Azithromycin for Meibomian Gland Disease

Dry Eye Clinical Trial

Official title:

A Randomized, Controlled Trial to Evaluate the Role of Oral Azithromycin in the Treatment of Symptomatic Meibomian Gland Disease and Its Effect on the Ocular Surface Microbiome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03953118
• Other study ID #: 17-23877
• Status: Recruiting
• Phase: Phase 4
• Start date: September 1, 2018
• Est. completion date: December 1, 2023

Study information

• Verified date: January 2021
• Source: University of California, San Francisco
• Contact: Khashayar Nattagh, BA
• Phone: 19499107667
• Email: khash.nattagh[@]ucsf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to elucidate the effectiveness of oral azithromycin in treating symptomatic dry eye syndrome secondary to Meibomian gland dysfunction.

Description:

This is a randomized, placebo-controlled, double masked trial of the effectiveness of oral azithromycin in treating symptomatic dry eye syndrome secondary to Meibomian gland dysfunction. Dry eye syndrome (DES) is a persistent feeling of ocular discomfort that encompasses dryness, irritation, foreign body sensation and burning. In the United States, it is the most common non-refractive cause of visits to eye care providers, and has been shown to have a significant impact on quality of life of patients who suffer from this condition. most common cause of DES is Meibomian gland disease (MGD). In the vast majority of cases, MGD is not binding, but rather causes persistant ocular discomfort. Oral antibiotics, particularly the tetracyclines and macrolides, are frequently prescribed for the treatment of MGD. There is little good-quality evidence to support this practice. This study is designed to evaluate the effectiveness of oral azithromycin on patient-reported dry eye symptoms. Concomitantly, we will also study the composition of the ocular surface microbiome in MGD, and its response for oral antibiotics.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 1, 2023
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Symptomatic Meibomian gland disease, defined as patient-reported ocular surface symptoms such as dryness, grittiness, foreign body sensation, or eye fatigue in combination with clinically identifiable Meibomian gland disease with Grade 2 or greater involvement on the Meibomian Gland Grading Scale (Section XV, item 2).
• OSDI Score greater than or equal to 20
• Ability to give informed consent

Exclusion Criteria:

• Age less than 18 years
• Allergy or intolerance to oral azithromycin or topical dexamethasone
• Allergy or intolerance to the preservatives used in topical ophthalmic 0.1% dexamethasone: sodium bisulfite, phenylethyl alcohol, benzalkonium chloride
• History of prolonged QT interval, history of torsades des pointes, congenital long QT syndrome, bradyarrhythmias, heart failure
• Patients currently taking medications that prolong the QT interval (Table 1)
• Aqueous deficiency dry eye defined as Schirmer's strip testing without anesthesia with £ 5mm of tears on two separate tests.
• Ocular surface inflammatory disease, including cicatrizing conjunctivitis, graft versus host disease, Stevens Johnson syndrome
• Atopic disease with ocular involvement
• Limbal stem cell deficiency
• Oral or topical ophthalmic antibiotic use within the last 90 days
• Oral prednisone use >5mg per day
• Topical ophthalmic steroid use within the past 30 days
• Topical ophthalmic anti-inflammatory (including non-steroidal anti-inflammatory medications, lifitegrast, or cyclosporine) use within the past 30 days
• Patients who are currently pregnant, planning on becoming pregnant during the study period, or currently breastfeeding.

Related Conditions & MeSH terms

• Depression, Anxiety
• Dry Eye
• Eye Pain
• Neuropathic Eye Pain
• Ocular Microbiome

Intervention

Drug:
• Azithromycin Oral Product
Oral azithromycin dosed at 1 gram per week for 3 weeks
• Placebo Oral
Oral placebo tablet

Locations

Country	Name	City	State
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (26)

Deinema LA, Vingrys AJ, Wong CY, Jackson DC, Chinnery HR, Downie LE. A Randomized, Double-Masked, Placebo-Controlled Clinical Trial of Two Forms of Omega-3 Supplements for Treating Dry Eye Disease. Ophthalmology. 2017 Jan;124(1):43-52. doi: 10.1016/j.ophtha.2016.09.023. Epub 2016 Nov 3. — View Citation

Foulks GN, Bron AJ. Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading. Ocul Surf. 2003 Jul;1(3):107-26. — View Citation

Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents. 2008 Jan;31(1):12-20. Epub 2007 Nov 1. Review. — View Citation

