<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/NCT02985619</url>
  </required_header>
  <id_info>
    <org_study_id>1.599.864</org_study_id>
    <nct_id>NCT02985619</nct_id>
  </id_info>
  <brief_title>Bevacizumabe or Triamcinolone for Persistent Diabetic Macular Edema</brief_title>
  <acronym>BEVATAAC</acronym>
  <official_title>Randomized Trial Evaluating Bevacizumabe or Triamcinolone for Persistent Diabetic Macular Edema</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Sao Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Sao Paulo</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Diabetic macular edema (DME) shows a sustained functional and morphologic&#xD;
      response to anti-vascular endothelial growth factor (VEGF) drugs, but the optimal approach&#xD;
      for persistent macular edema still in debate.&#xD;
&#xD;
      Purpose: To evaluate 24-week visual and anatomical effects of intravitreal bevacizumabe or&#xD;
      triamcinolone in patients who have residual edema after 24-weeks to &quot;pro re nata&quot;(prn)&#xD;
      intravitreal bevacizumabe therapy.&#xD;
&#xD;
      Methods: This study will enroll a total of 100 DME eyes. Each patient will receive &quot;prn&quot;&#xD;
      bevacizumabe therapy throughout 24 weeks. At week 24, patients who have recurrent or&#xD;
      persistent edema were randomized 1:1 to Group 1 (prn bevacizumane) or Group 2 (prn&#xD;
      triamcinolone). Patients with no recurrent or persistent edema at week 24 will comprise to&#xD;
      Group 3 and continue receive prn bevacizumabe. Prn treatment was administered when central&#xD;
      subfield thickness of the macula (CST) &gt; 300 µm and/or there are intraretinal cystoid spaces&#xD;
      in the fovea. Study visits will occur every 4 weeks with the endpoint at week 48. At each&#xD;
      visit, patients will have an eye exam and CST, best-corrected visual acuity (BCVA), and&#xD;
      intraocular pressure (IOP) were assessed. Fundus photography and fluorescein angiography will&#xD;
      also perform at baseline, week 16, week 40, and week 48. All patients will resume standard&#xD;
      care after exiting.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Methods Study Design. The current study is a prospective randomized clinical trial registered&#xD;
      at ClinicalTrials.gov (NCT02985619). The study protocol adhered to the tenets of the&#xD;
      Declaration of Helsinki and was approved by the local Institutional Review Board, research&#xD;
      ethics committee of School of Medicine of Ribeirão Preto at University of Sao Paulo. All&#xD;
      patients will give inform consent signature before entering one year study and will evaluate&#xD;
      in the Retina Section of Department of Ophthalmology, School of Medicine of Ribeirao Preto of&#xD;
      the University of Sao Paulo with center-involved DME in at least 1 eye. Recruiting phase will&#xD;
      be consider the first 6 months. All patients with diagnostic of DME in at least 1 eye from&#xD;
      July 2016 to December 2016 will invite to participate in the study.&#xD;
&#xD;
      Study Population. Inclusion criteria. Inclusion criteria are as follows: (1) Eligible&#xD;
      participants are age 18 years old with diabetes mellitus (type 1 or 2); (2) center-involved&#xD;
      DME, defined as a central subfield thickness &gt;300 µm on spectral domain optical coherence&#xD;
      tomography (SD-OCT), despite of macular laser photocoagulation, cataract surgery and&#xD;
      intraocular injection performed at least 4 months previously; (3) best-corrected ETDRS visual&#xD;
      acuity (BCVA) measurement between 0.3 logMAR (Snellen equivalent: 20/32) and 1.3 logMAR&#xD;
      (Snellen equivalent: 20/400); (4) signed informed consent. Exclusion criteria. Exclusion&#xD;
      criteria were: (1) vitreo-macular traction on SD-OCT; (2) proliferative diabetic retinopathy&#xD;
      needing panretinal photocoagulation (PRP) or anticipated to need PRP in the next 12 months;&#xD;
      (3) macular capillary dropout on fluorescein angiography; (4) history of glaucoma or ocular&#xD;
      hypertension (defined as an intraocular pressure higher than 25 mm Hg); (5) an ocular&#xD;
      condition (other than diabetes) that, in the opinion of the investigator, might affect&#xD;
      macular edema or alter visual acuity during the course of the study (eg, retinal vein&#xD;
      occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc); (6)&#xD;
