of&#xD;
      β-adrenergic receptors (β-AR) can inhibit the angiogenic cascade and interfere with further&#xD;
      proliferation of retinal vasculature. Also, angiogenesis seems to be impaired in β-Argene&#xD;
      deficient mice, when exposed to hypoxia and other stimuli, but this function is restored&#xD;
      after gene therapy.&#xD;
&#xD;
      Assuming in human preterm newborns with ROP that VEGF overexpression and retinal&#xD;
      neovascularization in response to hypoxia might involve b-AR activation, we design&#xD;
      prospective randomized study to assess the effect of oral propranolol on the progression of&#xD;
      early stages of ROP in very low birth weight infants.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Retinopathy of prematurity (ROP) is a major cause of blindness and visual impairment in&#xD;
      children in both developing and developed countries around the world. ROP is a multifactorial&#xD;
      disease characterized by perturbation of normal vascular development in the retina. The&#xD;
      pathogenesis of ROP is hypothesized to consist of two distinct phases of which the second&#xD;
      phase is characterized by hypoxia-induced up-regulation of vascular endothelial growth factor&#xD;
      (VEGF) and retinal neovascularization.&#xD;
&#xD;
      Recent studies have shown a relationship between the β-adrenergic system and angiogenesis.&#xD;
      This relationship has been observed in several diseases, like infantile hemangiomas, ROP, and&#xD;
      neoplasias. Studies in animal models have shown that norepinephrine stimulates VEGF&#xD;
      expression and secretion in retinal cells. In oxygen induced retinopathy, blockage of&#xD;
      β-adrenergic receptors (β-AR) can inhibit the angiogenic cascade and interfere with further&#xD;
      proliferation of retinal vasculature. Also, angiogenesis seems to be impaired in β-Argene&#xD;
      deficient mice, when exposed to hypoxia and other stimuli, but this function is restored&#xD;
      after gene therapy.&#xD;
&#xD;
      An association between ROP and infantile hemangiomas was observed over 50 years ago with a&#xD;
      higher prevalence of ROP in children with hemangiomas. Studies have also shown that β-AR&#xD;
      blockage reduces VEGF levels and favors the regression of infantile hemangiomas. The&#xD;
      treatment of choice in threshold stages of ROP is laser photocoagulation and/or intravitreal&#xD;
      bevacizumab injections, but management of early stages of ROP, until now has been expectant,&#xD;
      with ophthalmologic follow-up but no therapeutic interventions to prevent its progression.&#xD;
&#xD;
      Propranolol is a non-selective β-AR blocker, with equal affinity for β1 and β2 receptors. It&#xD;
      has a systemic effect, and acts in different tissues. In vivo models of proliferative&#xD;
      retinopathies have shown a strong inhibitory role of β-AR on vascular changes. In particular,&#xD;
      β2-AR seems to be the most involved in these responses&#xD;
&#xD;
      . Propranolol has shown to be highly effective in inhibiting both the increase of VEGF&#xD;
      expression caused by a hypoxic insult, and the consequent neovascular Response. Studies have&#xD;
      shown that propranolol reduces the overproduction of VEGF in oxygen induced retinopathy, but&#xD;
      VEGF levels remain unchanged in the normal retina. Assuming in human preterm newborns with&#xD;
      ROP that VEGF overexpression and retinal neovascularization in response to hypoxia might&#xD;
      involve b-AR activation, we design prospective randomized study to assess the effect of oral&#xD;
      propranolol on the progression of early stages of ROP in very low birth weight infants.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      A randomized controlled trial was performed with preterm newborns with GA &lt;32 weeks of age&#xD;
      and Stage 2 ROP without plus in zone II, Although infants were receiving supplemental oxygen,&#xD;
      the target range of oxygen saturation was maintained between 91% and 95%. The treated and&#xD;
      control newborns are randomized with a 1:1 allocation in blocks of 8 by using a computer&#xD;
      random number generator and stratified by center in 2 groups of GA 24-28 and 28-32 weeks;&#xD;
      Exclusion criteria included newborns with congenital or acquired cardiovascular anomalies,&#xD;
      renal failure or cerebral hemorrhage at enrollment, and newborns with ROP in zone I or at a&#xD;
      more advanced stage than Stage 2 without plus in zone II.&#xD;
&#xD;
      With severe adverse effects related to propranolol (severe bradycardia, hypotension, or&#xD;
      wheezing), the administration of propranolol was permanently discontinued. If these episodes&#xD;
      had been observed within the first 2 days of treatment, these newborns were included into the&#xD;
      control group.&#xD;
&#xD;
      All newborns withGA &lt;32 weeks had ophthalmologic evaluations through indirect ophthalmoscopy.&#xD;
      When ROP in zone II reached Stage 2 without plus, newborns were enrolled, and ophthalmologic&#xD;
      examinations were scheduled weekly or more frequently, according to the severity of ROP.&#xD;
      Propranolol was administered orally as a dose of 1.5 mg/kg.d divided q8h. investigators used&#xD;
      powdered drug, dissolved in 5% dextrose. The treatment was continued until complete&#xD;
      development of retinal vascularization, although administration was not permitted for more&#xD;
      than 90 days.&#xD;
&#xD;
      Statistical analyses were performed with the Statistical Software SPSS 17.0. investigators&#xD;
      used t tests to assess possible differences in demographic, biochemical, hemodynamic, and&#xD;
      respiratory variables between the treated and control newborns. The null hypothesis was&#xD;
      accepted with a P &gt; .05. The efficacy of the treatment was evaluated by means of the risk&#xD;
      ratio, which is the ratio between the proportion of subjects progressing to more&#xD;
      advanced-stage ROP in the propranolol group vs the control group. The relative reduction of&#xD;
      risk, which is the reduction percent of events in the treated group vs the control group&#xD;
      event rate, was calculated when it was not possible to calculate the risk ratio.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>May 2016</start_date>
  <completion_date type="Anticipated">May 2018</completion_date>
  <primary_completion_date type="Anticipated">March 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The rates of regression of Retinopathy of Prematurity</measure>
    <time_frame>2 years</time_frame>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Retinopathy of Prematurity</condition>
  <arm_group>
    <arm_group_label>Propranolol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Propranolol was administered orally as a dose of 1.5 mg/kg.d divided q8h. investigators used powdered drug, dissolved in 5% dextrose. The treatment was continued until complete development of retinal vascularization, although administration was not permitted for more than 90 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propranolol</intervention_name>
    <description>Propranolol was administered orally as a dose of 1.5 mg/kg.d divided q8h.investigators used powdered drug, dissolved in 5% dextrose. The treatment was continued until complete development of retinal vascularization, although administration was not permitted for more than 90 days.</description>
    <arm_group_label>Propranolol</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  preterm newborns with GA &lt;32 weeks of age and Stage 2 ROP without plus in zone II&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  newborns with congenital or acquired cardiovascular anomalies, renal failure or&#xD;
             cerebral hemorrhage at enrollment, and newborns with ROP in zone I or at a more&#xD;
             advanced stage than Stage 2 without plus in zone II.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>24 Weeks</minimum_age>
    <maximum_age>45 Weeks</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ligong Hou, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Chidren's Hospital of Zhengzhou</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Hunqing Sun, PhD</last_name>
    <phone>13838112692</phone>
    <email>s_huiqing@sina.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Propranolol</name>
      <address>
        <city>Zhengzhou</city>
        <state>Henan</state>
        <zip>450000</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Huiqing Sun, PhD</last_name>
      <phone>13838112692</phone>
      <email>s_huiqing@sina.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>November 2016</verification_date>
  <study_first_submitted>November 22, 2016</study_first_submitted>
  <study_first_submitted_qc>November 26, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 30, 2016</study_first_posted>
  <last_update_submitted>November 29, 2016</last_update_submitted>
  <last_update_submitted_qc>November 29, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 1, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Zhengzhou Children's Hospital, China</investigator_affiliation>
    <investigator_full_name>Huiqing Sun</investigator_full_name>
    <investigator_title>Department of Neonatology</investigator_title>
  </responsible_party>
  <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/NCT02977000
org study id: ROP-PROP
nct id: NCT02977000
lead sponsor: 
has dmc: Yes
Retinopathy of prematurity (ROP) is a major cause of blindness and visual impairment in
      children in both developing and developed countries around the world. ROP is a multifactorial
      disease characterized by perturbation of normal vascular development in the retina. The
      pathogenesis of ROP is hypothesized to consist of two distinct phases of which the second
      phase is characterized by hypoxia-induced up-regulation of vascular endothelial growth factor
      (VEGF) and retinal neovascularization.