Greene JB, Jeng BH, Fintelmann RE, Margolis TP. Oral azithromycin for the treatment of meibomitis. JAMA Ophthalmol. 2014 Jan;132(1):121-2. doi: 10.1001/jamaophthalmol.2013.5295. — View Citation

Haque RM, Torkildsen GL, Brubaker K, Zink RC, Kowalski RP, Mah FS, Pflugfelder SC. Multicenter open-label study evaluating the efficacy of azithromycin ophthalmic solution 1% on the signs and symptoms of subjects with blepharitis. Cornea. 2010 Aug;29(8):871-7. doi: 10.1097/ICO.0b013e3181ca38a0. — View Citation

Hosseini K, Lindstrom RL, Foulks G, Nichols KK. A randomized, double-masked, parallel-group, comparative study to evaluate the clinical efficacy and safety of 1% azithromycin-0.1% dexamethasone combination compared to 1% azithromycin alone, 0.1% dexamethasone alone, and vehicle in the treatment of subjects with blepharitis. Clin Ophthalmol. 2016 Aug 10;10:1495-503. doi: 10.2147/OPTH.S110739. eCollection 2016. — View Citation

Igami TZ, Holzchuh R, Osaki TH, Santo RM, Kara-Jose N, Hida RY. Oral azithromycin for treatment of posterior blepharitis. Cornea. 2011 Oct;30(10):1145-9. doi: 10.1097/ICO.0b013e318207fc42. — View Citation

King-Smith PE, Bailey MD, Braun RJ. Four characteristics and a model of an effective tear film lipid layer (TFLL). Ocul Surf. 2013 Oct;11(4):236-45. doi: 10.1016/j.jtos.2013.05.003. Epub 2013 Jul 12. Review. — View Citation

Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011 Mar 30;52(4):1938-78. doi: 10.1167/iovs.10-6997c. Print 2011 Mar. Review. — View Citation

Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry eye symptoms and gland location. Cornea. 2008 Dec;27(10):1142-7. doi: 10.1097/ICO.0b013e3181814cff. — View Citation

Lane SS, DuBiner HB, Epstein RJ, Ernest PH, Greiner JV, Hardten DR, Holland EJ, Lemp MA, McDonald JE 2nd, Silbert DI, Blackie CA, Stevens CA, Bedi R. A new system, the LipiFlow, for the treatment of meibomian gland dysfunction. Cornea. 2012 Apr;31(4):396-404. doi: 10.1097/ICO.0b013e318239aaea. — View Citation

Lee H, Chung B, Kim KS, Seo KY, Choi BJ, Kim TI. Effects of topical loteprednol etabonate on tear cytokines and clinical outcomes in moderate and severe meibomian gland dysfunction: randomized clinical trial. Am J Ophthalmol. 2014 Dec;158(6):1172-1183.e1. doi: 10.1016/j.ajo.2014.08.015. Epub 2014 Aug 13. — View Citation

Liu Y, Ding J. The combined effect of azithromycin and insulin-like growth factor-1 on cultured human meibomian gland epithelial cells. Invest Ophthalmol Vis Sci. 2014 Aug 14;55(9):5596-601. doi: 10.1167/iovs.14-14782. — View Citation

Liu Y, Kam WR, Ding J, Sullivan DA. Effect of azithromycin on lipid accumulation in immortalized human meibomian gland epithelial cells. JAMA Ophthalmol. 2014 Feb;132(2):226-8. doi: 10.1001/jamaophthalmol.2013.6030. — View Citation

Luchs J. Azithromycin in DuraSite for the treatment of blepharitis. Clin Ophthalmol. 2010 Jul 30;4:681-8. — View Citation

Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 2008;106:336-56. — View Citation

Meadows JF, Ramamoorthy P, Nichols JJ, Nichols KK. Development of the 4-3-2-1 meibum expressibility scale. Eye Contact Lens. 2012 Mar;38(2):86-92. doi: 10.1097/ICL.0b013e318242b494. — View Citation

Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am J Manag Care. 2008 Apr;14(3 Suppl):S102-6. Review. — View Citation

Prabhasawat P, Tesavibul N, Mahawong W. A randomized double-masked study of 0.05% cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction. Cornea. 2012 Dec;31(12):1386-93. doi: 10.1097/ICO.0b013e31823cc098. — View Citation

Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK. The international workshop on meibomian gland dysfunction: report of the subcommittee on the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci. 2011 Mar 30;52(4):1994-2005. doi: 10.1167/iovs.10-6997e. Print 2011 Mar. Review. — View Citation

Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000 May;118(5):615-21. — View Citation

