Discontinuation and nonpublication of interventional clinical trials conducted in ophthalmology.

OBJECTIVE: Discontinuation of interventional clinical trials and nonpublication of completed trials represent a waste of already scarce resources. We sought to identify the prevalence of discontinuation and nonpublication of interventional clinical trials conducted in ophthalmology patients. METHODS: A retrospective, cross-sectional study of ophthalmology-based interventional clinical trials in ClinicalTrials.gov dating back to 1972 was conducted. χ2 tests were used to determine any potential associations between trial characteristics and trial completion. The Mann-Whitney U test was used to compare median time to publication between academic and industry-sponsored trials. RESULTS: Of 2926 included trials, 413 (14%) were discontinued early with only 19 of these studies being published. A total of 2027 (81%) of the 2513 completed trials were not published. A total of 277 419 participants were enrolled in unpublished, completed trials, whereas an estimated 20 843 participants were enrolled in trials that were never completed and never to led to publication. The odds of study discontinuation among industry-sponsored trials were 27% greater than government/academia-sponsored (National Institutes of Health, National Eye Institute, National Institutes of Health Clinical Center, U.S. and foreign university-based teaching hospitals) trials (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.03-1.57, p = 0.03). Furthermore, the odds of nonpublication among industry-sponsored trials were 55% more than those funded by government/academia (OR = 1.55, 95% CI 1.27-1.89, p < 0.0001). CONCLUSIONS: The nonpublication of many completed trials and of preliminary results of trials that are discontinued early dilutes the quality and decreases the comprehensive nature of the medical literature. This occurs in both industry and academia. Greater transparency through the publication of the entire spectrum of clinical trials' results as well as those that are terminated early could minimize publication bias and thus lead to a more robust medical literature.

Comparing Prednisone and Methotrexate to Off-label Biologic Infliximab for Management of Ocular Uveitis: A Cost-minimization Analysis.

Background: Approximately 3.75% of cases of blindness in the United States are caused by uveitis. Incurred clinical costs and lost productivity related to vision loss in these cases totals $3.58 billion annually. Objective: To evaluate whether infliximab, a modern off-label biologic, is cost-effective for treating posterior uveitis and panuveitis compared to current standards of care, methotrexate and prednisone. Methods: A cost-effectiveness analysis using a Markov model to simulate a patient cohort with posterior uveitis or panuveitis. The model followed patients' therapy from the onset of posterior uveitis or panuveitis using the U.S. societal perspective. The lifetime model simulated health states that could lead to successful reversal of uveitis with standard or intensified treatment with prednisone, methotrexate, or infliximab. Probabilities, health utilities, and costs were included in the model based on findings from the literature. We conducted univariate sensitivity analyses and a Bayesian multivariate probablistic sensitivity analysis to estimate uncertainty in results. Outcomes were measured in terms of costs ($US, 2010) and effects (qualityadjusted life years; QALYs) discounted at 3% per year were estimated for each simulated treatment. An incremental cost-effectiveness ratio (ICER) for pairwise results was interpretted assuming a predetermined willingness-to-pay threshold of $100,000/QALY. Results: Average lifetime costs and QALYs for each drug were ($306.95; 15.80 QALYs) for prednisone, methotrexate ($36,232.24; 16.21 QALYs), and inflixmab ($74,762.63; 15.04 QALYs). Methotrexate was on average compared to prednisone, with an ICER of $86,901.16/QALY. Prednisone and methotrexate dominated infliximab. Sensitivity analyses suggested that the model was most sensitive to the utility for successful recovery from uveitis. The probabilistic sensitivity analysis returned results similar to the base case. Conclusion: This cost-effectiveness analysis suggests that despite advances in the use of biologics for treating sight-threatening posterior uveitis and panuveitis, infliximab had lower effectiveness and higher costs compared to both prednisone and methotrexate. As compared to prednisone, methotrexate was associated with increased costs and QALYs and was found to be a good value. Clinical trials of infliximab in the uveitis population are needed to reduce the uncertain estimates of inflixmab treatment success and the drug's cost-effectiveness.

Systematic review of intravitreal bevacizumab injection for treatment of primary diabetic macular oedema.

PURPOSE: To compare intravitreal bevacizumab (IVB) injection versus macular photocoagulation (MPC) or a combination of intravitreal bevacizumab and intravitreal triamcinolone acetonide (IVB/IVTA) injection in improving visual acuity (VA) of patients with primary diabetic macular oedema (DMO). METHODS: The following databases were searched: Medline (1950 - December week 3, 2009), The Cochrane Library (Issue 4, 2009), EMBASE (up to 24 December 2009), and the TRIP database (up to 23 December 2009), using no language or other limits. Randomized controlled trials were included that consisted of patients with primary DMO (not with refractory DMO), those comparing IVB injection with MPC or IVB/IVTA injection, those reporting VA outcomes, and those having a minimum follow-up of 6 weeks. RESULTS: In the four randomized clinical trials comparing IVB injection with MPC, IVB injection demonstrated significantly greater improvement in VA at 6 weeks, but not at 12 weeks. In the three randomized clinical trials comparing IVB injection with IVB/IVTA, IVB injection demonstrated greater improvement in VA at 6 weeks but the benefit was again no longer significant at 12 weeks. No adjunctive effect of IVTA was demonstrated. CONCLUSIONS: Intravitreal bevacizumab injection is effective in improving VA in patients with primary DMO for 6 weeks, but the benefits are no longer present 12 weeks following the injection.

