Patients and Methods
A prospective, randomised, double-masked, two-arm, parallel-group, placebo-controlled, multicentre study was designed to demonstrate the superiority of TobraDex® eye drops to Tobrex®/vehicle eye drops in controlling post-surgical inflammation after cataract extraction. The duration of the study was 23 days. The study was conducted at 22 ophthalmology clinics in Brazil, Belgium, Germany, Ireland, Portugal, Spain and Sweden.
The study protocol was approved by the Institutional Review Board of each of the participating centres, and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrolment in the study.
Patients of any race and either sex >18 years of age scheduled for cataract extraction by phacoemulsification with IOL implantation were eligible for study participation. Inclusion criteria included: normal fundus by direct and indirect ophthalmoscopy, intraocular pressure (IOP) readings =20mm Hg in both eyes, and a negative pregnancy test in women of childbearing potential who were not using adequate methods of contraception. Glaucoma patients were eligible if their IOP was adequately controlled with only one ocular hypotensive agent.
Patients were excluded from participating in the study for one or more of the following reasons: patients selected for secondary implants or IOL replacement in the treated eye; contact lens use in the operated/treated eye during the course of the study; one useful eye only; history or evidence of ocular or systemic disease that would interfere with efficacy evaluation (including ocular inflammatory disease, ocular herpes infection, iritis, uveitis or Sjögren's syndrome); diabetes mellitus (e.g. diabetic retinopathy); known or suspected hypersensitivity or intolerance to topical anaesthetics, ocular preservatives, or any components of the study medications; use of ocular medication other than a single ocular hypotensive agent; treatment for an ocular infection within 30 days prior to the study; use of topical or systemic corticosteroids within 30 days and topical anti-inflammatory drugs within 14 days prior to the study; use of an investigational intraocular lens; or participation in a clinical study within the previous 30 days.
On the day before ocular surgery (day -1), eligible patients were sequentially assigned to one of the two masked medications according to a predetermined computer-generated randomisation schedule. Patients were randomised (1:1) to an ophthalmic preparation containing tobramycin 3 mg/mL and dexamethasone 1 mg/mL (TobraDex® eye drops suspension) or tobramycin 3 mg/mL/placebo (Tobrex® eye drops solution, Alcon Couvreur NV, Puurs, Belgium) [Tobrex®/vehicle]. The patients were instructed to instil one drop of the assigned medication four times a day in the conjunctival sac of the operated eye, starting the day before ocular surgery until day 21. In the Tobrex®/vehicle group, the treatment was Tobrex® from day -1 to day 7 inclusive (period 1), and Tobrex®/vehicle from day 8 to day 21 (period 2).
In order to instruct the patients on the proper dosing procedure, the investigator's assistant instilled the first dose of study medication and provided the patients with posology instructions to follow during the study. On the day of surgery (day 0), the surgeon instilled only one drop of study medication immediately after ocular surgery.
Assessments were performed prior to surgery and at days 1, 3, 8, 14 and 21. As shown in Table I , ophthalmic examinations included visual acuity testing (Snellen charts), slit-lamp examination (aqueous cells, aqueous flare), IOP measurements by Goldmann applanation tonometry, and a dilated fundus examination (macula, choroid, optic nerve head and retina). Clinically significant changes in visual acuity, in the opinion of the investigator, were reported as adverse events. Clinically significant change in the fundus examination was defined as an increase in any of the fundus parameters of one or more units, in either eye, as compared with screening, and was reported as an adverse event. Anterior chamber cell count was measured on a 6-point whole unit scale as follows: 0 = <5 cells, 1 = mild (5-10 cells), 2 = moderate (11-20 cells), 3 = marked (21-50 cells), 4 = severe (>50 cells), and 5 = hypo-pyon. The aqueous flare (protein) was measured on a 5-point whole unit scale as follows: 0 = none to trace, 1 = mild (clearly noticeable, visible), 2 = moderate (without plastic aqueous), 3 = marked (with plastic aqueous), and 4 = severe (heavy with fibrin deposits and clots [iris details hazy]). The sum of the score of both variables (0-9) was the indicator for the degree of intraocular inflammation. The examining physician, at each site, was maintained masked to the treatment assignment.
The primary efficacy variable was the percentage of patients without a post-surgical anterior chamber inflammation, i.e. with a total score (sum of cells and flare scores) of zero. The secondary efficacy variables included clinical assessment of ocular pain (6-point scale; 0 = none, 5 = severe), physician's follow-up impression of inflammatory response (6-point scale; 0 = cure, 5 = worse), and treatment failure. A treatment failure was defined as an increase in sum of cells and flare that required discontinuation of treatment and physician's assessment of clinically worse (score 5) or suspected bacterial infection.
Safety-related parameters were an assessment of visual acuity, dilated fundus parameters, IOP and adverse events. Any increase in IOP =10mm Hg over day -1 (prior to surgery) was considered an adverse event.
Reasons leading to a patient's removal from the study included adverse events severe enough to require discontinuation from the study, lost to follow-up, noncompliance and patient's decision related or unrelated to an adverse event.
Statistical analyses were performed for the intent-to-treat (ITT) and the per-protocol (PP) populations. All patients who were randomised and received at least one dose of study drug were included in the safety analysis. All patients receiving drug and having at least one follow-up visit were included in the ITT analysis. All patients receiving drug, meeting selection criteria, and having at least one evaluable follow-up visit were included in the PP analysis.
According to a sample size of 200 patients in each arm, the study had at least 80% power to detect a difference between treatments >15% in the percentage of patients with scores of zero for anterior chamber inflammation. This sample size calculation assumed a 'worst case' scenario where 50% of patients assigned to the TobraDex® group would experience inflammation (sum of cells and flare scores greater than zero), which yielded the maximum variance estimated for this observed proportion.
A Chi-square analysis was used to assess differences between treatment groups in the percentage of patients without inflammation (score of zero) at each visit (primary inference was based on day 8); the Cochran-Mantel-Haenszel test was used to assess differences in cells, flare, ocular pain and physician's impression, and Fisher's Exact Probability test to assess differences in the proportion of patients classified as treatment failures. All hypotheses were conducted with a 0.05 probability of a type I error. The Statistical Analysis Systems (SAS) statistical software package (SAS Institute, Cary, NC, USA) for Windows (version 8.1) was used for the analysis of data.
Clin Drug Invest. 2004;24(9) © 2004 Adis Data Information BV
Cite this: Prophylactic Effectiveness of Tobramycin-Dexamethasone Eye Drops Compared with Tobramycin/Vehicle Eye Drops in Controlling Post-Surgical Inflammation in Cataract Patients - Medscape - Sep 01, 2004.
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