      systemic corticosteroid therapy; (7) any condition that, in the opinion of the investigator,&#xD;
      might preclude follow-up throughout the study period; (8) Recent (within 3 months)&#xD;
      thromboembolic events including acute myocardial infarction (MI) and cerebrovascular accident&#xD;
      (CVA); (9) Other Clinical trial participation in the last 30 days.&#xD;
&#xD;
      Randomization and Intervention. After eligibility phase, subjects with center-involving DME&#xD;
      will enroll and undergo comprehensive ophthalmologic evaluation at baseline and every 4 weeks&#xD;
      up to week 48. Patients will receive monthly prn 1.25 mg (0.05 cc) IVB throughout 24 weeks if&#xD;
      central subfield thickness (CSFT) will great than 300 µm. At week 24, patients who has&#xD;
      recurrent or persistent edema (CSFT&gt;300) will randomize 1:1 to Group 1 (prn IVB therapy) or&#xD;
      Group 2 (quarterly IVT therapy). Randomization will be do from binomial distribution with&#xD;
      parameters that it enters as function arguments. Patients with no recurrent or persistent&#xD;
      edema (CSFT≤300µm) at 24-week will comprise to Group 3 and continue receiving prn IVB&#xD;
      therapy. If patient have edema in both eyes and the patient agree to treat both eyes, 1 eye&#xD;
      will receive the random treatment according to a computer-generate sequence and the&#xD;
      contralateral eye will receive the other therapy option on the next day; thus if an eye was&#xD;
      randomized to the IVB group I, the contralateral eye will allocate to the IVT group II and&#xD;
      the reverse will also true.&#xD;
&#xD;
      Examination Procedures and follow-up. Each patient will receive a detailed ophthalmologic&#xD;
      examination including measurement of BCVA according to the standardized ETDRS refraction&#xD;
      protocol using a retroilluminate Lighthouse for the Blind distance visual acuity test chart&#xD;
      (using modified ETDRS charts 1, 2, and R; Precision Vision, IL), as well as applanation&#xD;
      tonometry, slit-lamp biomicroscopic examination, indirect fundus examination, and fluorescein&#xD;
      angiography using high-resolution angiography (HRA; Heidelberg Engineering, Heidelberg,&#xD;
      Germany). SD-OCT evaluation (HRA-OCT; Heidelberg Engineering) will be performe in all&#xD;
      patients, and retinal thickness measurements will be acquire using a standard 20, 15-degree&#xD;
      raster scan protocol. CSFT values will be calculate automatically as the average thickness of&#xD;
      a central macular region 1000 mm in diameter centered on the patient's foveola by built-in&#xD;
      Heidelberg software using retinal map analysis. Patients will schedule for follow-up&#xD;
      examinations at monthly intervals. At these visits the BCVA will be determined after ETDRS&#xD;
      refraction and complete ophthalmic examination similar to baseline valuations with the&#xD;
      exception of fluorescein angiography schedule at baseline and week 36.&#xD;
&#xD;
      Antiglaucomatous eyedrops criteria. Intraocular pressure (IOP) ≥ 25 mmHg and/or 10mmHg&#xD;
      increased from baseline measurement will be adopt to initiate anti-glaucomatous eyedrops.&#xD;
&#xD;
      Intravitreal Injection. All injections will be were performed using topical proparacaine&#xD;
      drops under sterile conditions (eyelid speculum and povidone-iodine). Topical antibiotics&#xD;
      will not use before the day of injection. Before the injection are perform, the eyelids will&#xD;
      scrubb with 10% povidone-iodine, and 5% povidone-iodine drops will be apply to the&#xD;
      conjunctiva. The time between application of 5% povidone-iodine solution to the conjunctiva&#xD;
      and administration of the intravitreal injection will be 2 minutes. Povidone-iodine will be&#xD;
      was apply to the conjunctiva directly over the intended injection site. Care will be take in&#xD;
      all cases to insure that the needle do not touch the lids or lashes. Bevacizumab (1.25&#xD;
      mg/0.05 cc; F. Hoffmann- La Roche Ltd., Basel, Switzerland) or Triamcinolone (1.20 mg/ 0.03&#xD;
      cc; Opthaac, Ophthalmos, São Paulo, Brazil) will be inject into the vitreous cavity using a&#xD;
      29-gauge 0.5- inch needle insert through the superotemporal pars plana 3.0-3.5 mm posterior&#xD;
      to the limbus.25 After the injection, central retinal artery perfusion will be confirm with&#xD;
