Low-Dose Doxycycline for Ocular Rosacea

(ORBS Trial)

Overseen By Brianna K Colado

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of California, San Francisco

Must not be taking: Oral antibiotics

Disqualifiers: Active infection, Tetracycline allergy, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: 8 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have used oral antibiotics in the last three months.

What data supports the effectiveness of the drug for treating ocular rosacea?

Research shows that a 40 mg dose of doxycycline, taken once daily, is effective in reducing inflammation in rosacea without causing antibiotic resistance. Clinical trials demonstrated significant improvement in rosacea symptoms compared to a placebo, with a rapid onset of action and a favorable safety profile. ^{1 2 3 4 5}

Is low-dose doxycycline safe for treating ocular rosacea?

Low-dose doxycycline, specifically the 40 mg formulation, is generally safe for treating rosacea, with most side effects being mild to moderate. Common side effects include diarrhea, nausea, and headache, and it should not be used by pregnant or nursing women, or those with known hypersensitivity to tetracyclines. ^{2 3 4 5 6}

What makes low-dose doxycycline unique for treating ocular rosacea?

Low-dose doxycycline is unique for treating ocular rosacea because it uses a sub-antimicrobial dose that reduces inflammation without promoting antibiotic resistance. This treatment is taken once daily, which can improve patient compliance, and it is effective without the higher doses typically needed for bacterial infections. ^{1 2 3 7 8}

Research Team

Gerami Seitzman, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults over 18 with symptomatic ocular rosacea, which affects the eyes and eyelids. Participants must be able to consent and not have used oral antibiotics in the last three months. They can't join if they're allergic to tetracycline antibiotics, currently have an infection, or are pregnant or might become pregnant during the study.

Inclusion Criteria

My main health issue is eye problems due to rosacea.

Ability to give informed consent

I am 18 years old or older.

Exclusion Criteria

You are allergic or intolerant to tetracycline antibiotics.

I have taken oral antibiotics in the last three months.

I currently have an eye or body-wide infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants are randomized to receive submicrobial dose doxycycline, treatment dose doxycycline, or placebo for 8 weeks

8 weeks

Regular visits as per protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of ocular surface disease index and microbiome diversity

3-6 months

Follow-up visits at 4 weeks, 8 weeks, and 3-6 months

Treatment Details

Interventions

• Doxycycline 100 MG Oral Tablet
• Doxycycline 200 MG ( 100 mg twice daily)
• Doxycycline 40 MG ( 20mg twice daily)
• Doxycycline 40 MG Oral Tablet
• Placebo

Trial Overview The study tests two doses of doxycycline (40mg daily as SDD and 200mg daily) against a placebo to see how well they control severe ocular rosacea symptoms like eye redness and corneal issues without causing antimicrobial resistance.

Participant Groups

Group I: 40mg of oral doxycycline Experimental Treatment 1 Intervention

Arm A will receive submicrobial dose doxycycline (40mg) administered as 20mg twice a day for 8 weeks

Group II: 100mg of oral doxycycline Active Control 1 Intervention

Arm B will receive 200mg of oral doxycycline administered as 100mg twice a day for 8 weeks

Group III: Placebo Placebo Group 1 Intervention

Arm C will receive a placebo twice a day for 8 weeks

Doxycycline 100 MG Oral Tablet is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Doxycycline for:

• Rosacea
• Acne
• Periodontal disease
• Chlamydia
• Lyme disease
• Rickettsial infections
• Anthrax

Approved in European Union as Doxycycline for:

• Rosacea
• Acne
• Periodontal disease
• Chlamydia
• Lyme disease
• Rickettsial infections
• Anthrax

Approved in Canada as Doxycycline for:

• Rosacea
• Acne
• Periodontal disease
• Chlamydia
• Lyme disease
• Rickettsial infections
• Anthrax

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Findings from Research

Subantibiotic dose doxycycline (SDD40) is effective in treating inflammatory lesions of rosacea, showing consistent results across multiple randomized controlled trials (RCTs) involving 72 to 142 subjects, regardless of the patient's weight or severity of the condition.

The treatment was well tolerated with minimal gastrointestinal side effects, indicating a favorable safety profile for SDD40 in managing rosacea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective Treatment of Inflammatory Lesions of Rosacea with Subantibiotic Dose Doxycycline Irrespective of Patient Weight or Baseline Lesion Count Severity. Del Rosso, JQ., York, JP., Bhatia, N.[2022]

Oracea, the first FDA-approved oral medication for rosacea, contains anti-inflammatory-dose doxycycline, which is not an antibiotic and does not contribute to antibiotic resistance, making it a safer long-term treatment option for the 13 million Americans affected by rosacea.