      Recent studies have shown a relationship between the β-adrenergic system and angiogenesis.
      This relationship has been observed in several diseases, like infantile hemangiomas, ROP, and
      neoplasias. Studies in animal models have shown that norepinephrine stimulates VEGF
      expression and secretion in retinal cells. In oxygen induced retinopathy, blockage of
      β-adrenergic receptors (β-AR) can inhibit the angiogenic cascade and interfere with further
      proliferation of retinal vasculature. Also, angiogenesis seems to be impaired in β-Argene
      deficient mice, when exposed to hypoxia and other stimuli, but this function is restored
      after gene therapy.

      Assuming in human preterm newborns with ROP that VEGF overexpression and retinal
      neovascularization in response to hypoxia might involve b-AR activation, we design
      prospective randomized study to assess the effect of oral propranolol on the progression of
      early stages of ROP in very low birth weight infants.
Retinopathy of prematurity (ROP) is a major cause of blindness and visual impairment in
      children in both developing and developed countries around the world. ROP is a multifactorial
      disease characterized by perturbation of normal vascular development in the retina. The
      pathogenesis of ROP is hypothesized to consist of two distinct phases of which the second
      phase is characterized by hypoxia-induced up-regulation of vascular endothelial growth factor
      (VEGF) and retinal neovascularization.