      indirect ophthalmoscopy. Patients will instruct to instill 1 drop of 0.3% ciprofloxacin into&#xD;
      the inject eye 4 times daily for 1 week after the procedure.&#xD;
&#xD;
      Retreatment Protocol. Retreatment with the originally assign treatment is perform monthly if&#xD;
      central subfield thickness is great than 300 µm.&#xD;
&#xD;
      Rescue Therapy. Before randomization, all patients will receive prn-IVB and if, after 3&#xD;
      consecutive visits, there will be not a reduction in CST of at least 10% or an increase in&#xD;
      BCVA of at least 5 ETDRS letters score when compare with baseline, the patient can continue&#xD;
      with the same intravitreal medication for an additional 3 consecutive visits or discontinue&#xD;
      treatment. After randomization, a similar strategy is used as rescue therapy for all 3&#xD;
      groups.&#xD;
&#xD;
      Outcomes. Primary outcome measure: Mean change in CSFT from baseline to week 48. Secondary&#xD;
      outcomes measures: Mean change in BCVA from baseline to week 48; mean change in IOP at any&#xD;
      visit; lens status changes, mean number of intravitreous injections Sample Size. Sample size&#xD;
      and powering is base on a previous clinical trial on bevacizumab use for diabetic macular&#xD;
      edema, where a mean change observed in central subfield thickness from baseline was 130 mm&#xD;
      with a standard deviation of 122 μm. Therefore, to have 80% power to detect a difference of&#xD;
      50 μm between central subfield thickness change found in both groups, the sample size require&#xD;
      in each group was 25 eyes. Thirty eyes per treatment group is require if one assume a 10%&#xD;
      dropout rate. With this sample size, there is a 20% chance for a failure to detect a true&#xD;
      mean difference of at least 50 μm between the treatment groups (type I error), or for an&#xD;
      incorrect conclusion that a difference of at least 50 μm exists between the treatment groups&#xD;
      (type II error).&#xD;
&#xD;
      Statistical Analysis. BCVA and central subfield thickness measured at each follow-up visit&#xD;
      will be compare with baseline BCVA and CSFT values for within- and between-group comparisons,&#xD;
      which is perform using multiple analysis of variance (MANOVA) for repeated measurements.&#xD;
      Proportions of eyes with central subfield thickness ≤ 300 mm is compare using the likelihood&#xD;
      ratio x2 test. In addition, a multivariate analysis comparing BCVA and CSFT outcomes in the&#xD;
      prn-IVB group and qIVT group is perform, considering number of injections, baseline BCVA, and&#xD;
      CSFT as effects. A statistically significant effect is define if P &lt; .05, and a trend towards&#xD;
      significance is report if P &lt; .1. Statistical analyses are performe using JMP 10.0.0 (2010;&#xD;
      SAS Institute Inc, Cary, North Carolina, USA) software.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 21, 2016</start_date>
  <completion_date type="Actual">December 21, 2017</completion_date>
  <primary_completion_date type="Actual">April 14, 2017</primary_completion_date>
  <phase>Phase 2/Phase 3</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>OCT measurements</measure>
    <time_frame>6 months.</time_frame>
    <description>Optical Coherence Tomography measurements in the central subfield thickness between baseline and 6 months 1st endpoint.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">100</enrollment>
  <condition>Diabetic Macular Edema</condition>
  <arm_group>
    <arm_group_label>IVB randomised group I</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Randomised patients [intravitreal bevacizumab (IVB) group I] with central foveal thickness &gt;300µm on OCT will be submitted to 6 months treatment with 0.05ml (1.25mg) intravitreous injection of Bevacizumabe &quot;prn&quot; (pro re nata, or as needed), with monthly visits for central subfoveal thickness map more than 300µm by Optic Coherence Tomography. Care will be take in all cases to insure that the needle do not touch the lids or lashes. Bevacizumab (1.25 mg/0.05 cc; F. Hoffmann- La Roche Ltd., Basel, Switzerland) will be inject into the vitreous cavity using a 29-gauge 0.5- inch needle insert through the superotemporal pars plana 3.0-3.5 mm posterior to the limbus.