In clinical trials, Oracea has shown promising results for treating rosacea, and its once-daily dosing may improve patient compliance compared to other therapies, although it is contraindicated for certain populations, including pregnant women and children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on rosacea and anti-inflammatory-dose doxycycline. Berman, B., Perez, OA., Zell, D.[2017]

Anti-inflammatory dose doxycycline 40 mg capsules significantly improve rosacea symptoms compared to placebo, with a notable reduction in inflammatory lesions observed as early as 3 weeks into treatment, based on results from two large, randomized trials.

The 40 mg dose is effective without the higher concentrations needed for antibacterial effects, and it was well tolerated by patients, with most side effects being mild to moderate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxycycline 40 mg capsules (30 mg immediate-release/10 mg delayed-release beads): anti-inflammatory dose in rosacea. McKeage, K., Deeks, ED.[2022]

Anti-inflammatory dose doxycycline (ADD) at 40 mg once daily is FDA-approved for treating rosacea and has shown effective anti-inflammatory activity without antibiotic effects, even with long-term use.

When used in combination with metronidazole gel, ADD leads to a faster therapeutic response in treating moderate to severe rosacea, while also having a better safety profile and lower gastrointestinal side effects compared to higher doses of doxycycline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflamatory dose doxycycline in the treatment of rosacea. Del Rosso, JQ.[2013]

Doxycycline, used for treating rosacea, shows similar skin concentrations in both fed and fasting conditions after a 14-day treatment, indicating that food intake does not significantly affect its efficacy at steady state.

The study found that doxycycline accumulates more in the skin than in plasma, suggesting that its effectiveness in treating rosacea may be due to this significant dermal accumulation of the drug, regardless of food effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target site pharmacokinetics of doxycycline for rosacea in healthy volunteers is independent of the food effect. Pal, A., Matzneller, P., Gautam, A., et al.[2021]

In the ORCA trial involving 1197 participants, the 40-mg formulation of doxycycline significantly improved rosacea symptoms, with about 75% of participants achieving clear or near-clear skin by week 12.

The treatment was generally safe, with only 6.7% of participants reporting mild to moderate adverse events, such as diarrhea and nausea, indicating that doxycycline is a well-tolerated option for managing papulopustular rosacea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads). Webster, GF.[2013]

In a study of 24 patients with ocular rosacea, doxycycline (100 mg/day) led to a 94% improvement in symptoms, with 12 patients becoming asymptomatic, while tetracycline hydrochloride (1g/day) resulted in 87% of patients being asymptomatic.

Both medications were effective in managing ocular rosacea symptoms, but gastrointestinal complications were noted in 13% of patients for both treatments, indicating a need for monitoring side effects during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of doxycycline and tetracycline in ocular rosacea. Fruchtpery, J., Sagi, E.[2012]

A once-daily treatment of 40 mg slow-release doxycycline significantly improved symptoms of ocular rosacea in 15 patients, with severe complaints dropping from 73.3% to only 13.3% after 12 weeks of therapy.

The treatment was found to be safe, with only one patient experiencing a mild stomach ache, and long-term follow-up showed continued improvement in symptoms even after treatment was discontinued.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ocular rosacea with once-daily low-dose doxycycline. Sobolewska, B., Doycheva, D., Deuter, C., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effective Treatment of Inflammatory Lesions of Rosacea with Subantibiotic Dose Doxycycline Irrespective of Patient Weight or Baseline Lesion Count Severity. [2022]

2. Spain pubmed.ncbi.nlm.nih.gov

Update on rosacea and anti-inflammatory-dose doxycycline. [2017]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Doxycycline 40 mg capsules (30 mg immediate-release/10 mg delayed-release beads): anti-inflammatory dose in rosacea. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Anti-inflamatory dose doxycycline in the treatment of rosacea. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Target site pharmacokinetics of doxycycline for rosacea in healthy volunteers is independent of the food effect. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads). [2013]

7. England pubmed.ncbi.nlm.nih.gov

The use of doxycycline and tetracycline in ocular rosacea. [2012]

8. United States pubmed.ncbi.nlm.nih.gov

Treatment of ocular rosacea with once-daily low-dose doxycycline. [2022]