<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/NCT04504123</url>
  </required_header>
  <id_info>
    <org_study_id>202001041</org_study_id>
    <nct_id>NCT04504123</nct_id>
  </id_info>
  <brief_title>MMP-9 Inhibition for Recalcitrant Wet AMD</brief_title>
  <official_title>MMP-9 Inhibition for Recalcitrant Wet Age-Related Macular Degeneration (AMD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Iowa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Iowa</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Wet (or neovascular) form of age-related macular degeneration (wAMD) is the most common cause&#xD;
      of blindness in the Western world. Currently, anti-vascular endothelial growth factor (VEGF)&#xD;
      intravitreal injections (IVI) remain the standard-of-care treatment for wAMD. Previous&#xD;
      studies show that about 90% of treated patients lose minimal visual function after 2 years of&#xD;
      follow-up. There is still, a subset of 15% patients, incomplete responders, that do not&#xD;
      improve and possibly worsen due to the persistence of sub-retinal fluid (with or without&#xD;
      intra-retinal fluid) with chronic treatment.&#xD;
&#xD;
      The investigators plan to evaluate the effect of oral doxycycline versus placebo on the&#xD;
      anatomic and functional outcomes in persistent sub-retinal eye fluid in neovascular wet&#xD;
      age-related macular degeneration. This subset are incomplete or non-responders to current&#xD;
      anti-VEGF intravitreal therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators plan to conduct a double masked, randomized study to assess the effect of&#xD;
      low dose, oral doxycycline 50 mg once a day versus placebo in patients with wet age-related&#xD;
      macular degeneration who are incomplete responders to anti-VEGF extended treatment regimens.&#xD;
&#xD;
      The study will be conducted over 9 months with every 3 month assessments; 6 months&#xD;
      administration period of doxycycline versus placebo (double masked, randomized) and a 3 month&#xD;
      follow up period. The participant visits will occur during clinic visits for standard-of-care&#xD;
      intravitreal injections (IVI).&#xD;
&#xD;
      Medical information will be acquired from the standard of care optical coherence tomography&#xD;
      (OCT), visual acuity (VA), and IVI administered (number, frequency and type of drug).&#xD;
&#xD;
      Blood plasma and aqueous fluid (anterior chamber tap) samples and study drug tolerability&#xD;
      will be obtained at baseline, 6 months and 9 months. Plasma will be obtained to assay for&#xD;
      inflammatory markers: MMP-9 levels and questionnaires will be obtained on 1) vision quality&#xD;
      of life, and 2) study drug tolerance at Baseline, 6 months and 9 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 4, 2020</start_date>
  <completion_date type="Anticipated">March 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</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>
    <intervention_model_description>Doxycycline Hyclate 50 mg versus placebo capsule</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Over encapsulation with opaque purple capsule</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Resolution of the persistent retinal fluid on optical coherence tomography (OCT)</measure>
    <time_frame>9 months</time_frame>
    <description>percentage of patients with retinal fluid-free status</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in optical coherence tomography (OCT) central media thickness (CMT)</measure>
    <time_frame>9 months compared to baseline</time_frame>
    <description>mean change in central media thickness</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in best corrected visual acuity (BCVA)</measure>
    <time_frame>6 months and 9 months compared to Baseline</time_frame>
    <description>mean change in logMAR / percentage of patients with a gain or loss of more than 5 ETDRS letters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of intravitreal injections (IVI) administered</measure>
    <time_frame>6 months and 9 months</time_frame>
    <description>total number of anti-VEGF intravitreal injections</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory mediators matrix metalloproteinases MMP-9 and MMP-9 activity</measure>
    <time_frame>Baseline, 6 months and 9 months</time_frame>
    <description>anterior eye aqueous fluid and blood plasma</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Ocular Adverse Events</measure>