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IVT randomised group II</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Randomised patients [intravitreal triamcinolone (IVT) group II] with central foveal thickness &gt;300µm on OCT will be submitted to 6 months treatment with 0.03ml (1.20mg) intravitreous injection of triamcinolone each 3 months (prn, as needed) for central sufoveal thickness map more than 300µm by Optic Coherence Tomography. Care will be take in all cases to insure that the needle do not touch the lids or lashes. Triamcinolone (1.20 mg/ 0.03 cc; Opthaac, Ophthalmos, São Paulo, Brazil) will be inject into the vitreous cavity using a 29-gauge 0.5- inch needle insert through the superotemporal pars plana 3.0-3.5 mm posterior to the limbus.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IVB group III (not randomised)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with central foveal thickness ≤300µm at week visit 24 will be allocated to group III (IVB, intravitreal bevacizumab). So, it won't get IVB injection at week visit 24 due OCT regular thickness (≤300µm) but will do regular monthly follow-up visits and prn-IVB therapy if central foveal thickness &gt;300µm on OCT until last visit of study (48 week-visit). Care will be take in all cases to insure that the needle do not touch the lids or lashes. Bevacizumab (1.25 mg/0.05 cc; F. Hoffmann- La Roche Ltd., Basel, Switzerland) will be inject into the vitreous cavity using a 29-gauge 0.5- inch needle insert through the superotemporal pars plana 3.0-3.5 mm posterior to the limbus.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab Injection [Avastin] (IVB-I)</intervention_name>
    <description>0,05ml intravitreal injection</description>
    <arm_group_label>IVB randomised group I</arm_group_label>
    <other_name>Avastin®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Triamcinolone Acetonide 10mg/mL (IVT-II)</intervention_name>
    <description>0,03ml intravitreal injection</description>
    <arm_group_label>IVT randomised group II</arm_group_label>
    <other_name>OPTHTAAC®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab Injection [Avastin] (IVB-III)</intervention_name>
    <description>0,05ml intravitreal injection</description>
    <arm_group_label>IVB group III (not randomised)</arm_group_label>
    <other_name>Avastin®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diabetic macular edema with &gt;300µm on central subfield macular thickness by OCT;&#xD;
&#xD;
          -  Best corrected vision acuity minimum: 20/32 to 20/320;&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Vitreomacular traction;&#xD;
&#xD;
          -  Macular ischemia;&#xD;
&#xD;
          -  Laser or injection therapy before 3 months to assign the protocol.\&#xD;
&#xD;
          -  Pregnancy;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>December 1, 2016</study_first_submitted>
  <study_first_submitted_qc>December 3, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 7, 2016</study_first_posted>
  <disposition_first_submitted>March 24, 2020</disposition_first_submitted>
  <disposition_first_submitted_qc>May 4, 2021</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">May 7, 2021</disposition_first_posted>
  <last_update_submitted>May 24, 2022</last_update_submitted>
  <last_update_submitted_qc>May 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Sao Paulo</investigator_affiliation>
    <investigator_full_name>Murilo Wendeborn Rodrigues Junior</investigator_full_name>
    <investigator_title>USP Ribeirao Preto</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Edema</mesh_term>
    <mesh_term>Edema</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Triamcinolone</mesh_term>
    <mesh_term>Triamcinolone Acetonide</mesh_term>
    <mesh_term>Triamcinolone hexacetonide</mesh_term>
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Triamcinolone diacetate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 29, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/19/NCT02985619/Prot_SAP_ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT02985619
org study id: 1.599.864
nct id: NCT02985619
lead sponsor: 
has dmc: Yes
Background: Diabetic macular edema (DME) shows a sustained functional and morphologic
      response to anti-vascular endothelial growth factor (VEGF) drugs, but the optimal approach
      for persistent macular edema still in debate.

      Purpose: To evaluate 24-week visual and anatomical effects of intravitreal bevacizumabe or
      triamcinolone in patients who have residual edema after 24-weeks to "pro re nata"(prn)
      intravitreal bevacizumabe therapy.