Triamcinolone and intraocular sustained-release delivery systems in diabetic retinopathy.

Diabetic retinopathy (DR) still represents one of the leading causes of vision loss worldwide. Since this condition affects the posterior segment of the eye, topical application of ophthalmic medicines is of limited benefit, considering that they seldom reach therapeutic levels in the affected tissues. Systemic medications can be insufficient due to the eye's immunoprivileged condition and existence of both inner and outer blood-retinal barriers, which place limitations on the potential role of this route of administration for retinal diseases. In this setting, intraocular therapies have emerged as novel and vital tools in the ophthalmologist's armamentarium against DR, allowing for maximization of drug efficacy and limited risk of systemic side effects. Intravitreal injections of triamcinolone acetonide have been widely used for treating DR particularly in the 21(st) century. Other agents targeting molecules, such as anti-vascular endothelial growth factor, have also demonstrated a potential therapeutic role for treatment. Recent advances in ocular drug delivery methods have led to the development of intraocular implants, which help to provide prolonged treatment with controlled drug release. Moreover, they may add some potential advantages over traditional intraocular injections by delivering certain rates of drug directly to the site of action, amplifying the drug's half-life, contributing in the minimization of peak plasma levels of the drug, and avoiding the side effects associated with repeated intravitreal injections.

Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema: a systematic review.

OBJECTIVE: To compare intravitreal triamcinolone acetonide (IVTA) injection versus no treatment or sub-Tenon triamcinolone acetonide (STTA) injection in improving visual acuity (VA) of patients with refractory diabetic macular edema (DME; unresponsive to focal laser therapy). CLINICAL RELEVANCE: Diabetic macular edema is the leading cause of visual loss in diabetic retinopathy. Laser therapy has been the standard of care for patients with persistent or progressive disease. More recently, it has been suggested that IVTA injection may improve VA. METHODS AND LITERATURE REVIEWED: The following databases were searched: Medline (1950-September Week 2 2008), The Cochrane Library (Issue 3, 2008), and the TRIP Database (up to September 1, 2008), using no language or other limits. Randomized controlled trials were included that consisted of patients with refractory DME, those comparing IVTA injection with no treatment or STTA injection, those reporting VA outcomes, and those having a minimum follow-up of 3 months. RESULTS: In the 4 randomized clinical trials comparing IVTA injection with placebo or no treatment, IVTA injection demonstrated greater improvement in VA at 3 months, but the benefit was no longer significant at 6 months. Those who received IVTA injection had significantly higher IOP at 3 months and at 6 months. In the 2 randomized clinical trials comparing IVTA injection with STTA injection, IVTA injection demonstrated greater improvement in VA at 3 months, but not at 6 months. Intravitreal triamcinolone acetonide injection demonstrated no difference in IOP at 3 months or at 6 months. CONCLUSIONS: Intravitreal triamcinolone acetonide injection is effective in improving VA in patients with refractory DME in the short-term, but the benefits do not seem to persist in the long-term. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Post-streptococcal uveitis.

PURPOSE: To describe the clinical features of post-streptococcal uveitis (PSU) and examine management strategies in the treatment of this under-recognized condition. METHODS: Patients were identified from the world literature using the Pubmed search engine. We examined two new cases of post-streptococcal intermediate uveitis. The epidemiology, immune mechanisms, clinical features, investigations, treatments and visual outcomes were examined and recorded. RESULTS: We reviewed 11 patients including our own two cases. There was a statistically significant seasonal difference in antistreptolysin-O titres (ASOT), and age-related ASOT was identified. Of the 11 patients, eight (72.7%) had anterior uveitis, two (18.2%) had intermediate uveitis and one (9.1%) had panuveitis. Their ages ranged from 5 to 56 years (mean 17 years). The majority of cases had significantly elevated ASOT; most patients were treated with topical steroids and oral antibiotics and four cases underwent adenotonsillectomy. The visual prognosis was good in most cases. CONCLUSIONS: Uveitis may be the sole presenting clinical feature, or it may occur in combination with other features of post-streptococcal infection. Ophthalmologists should be aware of the clinical features of PSU and maintain a high level of suspicion, particularly in childhood uveitis.