    <time_frame>Baseline to 9 months</time_frame>
    <description>intra-ocular pressure elevation ( more than 10 mmHg) requiring topical ocular hypertensive medications, endophthalmitis, retinal tear and detachment, uveitis, and thromboembolic events will be recorded</description>
  </other_outcome>
  <other_outcome>
    <measure>Systemic Adverse Events</measure>
    <time_frame>Baseline to 9 months</time_frame>
    <description>Allergy or hypersensitivity drug reactions</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Exudative Macular Degeneration</condition>
  <condition>Wet Age-related Macular Degeneration</condition>
  <arm_group>
    <arm_group_label>Doxycycline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received doxycycline hyclate 50 mg capsule orally once a day for 6 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants received placebo (inactive) capsule orally once a day for 6 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxycycline Hyclate</intervention_name>
    <description>Doxycycline Hyclate capsules, USP 50 mg</description>
    <arm_group_label>Doxycycline</arm_group_label>
    <other_name>Antibiotic - tetracycline compound</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Inactive substance</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Wet age-related macular degeneration (wAMD);&#xD;
&#xD;
          -  Solely treated with anti-VEGF IVI for active CNV due to wAMD. However, enrolled&#xD;
             patients can have other retinal pathologies such as diabetic retinopathy or vein&#xD;
             occlusion for which they are not being treated with anti-VEGF IVI;&#xD;
&#xD;
          -  Must have persistent sub-retinal with or without intra-retinal fluid due to active CNV&#xD;
             from wAMD despite receiving at least three consecutive injections with any anti-VEGF&#xD;
             agent;&#xD;
&#xD;
          -  Must not have encountered previous side effects from tetracycline medications.&#xD;
&#xD;
        Exclusion Criteria - Ocular:&#xD;
&#xD;
          -  History of uveitis (including endophthalmitis) or presence of intraocular&#xD;
             inflammation;&#xD;
&#xD;
          -  Presence of significant epiretinal membrane or macular hole causing distortion of&#xD;
             macular anatomy;&#xD;
&#xD;
          -  Presence of media opacity preventing discerning of fluid on OCT;&#xD;
&#xD;
          -  Any prior ophthalmic surgery (including YAG or retinal laser) within the previous 3&#xD;
             months or anticipated need for any ophthalmic surgery (including cataract extraction)&#xD;
             for 9 months following randomization;&#xD;
&#xD;
          -  History of peribulbar corticosteroid injection to the studied eye or the fellow eye&#xD;
             within the past 6 months;&#xD;
&#xD;
          -  History of intravitreal triamcinolone acetonide injection to the studied eye within&#xD;
             the past 4 months;&#xD;
&#xD;
          -  An ocular condition (other than AMD) is present in the studied eye that, in the&#xD;
             opinion of the investigator, might alter visual acuity during the course of the study&#xD;
             (e.g., retinal vein occlusion, uveitis or other ocular inflammatory disease,&#xD;
             neovascular glaucoma, and Irvine-Gass syndrome);&#xD;
&#xD;
          -  CNV due to causes other than wAMD;&#xD;
&#xD;
          -  Inability to follow up at the 6th and 9th months time points after recruitment;&#xD;
&#xD;
          -  Missing two or more consecutive injections during the six months treatment period;&#xD;
&#xD;
          -  Patient requiring imminent need for IVI anti-VEGF medication switch or another&#xD;
             treatment intervention, such as photodynamic therapy, during the 9 months trial&#xD;
             period;&#xD;
&#xD;
          -  Presence of fluid associated with geographic atrophy or disciform scar;&#xD;
&#xD;
          -  Any patient with sub-retinal and/or intra-retinal fluid that is not due to CNV (eg,&#xD;
             overlying areas of geographic atrophy;&#xD;
&#xD;
          -  Any patient actively being actively treated for Irvine-Gass Syndrome.&#xD;
&#xD;
        Exclusion Criteria - Systemic:&#xD;
&#xD;
          -  Patient with and/or who developed an unstable medical status (e.g., glycemic control,&#xD;
             blood pressure, cardiovascular disease, individuals who are unlikely or unable to&#xD;
             complete the 9 months trial period) in the opinion of the investigator;&#xD;
&#xD;
          -  Significant renal disease (defined as a serum creatinine &gt;2.5 mg/dL);&#xD;