      Methods: This study will enroll a total of 100 DME eyes. Each patient will receive "prn"
      bevacizumabe therapy throughout 24 weeks. At week 24, patients who have recurrent or
      persistent edema were randomized 1:1 to Group 1 (prn bevacizumane) or Group 2 (prn
      triamcinolone). Patients with no recurrent or persistent edema at week 24 will comprise to
      Group 3 and continue receive prn bevacizumabe. Prn treatment was administered when central
      subfield thickness of the macula (CST) > 300 µm and/or there are intraretinal cystoid spaces
      in the fovea. Study visits will occur every 4 weeks with the endpoint at week 48. At each
      visit, patients will have an eye exam and CST, best-corrected visual acuity (BCVA), and
      intraocular pressure (IOP) were assessed. Fundus photography and fluorescein angiography will
      also perform at baseline, week 16, week 40, and week 48. All patients will resume standard
      care after exiting.
Methods Study Design. The current study is a prospective randomized clinical trial registered
      at ClinicalTrials.gov (NCT02985619). The study protocol adhered to the tenets of the
      Declaration of Helsinki and was approved by the local Institutional Review Board, research
      ethics committee of School of Medicine of Ribeirão Preto at University of Sao Paulo. All
      patients will give inform consent signature before entering one year study and will evaluate
      in the Retina Section of Department of Ophthalmology, School of Medicine of Ribeirao Preto of
      the University of Sao Paulo with center-involved DME in at least 1 eye. Recruiting phase will
      be consider the first 6 months. All patients with diagnostic of DME in at least 1 eye from
      July 2016 to December 2016 will invite to participate in the study.

      Study Population. Inclusion criteria. Inclusion criteria are as follows: (1) Eligible
      participants are age 18 years old with diabetes mellitus (type 1 or 2); (2) center-involved
      DME, defined as a central subfield thickness >300 µm on spectral domain optical coherence
      tomography (SD-OCT), despite of macular laser photocoagulation, cataract surgery and
      intraocular injection performed at least 4 months previously; (3) best-corrected ETDRS visual
      acuity (BCVA) measurement between 0.3 logMAR (Snellen equivalent: 20/32) and 1.3 logMAR
      (Snellen equivalent: 20/400); (4) signed informed consent. Exclusion criteria. Exclusion
      criteria were: (1) vitreo-macular traction on SD-OCT; (2) proliferative diabetic retinopathy
      needing panretinal photocoagulation (PRP) or anticipated to need PRP in the next 12 months;
      (3) macular capillary dropout on fluorescein angiography; (4) history of glaucoma or ocular
      hypertension (defined as an intraocular pressure higher than 25 mm Hg); (5) an ocular
      condition (other than diabetes) that, in the opinion of the investigator, might affect
      macular edema or alter visual acuity during the course of the study (eg, retinal vein
      occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc); (6)
      systemic corticosteroid therapy; (7) any condition that, in the opinion of the investigator,
      might preclude follow-up throughout the study period; (8) Recent (within 3 months)
      thromboembolic events including acute myocardial infarction (MI) and cerebrovascular accident
      (CVA); (9) Other Clinical trial participation in the last 30 days.

      Randomization and Intervention. After eligibility phase, subjects with center-involving DME
      will enroll and undergo comprehensive ophthalmologic evaluation at baseline and every 4 weeks
      up to week 48. Patients will receive monthly prn 1.25 mg (0.05 cc) IVB throughout 24 weeks if
      central subfield thickness (CSFT) will great than 300 µm. At week 24, patients who has
      recurrent or persistent edema (CSFT>300) will randomize 1:1 to Group 1 (prn IVB therapy) or
      Group 2 (quarterly IVT therapy). Randomization will be do from binomial distribution with
      parameters that it enters as function arguments. Patients with no recurrent or persistent
      edema (CSFT≤300µm) at 24-week will comprise to Group 3 and continue receiving prn IVB
      therapy. If patient have edema in both eyes and the patient agree to treat both eyes, 1 eye
      will receive the random treatment according to a computer-generate sequence and the
      contralateral eye will receive the other therapy option on the next day; thus if an eye was
      randomized to the IVB group I, the contralateral eye will allocate to the IVT group II and
      the reverse will also true.

