MMP-9 Inhibition for Recalcitrant Wet AMD

March 3, 2023 updated by: Elliott Sohn, University of Iowa

MMP-9 Inhibition for Recalcitrant Wet Age-Related Macular Degeneration (AMD)

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

50

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • Recruiting
        • University of Iowa Hospitals & Clinics Department of Ophthalmology & Visual Sciences
        • Contact:
        • Principal Investigator:
          • Elliott H Sohn, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years to 99 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Wet age-related macular degeneration (wAMD);
  • Solely treated with anti-VEGF IVI for active CNV due to wAMD. However, enrolled patients can have other retinal pathologies such as diabetic retinopathy or vein occlusion for which they are not being treated with anti-VEGF IVI;
  • Must have persistent sub-retinal with or without intra-retinal fluid due to active CNV from wAMD despite receiving at least three consecutive injections with any anti-VEGF agent;
  • Must not have encountered previous side effects from tetracycline medications.

Exclusion Criteria - Ocular:

  • History of uveitis (including endophthalmitis) or presence of intraocular inflammation;
  • Presence of significant epiretinal membrane or macular hole causing distortion of macular anatomy;
  • Presence of media opacity preventing discerning of fluid on OCT;
  • Any prior ophthalmic surgery (including YAG or retinal laser) within the previous 3 months or anticipated need for any ophthalmic surgery (including cataract extraction) for 9 months following randomization;
  • History of peribulbar corticosteroid injection to the studied eye or the fellow eye within the past 6 months;
  • History of intravitreal triamcinolone acetonide injection to the studied eye within the past 4 months;
  • An ocular condition (other than AMD) is present in the studied eye that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g., retinal vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, and Irvine-Gass syndrome);
  • CNV due to causes other than wAMD;
  • Inability to follow up at the 6th and 9th months time points after recruitment;
  • Missing two or more consecutive injections during the six months treatment period;
  • Patient requiring imminent need for IVI anti-VEGF medication switch or another treatment intervention, such as photodynamic therapy, during the 9 months trial period;
  • Presence of fluid associated with geographic atrophy or disciform scar;
  • Any patient with sub-retinal and/or intra-retinal fluid that is not due to CNV (eg, overlying areas of geographic atrophy;
  • Any patient actively being actively treated for Irvine-Gass Syndrome.

Exclusion Criteria - Systemic:

  • Patient with and/or who developed an unstable medical status (e.g., glycemic control, blood pressure, cardiovascular disease, individuals who are unlikely or unable to complete the 9 months trial period) in the opinion of the investigator;
  • Significant renal disease (defined as a serum creatinine >2.5 mg/dL);
  • Systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg;
  • History of headaches associated with tetracycline therapy
  • History of pseudotumor cerebri;
  • History of tetracycline therapy within the past 6 months;
  • Pregnancy or patient intending to become pregnant within the 9 months of the trial period. For women of child-bearing potential, a pregnancy test will be performed;
  • Sexually active women of child-bearing potential not actively practicing birth control by using a medically accepted device or therapy (i.e., intrauterine device, hormonal contraceptive, or barrier device) during the study period (at least 24 months). This is important as doxycycline may interfere with the effectiveness of hormonal contraceptives. Hence, sexually active women of child-bearing potential who use a hormonal contraceptive will be required to use a second form of contraception to safeguard against contraceptive failure while participating in the study;
  • Known allergy/intolerance to doxycycline, tetracyclines, or any ingredient in the study drug or placebo;
  • Patients receiving phenytoin, barbiturates, carbamazepine, digoxin, or isotretinoin; patients with gastroparesis; patients with a history of gastrectomy, gastric bypass surgery, or otherwise deemed achlorhydric should all be excluded due to altered doxycycline pharmacokinetics and/or bioavailability;
  • Patients taking strontium, acitretin, or tretinoin should excluded due to the potential for serious interactions with doxycycline;
  • Patients with abnormal ALT or AST at baseline will be referred to their primary care physician for medical clearance for participation in this study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Doxycycline
Participants received doxycycline hyclate 50 mg capsule orally once a day for 6 months
Drug: Doxycycline Hyclate
Doxycycline Hyclate capsules, USP 50 mg
Other Names:
  • Antibiotic - tetracycline compound
Placebo Comparator: Placebo
Participants received placebo (inactive) capsule orally once a day for 6 months
Drug: Placebo
Placebo
Other Names:
  • Inactive substance

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Resolution of the persistent retinal fluid on optical coherence tomography (OCT)
Time Frame: 9 months
percentage of patients with retinal fluid-free status
9 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in optical coherence tomography (OCT) central media thickness (CMT)
Time Frame: 9 months compared to baseline
mean change in central media thickness
9 months compared to baseline
Change in best corrected visual acuity (BCVA)
Time Frame: 6 months and 9 months compared to Baseline
mean change in logMAR / percentage of patients with a gain or loss of more than 5 ETDRS letters
6 months and 9 months compared to Baseline
Number of intravitreal injections (IVI) administered
Time Frame: 6 months and 9 months
total number of anti-VEGF intravitreal injections
6 months and 9 months
Inflammatory mediators matrix metalloproteinases MMP-9 and MMP-9 activity
Time Frame: Baseline, 6 months and 9 months
anterior eye aqueous fluid and blood plasma
Baseline, 6 months and 9 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ocular Adverse Events
Time Frame: Baseline to 9 months
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
Baseline to 9 months
Systemic Adverse Events
Time Frame: Baseline to 9 months
Allergy or hypersensitivity drug reactions
Baseline to 9 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Iowa

Investigators

  • Principal Investigator: Elliott H Sohn, MD, University of Iowa

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 4, 2020

Primary Completion (Anticipated)

December 31, 2023

Study Completion (Anticipated)

March 1, 2024

Study Registration Dates

First Submitted

August 4, 2020

First Submitted That Met QC Criteria

August 4, 2020

First Posted (Actual)

August 7, 2020

Study Record Updates

Last Update Posted (Estimate)

March 7, 2023

Last Update Submitted That Met QC Criteria

March 3, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 202001041

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

The investigators do not plan to share the data with other researchers

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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