Ocular Rosacea Biome Study

Study Overview
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Brief Summary
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Ocular rosacea is an inflammatory disease of the eyelids and ocular surface. Like the facial disease, the ocular condition is chronic and recurrent. Sequelae of ocular rosacea vary from mild to severe. Ocular rosacea may cause chronic eye redness, blepharitis, recurrent chalazia, dry eye, corneal erosion, corneal vascularization, and corneal ulceration. Rosacea affecting the cornea can result in vision loss. Prescription eye drops and ointments can be used topically to control mild ocular rosacea. However, severe disease, or rosacea that is not well controlled with local treatments is treated systemically. The most commonly used systemic treatment for rosacea is the bacteriostatic antibiotic doxycycline. Rosacea treatment doses of doxycycline vary widely. Treatment-dose doxycycline for systemic infections is 100mg twice a day. However, as rosacea is considered an inflammatory disease, doxycycline is often dosed at what is termed, sub-microbial dose doxycycline (SDD). Initially introduced in the oral medicine literature, SDD are doses 40mg and lower because systemic administration at this dose does not appear to alter the oral mucosa flora or increase resistance rates when given long-term for periodontal disease. Whereas 100mg doxycycline, even when given short term, may increase the percentage of culturable nasopharyngeal flora that is resistant to doxycycline. The FDA does not categorize SDD an antibiotic, stating this dosing is expected to exhibit only anti-inflammatory activity.

Detailed Description
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Even though SDD is widely used for the treatment of rosacea, very little confirmatory data exists, to indicate if this dose alters any other systemic mucosa flora or increases antibiotic resistance rates. The classification of 40mg as sub-microbial has never been evaluated in patients diagnosed with ocular rosacea. Additionally, confirmation of a sub-microbial dose has not been investigated with more sophisticated genomics and resistance tools such as metagenomic deep sequencing (MDS). The goal of this proposal is to use MDS to determine whether SDD given to patients with ocular rosacea can be truly considered sub-microbial, or if a 40mg dose of doxycycline can in fact alter the microbiome of the conjunctiva and gut and increase resistance rates when prescribed for 8 weeks. The investigators plan to evaluate the effect of SDD on resistance and microbiome alteration through a randomized controlled masked trial. This is a randomized, controlled, masked trial comparing sub-microbial dose doxycycline, treatment dose Doxycycline, and placebo in the treatment of ocular rosacea. Participants will be recruited from the F.I. Proctor Foundation and the Ophthalmology clinics at the UCSF Wayne and Gladys Valley Center for Vision and consented for participation in an IRB-approved study protocol. Participants with a diagnosis of ocular rosacea (n=50) will be prospectively enrolled and randomized to one of three arms in a 2:2:1 fashion: Arm A will receive submicrobial dose doxycycline (40mg) administered as 20mg twice day for 8 weeks Arm B will receive 200mg of oral doxycycline administered as 100mg twice a day for 8 weeks Arm C will receive a placebo twice a day for 8 weeks

Official Title
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ORBS: Ocular Rosacea Biome Study

Conditions
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Ocular Rosacea, Antimicrobial Resistance

Intervention / Treatment
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* Drug: Doxycycline 40 MG ( 20mg twice daily)
* Drug: Doxycycline 200 MG ( 100 mg twice daily)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have symptomatic ocular disease attributed to ocular rosacea as the primary diagnosis Ability to give informed consent Be aged 18 years old or older Exclusion Criteria: Have an active ocular or systemic infection Have a known allergy or intolerance to tetracycline antibiotics Have had prior use of oral antibiotics within the last three months Pregnancy or the possibility of becoming pregnant within the 8-week study medication timeline.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 40mg of oral doxycycline<br>Arm A will receive submicrobial dose doxycycline (40mg) administered as 20mg twice a day for 8 weeks | Drug: Doxycycline 40 MG ( 20mg twice daily)<br>* Submicrobial dose doxycycline (40mg) to be administered as 20mg twice daily<br>|
| Active Comparator: 100mg of oral doxycycline<br>Arm B will receive 200mg of oral doxycycline administered as 100mg twice a day for 8 weeks | Drug: Doxycycline 200 MG ( 100 mg twice daily)<br>* 200 mg dose doxycycline to be administered as 100mg twice daily<br>|
| Placebo Comparator: Placebo<br>Arm C will receive a placebo twice a day for 8 weeks | Drug: Placebo<br>* Placebo to be administered in tablet form twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Antimicrobial Resistance (AMR) genetic determinants | The frequency of AMR genetic determinants in rectal swab samples between arms will be compared, correcting for baseline | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in Simpson's diversity of the microbiome of the conjunctiva and gut | Simpson's diversity is the probability that any two randomly chosen reads will be for different organisms (at the genus level). This will be expressed in terms of effective number. | 4 weeks , 8 weeks, 3 - 6 months | 
| Ocular Surface Disease Index (OSDI) will be compared | Scores range from 0 to 100, with higher scores indicating greater symptom severity. Standard 12-question created by the Outcomes Research Group at Allergan Inc will be used. | 4 weeks , 8 weeks, 3 - 6 months | 
| Tear Breakup Time (TBUT) scores will be compared | Numbers representing how many seconds after a full blink a discontinuity in the tear film appears. Obtained with the Oculus keratography topographer This is a scale typically measured from 1-10, and the seconds correspond to the amount of time it takes for a tear film discontinuity to be observed. The lower the number the faster the tear break up and the worse the objective dry eye. | 4 weeks , 8 weeks, 3 - 6 months |