      Examination Procedures and follow-up. Each patient will receive a detailed ophthalmologic
      examination including measurement of BCVA according to the standardized ETDRS refraction
      protocol using a retroilluminate Lighthouse for the Blind distance visual acuity test chart
      (using modified ETDRS charts 1, 2, and R; Precision Vision, IL), as well as applanation
      tonometry, slit-lamp biomicroscopic examination, indirect fundus examination, and fluorescein
      angiography using high-resolution angiography (HRA; Heidelberg Engineering, Heidelberg,
      Germany). SD-OCT evaluation (HRA-OCT; Heidelberg Engineering) will be performe in all
      patients, and retinal thickness measurements will be acquire using a standard 20, 15-degree
      raster scan protocol. CSFT values will be calculate automatically as the average thickness of
      a central macular region 1000 mm in diameter centered on the patient's foveola by built-in
      Heidelberg software using retinal map analysis. Patients will schedule for follow-up
      examinations at monthly intervals. At these visits the BCVA will be determined after ETDRS
      refraction and complete ophthalmic examination similar to baseline valuations with the
      exception of fluorescein angiography schedule at baseline and week 36.

      Antiglaucomatous eyedrops criteria. Intraocular pressure (IOP) ≥ 25 mmHg and/or 10mmHg
      increased from baseline measurement will be adopt to initiate anti-glaucomatous eyedrops.

      Intravitreal Injection. All injections will be were performed using topical proparacaine
      drops under sterile conditions (eyelid speculum and povidone-iodine). Topical antibiotics
      will not use before the day of injection. Before the injection are perform, the eyelids will
      scrubb with 10% povidone-iodine, and 5% povidone-iodine drops will be apply to the
      conjunctiva. The time between application of 5% povidone-iodine solution to the conjunctiva
      and administration of the intravitreal injection will be 2 minutes. Povidone-iodine will be
      was apply to the conjunctiva directly over the intended injection site. Care will be take in
      all cases to insure that the needle do not touch the lids or lashes. Bevacizumab (1.25
      mg/0.05 cc; F. Hoffmann- La Roche Ltd., Basel, Switzerland) or Triamcinolone (1.20 mg/ 0.03
      cc; Opthaac, Ophthalmos, São Paulo, Brazil) will be inject into the vitreous cavity using a
      29-gauge 0.5- inch needle insert through the superotemporal pars plana 3.0-3.5 mm posterior
      to the limbus.25 After the injection, central retinal artery perfusion will be confirm with
      indirect ophthalmoscopy. Patients will instruct to instill 1 drop of 0.3% ciprofloxacin into
      the inject eye 4 times daily for 1 week after the procedure.

      Retreatment Protocol. Retreatment with the originally assign treatment is perform monthly if
      central subfield thickness is great than 300 µm.

      Rescue Therapy. Before randomization, all patients will receive prn-IVB and if, after 3
      consecutive visits, there will be not a reduction in CST of at least 10% or an increase in
      BCVA of at least 5 ETDRS letters score when compare with baseline, the patient can continue
      with the same intravitreal medication for an additional 3 consecutive visits or discontinue
      treatment. After randomization, a similar strategy is used as rescue therapy for all 3
      groups.

      Outcomes. Primary outcome measure: Mean change in CSFT from baseline to week 48. Secondary
      outcomes measures: Mean change in BCVA from baseline to week 48; mean change in IOP at any
      visit; lens status changes, mean number of intravitreous injections Sample Size. Sample size
      and powering is base on a previous clinical trial on bevacizumab use for diabetic macular
      edema, where a mean change observed in central subfield thickness from baseline was 130 mm
      with a standard deviation of 122 μm. Therefore, to have 80% power to detect a difference of
      50 μm between central subfield thickness change found in both groups, the sample size require
      in each group was 25 eyes. Thirty eyes per treatment group is require if one assume a 10%
      dropout rate. With this sample size, there is a 20% chance for a failure to detect a true
      mean difference of at least 50 μm between the treatment groups (type I error), or for an
      incorrect conclusion that a difference of at least 50 μm exists between the treatment groups
      (type II error).

