InSite Vision Inc. conducted a Phase 3 multi-site, randomized, double-masked, 4-arm, parallel group, clinical trial of 907 subjects with clinically diagnosed blepharitis. All enrolled subjects had used lid-scrub therapy prior to study enrollment and were at least 18 years of age; sex and race were not considered in the inclusion criteria. All subjects had best-corrected visual acuity of 20/100 or better in each eye, intraocular pressure (IOP) of #22 mmHg in either eye, had used lid scrubs for at least 1 week prior to the day 1 study visit, and had a clinical diagnosis of blepharitis.
Among the study-exclusion criteria were previous eyelid surgery within 12 months of study entry that would interfere with study parameters, as determined by the investigator of record; acute ocular infection (bacterial, viral, or fungal) or active ocular inflammation other than blepharitis in the study eye; used topical corticosteroid or topical ophthalmic medications within 14 days before study enrollment; used any non-diagnostic topical ophthalmic solution in the study eye within 2 h before study enrollment; used eye makeup during the dosing period; had any clinically significant lash or lid abnormality other than blepharitis in the study eye; or had moderate-to-severe dry eye in the study eye.
The study questionnaire was available in English and Spanish. Assigned office and research staff provided the questionnaire to study participants during their first study visit. Participants self-administered the questionnaire throughout the study in a private room at the investigational site. Investigators were instructed to not be present during the administration of the questionnaire. There were no case reports from any of the investigational sites citing any issues with a non- or limited English speaking patients. Subjects completed the BLISS at screening, 7 days later at the beginning of treatment, and 15 days later at the end of treatment. This paper focuses on data collected at the beginning and end of treatment. Treatment group comparisons are reported elsewhere [8].
The study was approved by the Copernicus Group IRB.
Sample and clinical measures
At each visit, investigators at the clinical sites assessed eyelid redness, eyelid swelling, and eyelid debris using the following 0–3 (four categories) rating scales.
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Eyelid redness: 0, None = normal age-related lid coloration; 1, Mild = pink capillary involvement along the lid edge, no patches of confluent capillary redness throughout the lid edge; 2, Moderate = deep pink or red confluent capillary redness present locally along the lid edge; or 3, Severe = deep red, diffuse confluent capillary redness present along the lid edge.
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Eyelid swelling: 0 = None; 1 = Mild; 2 = Moderate; or 3 = Severe.
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Eyelid debris: 0 = no lid/lash debris; 1 = < \( \raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$3$}\right. \) of lid/lash has collarettes or debris; 2 = > \( \raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$3$}\right. \) of lid/lash has collarettes or debris; or 3 = \( \raisebox{1ex}{$2$}\!\left/ \!\raisebox{-1ex}{$3$}\right. \) of lid lash has collarettes or debris.
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Eyelid irritation: Clinicians asked subjects to grade their present eyelid irritation according to the following scale: 0 = almost none of the time - ≤ 25% of the time; 1 = occasionally – 26-50% of the time; 2 = frequently – 51-75% of the time; or 3 = almost all of the time - ≥76% of the time.
To qualify for the study, subjects at enrollment had to have a combined score of 5 or more in at least one eye, and that eye had to have a score of 1 or greater for eyelid redness and for eyelid irritation. Subjects were required to use standard lid scrubs for 1 week and if their clinical blepharitis score remained ≥5, they were admitted to the study and randomized to treatment. Subjects were screened between November 9, 2011, and September 5, 2012. Data reported here are for the 907 subjects who completed questionnaires at screening, and at the beginning and end of treatment.
Questionnaire
The BLISS had 13 items assessing blepharitis symptoms developed through review of available clinical reports, other research, and consultation with health care providers active in the diagnosis and treatment of patients with blepharitis. The items were evaluated for comprehensiveness iteratively by investigators at Insight Vision. The items were also reviewed by representatives of the Food and Drug Administration (FDA) Division of Transplant and Ophthalmology Products. For example, the FDA expressed a preference for assessing patient-reported symptom questions using a very recent recall interval (“today”) during the study team’s preliminary discussions with them. Hence, the 13 items asked patients to:
Please think about your eyes today. Are you having any of the following problems with your eyes today? Would you say none of the time, occasionally, frequently, or all of the time?
Symptoms asked about were: eyes that itch; eyes that burn; eyelids feel heavy or puffy; feel like something is in your eye; dry eyes; gritty eyes; irritated eyes; eyes that tear or water; crusty eyes; flaking from your eyelids; eyelids that are stuck together; red eyes or eyelids; and debris like pieces of skin or dandruff in your eyes.
We also administered the 12-item Ocular Surface Disease Index (OSDI) [4]: Have you experienced any of the following today.. . eyes that are sensitive to light; eyes that feel gritty; painful or sore eyes; blurred vision; or poor vision? Are problems with your eyes limiting you in performing any of the following today. .. reading; driving at night; working with a computer or bank machine (ATM); and watching TV? Do your eyes feel uncomfortable in any of the following situations today. .. windy conditions; places or areas with low humidity (very dry); areas that are air conditioned?
Answer responses provided are: all of the time; most of the time; half of the time; some of the time; none of the time; or not applicable. Scores for the 12-item OSDI were created using standard scoring recommendations: http://www.dryeyezone.com/documents/osdi.pdf. Internal consistency reliability (Cronbach’s alpha) for the 12-item OSDI scale (n = 571) was 0.91.
We also administered the widely used single item rating of general health recommended by the Institute of Medicine’s Committee on the State of the USA Health Indicators to assess global physical and mental health [9]: In general, would you say your health is excellent, very good, good, fair or poor?
We hypothesized that the BLISS would be strongly associated with the OSDI and less strongly related to the general health item.
Analysis plan
Frequencies for the 13 symptoms items and test-retest reliability (Spearman rank-order correlations) from screening to 7 days later at the beginning of treatment were estimated. Exploratory factor analysis was conducted for the symptom items with principal axis extraction and PROMAX rotation, and confirmed with categorical confirmatory factor analysis using Mplus, Version 7. Spearman correlations were computed between Irritation and Debris symptom scales with the OSDI total score and the general health rating item.
To evaluate the uniqueness of information provided by the BLISS items, we compared patient responses to questions about irritated eyes, heavy puffy eyelids, red eyelids and debris in the eyes to clinical assessments of irritation, swelling, red eyelids, and debris.