Ta CN, Shine WE, McCulley JP, Pandya A, Trattler W, Norbury JW. Effects of minocycline on the ocular flora of patients with acne rosacea or seborrheic blepharitis. Cornea. 2003 Aug;22(6):545-8. — View Citation

The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007 Apr;5(2):93-107. Review. — View Citation

Watters GA, Turnbull PR, Swift S, Petty A, Craig JP. Ocular surface microbiome in meibomian gland dysfunction. Clin Exp Ophthalmol. 2017 Mar;45(2):105-111. doi: 10.1111/ceo.12810. Epub 2016 Sep 7. — View Citation

Wladis EJ, Bradley EA, Bilyk JR, Yen MT, Mawn LA. Oral Antibiotics for Meibomian Gland-Related Ocular Surface Disease: A Report by the American Academy of Ophthalmology. Ophthalmology. 2016 Mar;123(3):492-6. doi: 10.1016/j.ophtha.2015.10.062. Epub 2015 Dec 23. Review. — View Citation

Yoo SE, Lee DC, Chang MH. The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction. Korean J Ophthalmol. 2005 Dec;19(4):258-63. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ocular Surface Disease Index (OSDI) Questionnaire	Ocular surface disease index - used to evaluate the degree of dry eye symptoms. Scores will range from 0 to 48, where 48 indicates severe dry eye.	Baseline to 1 month.
Primary	Ocular Surface Disease Index (OSDI) Questionnaire	Ocular surface disease index - used to evaluate the degree of dry eye symptoms. Scores will range from 0 to 48, where 48 indicates severe dry eye.	Baseline to 3 months.
Secondary	Ocular surface microbiome testing	To evaluate the composition of the ocular surface microbiome using Shannon's diversity index. The alpha diversity (local species pool) of the population will be analyzed and compared pre-and post-treatment within and between the azithromycin and control groups. The difference between the bacterial microbiome in the azithromycin and placebo arm will be assessed using a PERMANOVA with an L2 norm distance measure.; Secondary analyses will include L1 and L0 norms, as well as a phylogenetic distance. In addition, we will assess whether bacterial alpha diversity is decreased in the antibiotic treated arm with the primary outcome being the Simpson's index (L2), with secondary analyses assessing Shannon's (L1) and Richness (L0).	Baseline to 1 month.
Secondary	Ocular surface microbiome testing	To evaluate the composition of the ocular surface microbiome using Shannon's diversity index. The alpha diversity (local species pool) of the population will be analyzed and compared pre-and post-treatment within and between the azithromycin and control groups. The difference between the bacterial microbiome in the azithromycin and placebo arm will be assessed using a PERMANOVA with an L2 norm distance measure.; Secondary analyses will include L1 and L0 norms, as well as a phylogenetic distance. In addition, we will assess whether bacterial alpha diversity is decreased in the antibiotic treated arm with the primary outcome being the Simpson's index (L2), with secondary analyses assessing Shannon's (L1) and Richness (L0).	Baseline to 3 months.
Secondary	Dry Eye Questionnaire 5 (DE-5)	Dry eye questionnaire 5 - used to evaluate the degree of dry eye symptoms. Scores range from 0-22. A score of 0 represents the minimum dry eye symptoms someone may have and a score of 22 represents the maximum dry eye symptoms someone may have.	Baseline to 1 month.
Secondary	Dry Eye Questionnaire 5 (DE-5)	Dry eye questionnaire 5 - used to evaluate the degree of dry eye symptoms. Scores range from 0-22. A score of 0 represents the minimum dry eye symptoms someone may have and a score of 22 represents the maximum dry eye symptoms someone may have.	Baseline to 3 months.
Secondary	Neuropathic Pain Inventory for the Eye (NPSI-E)	Neuropathic pain inventory for the eye - used to study neuropathic vs stimulatory eye pain.	Baseline to 1 month.
Secondary	Neuropathic Pain Inventory for the Eye (NPSI-E)	Neuropathic pain inventory for the eye - used to study neuropathic vs stimulatory eye pain.	Baseline to 3 months.
Secondary	Personal Health Questionnaire (PHQ-9)	Personal Health Questionnaire - a brief anxiety and depression questionnaire. Will be used in this study to evaluate the interaction between depression/anxiety and response to treatment.	Baseline to 1 month.
Secondary	Personal Health Questionnaire (PHQ-9)	Personal Health Questionnaire - a brief anxiety and depression questionnaire. Will be used in this study to evaluate the interaction between depression/anxiety and response to treatment.	Baseline to 3 months.