Low-dose oral doxycycline targeting MMP-9 for persistent wet AMD

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

This trial tests whether taking low-dose doxycycline daily can help people with wet AMD who still have sub-retinal fluid despite regular anti-VEGF eye injections.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 50 Years to 99 Years
• Sex: All
• Sponsor: University of Iowa (Academic / other)
• Locations: 1 site (Iowa City, Iowa)
• Trial ID: NCT04504123 on ClinicalTrials.gov

What this trial studies

This randomized, double-masked Phase 2 trial gives eligible patients either low-dose oral doxycycline (50 mg once daily) or matching placebo for six months alongside their regular anti-VEGF intravitreal injections. Participants are followed for nine months with clinic visits every three months that coincide with standard-of-care injections, and outcomes include OCT imaging and visual acuity. Plasma and anterior chamber aqueous samples are collected at baseline, 6 months and 9 months to measure MMP-9 and other inflammatory markers, and patients complete questionnaires on vision-related quality of life and drug tolerability. The main goal is to see if adding doxycycline reduces persistent sub-retinal (and intra-retinal) fluid and improves anatomic or functional outcomes in incomplete responders to anti-VEGF therapy.

Who should consider this trial

Good fit: Adults with wet age-related macular degeneration and active CNV who continue to have persistent sub-retinal (with or without intra-retinal) fluid despite at least three consecutive anti-VEGF injections and who have no prior tetracycline intolerance are ideal candidates.

Not a fit: Patients with significant macular structural damage (like a large epiretinal membrane or macular hole), active intraocular inflammation, recent ophthalmic surgery, media opacity preventing OCT assessment, or prior tetracycline side effects are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, the treatment could reduce persistent retinal fluid and improve vision or responsiveness to anti-VEGF therapy for a subset of patients with recalcitrant wet AMD.

How similar studies have performed: Preclinical and small clinical reports implicate MMP-9 in neovascular AMD and suggest matrix-modulating drugs like doxycycline might help, but well-controlled clinical evidence is limited.

Eligibility criteria

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.

Where this trial is running

Iowa City, Iowa

• University of Iowa Hospitals & Clinics Department of Ophthalmology & Visual Sciences — Iowa City, Iowa, United States (Recruiting)

Study contacts

• Principal investigator: Elliott H Sohn, MD — University of Iowa
• Study coordinator: Elliott H Sohn, MD

Conditions Exudative Macular Degeneration; Wet Age-related Macular Degeneration; Active choroidal neovascularization