      Statistical Analysis. BCVA and central subfield thickness measured at each follow-up visit
      will be compare with baseline BCVA and CSFT values for within- and between-group comparisons,
      which is perform using multiple analysis of variance (MANOVA) for repeated measurements.
      Proportions of eyes with central subfield thickness ≤ 300 mm is compare using the likelihood
      ratio x2 test. In addition, a multivariate analysis comparing BCVA and CSFT outcomes in the
      prn-IVB group and qIVT group is perform, considering number of injections, baseline BCVA, and
      CSFT as effects. A statistically significant effect is define if P < .05, and a trend towards
      significance is report if P < .1. Statistical analyses are performe using JMP 10.0.0 (2010;
      SAS Institute Inc, Cary, North Carolina, USA) software.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: OCT measurements
time frame: 6 months.
description: Optical Coherence Tomography measurements in the central subfield thickness between baseline and 6 months 1st endpoint.
arm group label: IVB randomised group I
arm group type: Active Comparator
description: Randomised patients [intravitreal bevacizumab (IVB) group I] with central foveal thickness >300µm on OCT will be submitted to 6 months treatment with 0.05ml (1.25mg) intravitreous injection of Bevacizumabe "prn" (pro re nata, or as needed), with monthly visits for central subfoveal thickness map more than 300µm by Optic Coherence Tomography. Care will be take in all cases to insure that the needle do not touch the lids or lashes. Bevacizumab (1.25 mg/0.05 cc; F. Hoffmann- La Roche Ltd., Basel, Switzerland) will be inject into the vitreous cavity using a 29-gauge 0.5- inch needle insert through the superotemporal pars plana 3.0-3.5 mm posterior to the limbus.
arm group label: IVT randomised group II
arm group type: Active Comparator
description: Randomised patients [intravitreal triamcinolone (IVT) group II] with central foveal thickness >300µm on OCT will be submitted to 6 months treatment with 0.03ml (1.20mg) intravitreous injection of triamcinolone each 3 months (prn, as needed) for central sufoveal thickness map more than 300µm by Optic Coherence Tomography. Care will be take in all cases to insure that the needle do not touch the lids or lashes. Triamcinolone (1.20 mg/ 0.03 cc; Opthaac, Ophthalmos, São Paulo, Brazil) will be inject into the vitreous cavity using a 29-gauge 0.5- inch needle insert through the superotemporal pars plana 3.0-3.5 mm posterior to the limbus.
arm group label: IVB group III (not randomised)
arm group type: Active Comparator
description: Patients with central foveal thickness ≤300µm at week visit 24 will be allocated to group III (IVB, intravitreal bevacizumab). So, it won't get IVB injection at week visit 24 due OCT regular thickness (≤300µm) but will do regular monthly follow-up visits and prn-IVB therapy if central foveal thickness >300µm on OCT until last visit of study (48 week-visit). Care will be take in all cases to insure that the needle do not touch the lids or lashes. Bevacizumab (1.25 mg/0.05 cc; F. Hoffmann- La Roche Ltd., Basel, Switzerland) will be inject into the vitreous cavity using a 29-gauge 0.5- inch needle insert through the superotemporal pars plana 3.0-3.5 mm posterior to the limbus.
intervention type: Drug
intervention name: Bevacizumab Injection [Avastin] (IVB-I)
description: 0,05ml intravitreal injection
arm group label: IVB randomised group I
other name: Avastin®
intervention type: Drug
intervention name: Triamcinolone Acetonide 10mg/mL (IVT-II)
description: 0,03ml intravitreal injection
arm group label: IVT randomised group II
other name: OPTHTAAC®
intervention type: Drug
intervention name: Bevacizumab Injection [Avastin] (IVB-III)
description: 0,05ml intravitreal injection
arm group label: IVB group III (not randomised)
other name: Avastin®
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Principal Investigator
investigator affiliation: University of Sao Paulo
investigator full name: Murilo Wendeborn Rodrigues Junior
investigator title: USP Ribeirao Preto
mesh term: Macular Edema
mesh term: Edema
mesh term: Triamcinolone
mesh term: Triamcinolone Acetonide
mesh term: Triamcinolone hexacetonide
mesh term: Bevacizumab
mesh term: Triamcinolone diacetate
sharing ipd: No
provided document: 