&#xD;
          -  Systolic blood pressure &gt;180 mm Hg or diastolic blood pressure &gt;110 mm Hg;&#xD;
&#xD;
          -  History of headaches associated with tetracycline therapy&#xD;
&#xD;
          -  History of pseudotumor cerebri;&#xD;
&#xD;
          -  History of tetracycline therapy within the past 6 months;&#xD;
&#xD;
          -  Pregnancy or patient intending to become pregnant within the 9 months of the trial&#xD;
             period. For women of child-bearing potential, a pregnancy test will be performed;&#xD;
&#xD;
          -  Sexually active women of child-bearing potential not actively practicing birth control&#xD;
             by using a medically accepted device or therapy (i.e., intrauterine device, hormonal&#xD;
             contraceptive, or barrier device) during the study period (at least 24 months). This&#xD;
             is important as doxycycline may interfere with the effectiveness of hormonal&#xD;
             contraceptives. Hence, sexually active women of child-bearing potential who use a&#xD;
             hormonal contraceptive will be required to use a second form of contraception to&#xD;
             safeguard against contraceptive failure while participating in the study;&#xD;
&#xD;
          -  Known allergy/intolerance to doxycycline, tetracyclines, or any ingredient in the&#xD;
             study drug or placebo;&#xD;
&#xD;
          -  Patients receiving phenytoin, barbiturates, carbamazepine, digoxin, or isotretinoin;&#xD;
             patients with gastroparesis; patients with a history of gastrectomy, gastric bypass&#xD;
             surgery, or otherwise deemed achlorhydric should all be excluded due to altered&#xD;
             doxycycline pharmacokinetics and/or bioavailability;&#xD;
&#xD;
          -  Patients taking strontium, acitretin, or tretinoin should excluded due to the&#xD;
             potential for serious interactions with doxycycline;&#xD;
&#xD;
          -  Patients with abnormal ALT or AST at baseline will be referred to their primary care&#xD;
             physician for medical clearance for participation in this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elliott H Sohn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Iowa</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Elliott H Sohn, MD</last_name>
    <phone>3193563285</phone>
    <email>elliott-sohn@uiowa.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Iowa Hospitals &amp; Clinics Department of Ophthalmology &amp; Visual Sciences</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christine A Sinkey, BSN, CCRC</last_name>
      <phone>319-353-8723</phone>
      <email>christine-sinkey@uiowa.edu</email>
    </contact>
    <investigator>
      <last_name>Elliott H Sohn, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>March 2023</verification_date>
  <study_first_submitted>August 4, 2020</study_first_submitted>
  <study_first_submitted_qc>August 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2020</study_first_posted>
  <last_update_submitted>March 3, 2023</last_update_submitted>
  <last_update_submitted_qc>March 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Iowa</investigator_affiliation>
    <investigator_full_name>Elliott Sohn</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Active choroidal neovascularization (CNV)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Degeneration</mesh_term>
    <mesh_term>Wet Macular Degeneration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anti-Bacterial Agents</mesh_term>
    <mesh_term>Doxycycline</mesh_term>
    <mesh_term>Tetracycline</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>The investigators do not plan to share the data with other researchers</ipd_description>
  </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/NCT04504123
org study id: 202001041
nct id: NCT04504123
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Wet (or neovascular) form of age-related macular degeneration (wAMD) is the most common cause
      of blindness in the Western world. Currently, anti-vascular endothelial growth factor (VEGF)
      intravitreal injections (IVI) remain the standard-of-care treatment for wAMD. Previous
      studies show that about 90% of treated patients lose minimal visual function after 2 years of
      follow-up. There is still, a subset of 15% patients, incomplete responders, that do not
      improve and possibly worsen due to the persistence of sub-retinal fluid (with or without
      intra-retinal fluid) with chronic treatment.