      Recent studies have shown a relationship between the β-adrenergic system and angiogenesis.
      This relationship has been observed in several diseases, like infantile hemangiomas, ROP, and
      neoplasias. Studies in animal models have shown that norepinephrine stimulates VEGF
      expression and secretion in retinal cells. In oxygen induced retinopathy, blockage of
      β-adrenergic receptors (β-AR) can inhibit the angiogenic cascade and interfere with further
      proliferation of retinal vasculature. Also, angiogenesis seems to be impaired in β-Argene
      deficient mice, when exposed to hypoxia and other stimuli, but this function is restored
      after gene therapy.

      An association between ROP and infantile hemangiomas was observed over 50 years ago with a
      higher prevalence of ROP in children with hemangiomas. Studies have also shown that β-AR
      blockage reduces VEGF levels and favors the regression of infantile hemangiomas. The
      treatment of choice in threshold stages of ROP is laser photocoagulation and/or intravitreal
      bevacizumab injections, but management of early stages of ROP, until now has been expectant,
      with ophthalmologic follow-up but no therapeutic interventions to prevent its progression.

      Propranolol is a non-selective β-AR blocker, with equal affinity for β1 and β2 receptors. It
      has a systemic effect, and acts in different tissues. In vivo models of proliferative
      retinopathies have shown a strong inhibitory role of β-AR on vascular changes. In particular,
      β2-AR seems to be the most involved in these responses

      . Propranolol has shown to be highly effective in inhibiting both the increase of VEGF
      expression caused by a hypoxic insult, and the consequent neovascular Response. Studies have
      shown that propranolol reduces the overproduction of VEGF in oxygen induced retinopathy, but
      VEGF levels remain unchanged in the normal retina. Assuming in human preterm newborns with
      ROP that VEGF overexpression and retinal neovascularization in response to hypoxia might
      involve b-AR activation, we design prospective randomized study to assess the effect of oral
      propranolol on the progression of early stages of ROP in very low birth weight infants.

      Methods:

      A randomized controlled trial was performed with preterm newborns with GA <32 weeks of age
      and Stage 2 ROP without plus in zone II, Although infants were receiving supplemental oxygen,
      the target range of oxygen saturation was maintained between 91% and 95%. The treated and
      control newborns are randomized with a 1:1 allocation in blocks of 8 by using a computer
      random number generator and stratified by center in 2 groups of GA 24-28 and 28-32 weeks;
      Exclusion criteria included newborns with congenital or acquired cardiovascular anomalies,
      renal failure or cerebral hemorrhage at enrollment, and newborns with ROP in zone I or at a
      more advanced stage than Stage 2 without plus in zone II.

      With severe adverse effects related to propranolol (severe bradycardia, hypotension, or
      wheezing), the administration of propranolol was permanently discontinued. If these episodes
      had been observed within the first 2 days of treatment, these newborns were included into the
      control group.

      All newborns withGA <32 weeks had ophthalmologic evaluations through indirect ophthalmoscopy.
      When ROP in zone II reached Stage 2 without plus, newborns were enrolled, and ophthalmologic
      examinations were scheduled weekly or more frequently, according to the severity of ROP.
      Propranolol was administered orally as a dose of 1.5 mg/kg.d divided q8h. investigators used
      powdered drug, dissolved in 5% dextrose. The treatment was continued until complete
      development of retinal vascularization, although administration was not permitted for more
      than 90 days.

      Statistical analyses were performed with the Statistical Software SPSS 17.0. investigators
      used t tests to assess possible differences in demographic, biochemical, hemodynamic, and
      respiratory variables between the treated and control newborns. The null hypothesis was
      accepted with a P > .05. The efficacy of the treatment was evaluated by means of the risk
      ratio, which is the ratio between the proportion of subjects progressing to more
      advanced-stage ROP in the propranolol group vs the control group. The relative reduction of
      risk, which is the reduction percent of events in the treated group vs the control group
      event rate, was calculated when it was not possible to calculate the risk ratio.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The rates of regression of Retinopathy of Prematurity
time frame: 2 years
arm group label: Propranolol
arm group type: Experimental
description: Propranolol was administered orally as a dose of 1.5 mg/kg.d divided q8h. investigators used powdered drug, dissolved in 5% dextrose. The treatment was continued until complete development of retinal vascularization, although administration was not permitted for more than 90 days.
intervention type: Drug
intervention name: Propranolol
description: Propranolol was administered orally as a dose of 1.5 mg/kg.d divided q8h.investigators used powdered drug, dissolved in 5% dextrose. The treatment was continued until complete development of retinal vascularization, although administration was not permitted for more than 90 days.
arm group label: Propranolol
criteria: 
gender: All
minimum age: 24 Weeks
maximum age: 45 Weeks
healthy volunteers: Accepts Healthy Volunteers
last name: Ligong Hou, MD
role: Study Chair
affiliation: Chidren's Hospital of Zhengzhou
last name: Hunqing Sun, PhD
phone: 13838112692
email: s_huiqing@sina.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor-Investigator
investigator affiliation: Zhengzhou Children's Hospital, China
investigator full name: Huiqing Sun
investigator title: Department of Neonatology
mesh term: Retinal Diseases
mesh term: Retinopathy of Prematurity
mesh term: Premature Birth
mesh term: Propranolol
sharing ipd: No