      The investigators plan to evaluate the effect of oral doxycycline versus placebo on the
      anatomic and functional outcomes in persistent sub-retinal eye fluid in neovascular wet
      age-related macular degeneration. This subset are incomplete or non-responders to current
      anti-VEGF intravitreal therapy.
The investigators plan to conduct a double masked, randomized study to assess the effect of
      low dose, oral doxycycline 50 mg once a day versus placebo in patients with wet age-related
      macular degeneration who are incomplete responders to anti-VEGF extended treatment regimens.

      The study will be conducted over 9 months with every 3 month assessments; 6 months
      administration period of doxycycline versus placebo (double masked, randomized) and a 3 month
      follow up period. The participant visits will occur during clinic visits for standard-of-care
      intravitreal injections (IVI).

      Medical information will be acquired from the standard of care optical coherence tomography
      (OCT), visual acuity (VA), and IVI administered (number, frequency and type of drug).

      Blood plasma and aqueous fluid (anterior chamber tap) samples and study drug tolerability
      will be obtained at baseline, 6 months and 9 months. Plasma will be obtained to assay for
      inflammatory markers: MMP-9 levels and questionnaires will be obtained on 1) vision quality
      of life, and 2) study drug tolerance at Baseline, 6 months and 9 months.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Doxycycline Hyclate 50 mg versus placebo capsule
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Over encapsulation with opaque purple capsule
measure: Resolution of the persistent retinal fluid on optical coherence tomography (OCT)
time frame: 9 months
description: percentage of patients with retinal fluid-free status
measure: Change in optical coherence tomography (OCT) central media thickness (CMT)
time frame: 9 months compared to baseline
description: mean change in central media thickness
measure: Change in best corrected visual acuity (BCVA)
time frame: 6 months and 9 months compared to Baseline
description: mean change in logMAR / percentage of patients with a gain or loss of more than 5 ETDRS letters
measure: Number of intravitreal injections (IVI) administered
time frame: 6 months and 9 months
description: total number of anti-VEGF intravitreal injections
measure: Inflammatory mediators matrix metalloproteinases MMP-9 and MMP-9 activity
time frame: Baseline, 6 months and 9 months
description: anterior eye aqueous fluid and blood plasma
measure: Ocular Adverse Events
time frame: Baseline to 9 months
description: intra-ocular pressure elevation ( more than 10 mmHg) requiring topical ocular hypertensive medications, endophthalmitis, retinal tear and detachment, uveitis, and thromboembolic events will be recorded
measure: Systemic Adverse Events
time frame: Baseline to 9 months
description: Allergy or hypersensitivity drug reactions
arm group label: Doxycycline
arm group type: Experimental
description: Participants received doxycycline hyclate 50 mg capsule orally once a day for 6 months
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants received placebo (inactive) capsule orally once a day for 6 months
intervention type: Drug
intervention name: Doxycycline Hyclate
description: Doxycycline Hyclate capsules, USP 50 mg
arm group label: Doxycycline
other name: Antibiotic - tetracycline compound
intervention type: Drug
intervention name: Placebo
description: Placebo
arm group label: Placebo
other name: Inactive substance
criteria: 
gender: All
minimum age: 50 Years
maximum age: 99 Years
healthy volunteers: No
last name: Elliott H Sohn, MD
role: Principal Investigator
affiliation: University of Iowa
last name: Elliott H Sohn, MD
phone: 3193563285
email: elliott-sohn@uiowa.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
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responsible party type: Principal Investigator
investigator affiliation: University of Iowa
investigator full name: Elliott Sohn
investigator title: Associate Professor
mesh term: Macular Degeneration
mesh term: Wet Macular Degeneration
mesh term: Anti-Bacterial Agents
mesh term: Doxycycline
mesh term: Tetracycline
sharing ipd: No
ipd description: The investigators do not plan to share the data with other researchers