Statistical approaches to interim analysis : a critical appraisal

Several important questions have been raised about decision of stopping a trial early and on what basis to reach such a decision. It seemed therefore of interest to investigate the forms of monitoring used in cancer clinical trials and to gather information on the role of interim analyses in the data monitoring process of a clinical trial. The project addressed the following issues: - what is the performance of different interim analysis approaches; - how often interim analyses are used in cancer clinical trials; - which types of statistical analyses are more frequently adopted; - how the data monitoring is organised and which is the weight of statistical analyses in the decisional process. Analysis of performance of different statistical analysis approaches has been conducted by comparing the probability of stopping and the estimation bias on clinical scenarios based on real data of trials performed in ovarian and colorectal cancers. The project also focused on the prevalence of different types of interim analyses and data monitoring for both safety and efficacy in cancer clinical trials. Sources of investigation were the literature data and the protocols of cancer clinical trials included in the in the Italian registry of clinical trials.Results of our research indicate that the more widely used statistical approaches reduce the risk of “incorrect “ early stopping, compared with the adoption of no stopping rule, with similar performance. Analysis of protocols and early reports suggests that the implementation of these procedures in a monitoring strategy is not satisfactory. Use of interim analyses is still limited to the frequentist approach of the alpha-spending function, while the Bayesian is not considered. Interim analysis plans are still scarcely described, even in more recent protocols, denoting a not yet sufficient attention to this issue not only by the researchers, but also by regulatory bodies

Safety and efficacy of travoprost solution for the treatment of elevated intraocular pressure

Travoprost is a prostaglandin analogue widely used for reducing intraocular pressure (IOP) in patients affected with glaucoma and ocular hypertension. It exerts its ocular hypotensive effect through the prostaglandin FP receptors, located in the ciliary muscle and the trabecular meshwork. Several studies have shown that topical administration of travoprost induces a mean IOP reduction ranging from 25% to 32%, and sustained throughout the 24-hour cycle. When compared with timolol, travoprost is more effective at reducing IOP, while generally no difference has been found in the head-to-head comparison with other prostaglandin analogues. The fixed combination of travoprost and timolol has demonstrated a hypotensive efficacy comparable to the concomitant administration of the two drugs. Recently, a new preservative-free formulation of travoprost 0.004% has been marketed for reducing tolerability-related problems in subjects affected with ocular surface disease. Low rates of topical and systemic adverse reactions, strong ocular hypotensive efficacy, and once-a-day dosing make travoprost a first-line treatment for patients affected with elevated IOP

Long-term 24-hour intraocular pressure control with travoprost monotherapy in patients with primary open-angle glaucoma

The aim of the study was to evaluate the long-term 24-hour intraocular pressure (IOP) efficacy of travoprost monotherapy in primary open-angle glaucoma patients

Elevated intraocular pressure in patients with acromegaly

To evaluate central corneal thickness (CCT) and intraocular pressure (IOP) in a cohort of acromegalic patients, and to correlate CCT with serum levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1)

Differential Protein Expression Profiles in Glaucomatous Trabecular Meshwork: An Evaluation Study on a Small Primary Open Angle Glaucoma Population

INTRODUCTION: Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by impaired aqueous outflow and extensive remodeling in the trabecular meshwork (TM). The aim of this study was to characterize and compare the expression patterns of selected proteins belonging to the tissue remodeling, inflammation and growth factor pathways in ex vivo glaucomatous and post-mortem TMs using protein-array analysis. METHODS: TM specimens were collected from 63 white subjects, including 40 patients with glaucoma and 23 controls. Forty POAG TMs were collected at the time of surgery and 23 post-mortem specimens were from non-glaucomatous donor sclerocorneal tissues. Protein profiles were evaluated using a chip-based array consisting of 60 literature-selected antibodies. RESULTS: A different expression of some factors was observed in POAG TMs with respect to post-mortem specimens, either in abundance (interleukin [IL]10, IL6, IL5, IL7, IL12, IL3, macrophage inflammatory protein [MIP]1δ/α, vascular endothelial growth factor [VEGF], transforming growth factor beta 1 [TGFβ1], soluble tumor necrosis factor receptor I [sTNFRI]) or in scarcity (IL16, IL18, intercellular adhesion molecule 3 [ICAM3], matrix metalloproteinase-7 [MMP7], tissue inhibitor of metalloproteinase 1 [TIMP1]). MMP2, MMP7, TGFβ1, and VEGF expressions were confirmed by Western blot, zymography, and polymerase chain reaction. No difference in protein profile expression was detected between glaucomatous subtypes. CONCLUSION: The analysis of this small TM population highlighted some proteins linked to POAG, some previously reported and others of new detection (IL7, MIPs, sTNFαRI). A larger POAG population is required to select promising disease-associated biomarker candidates. FUNDING: This study was partially supported by the Fondazione Roma, the Italian Ministry of Health and the “National 5xMille 2010 tax donation to IRCCS-G.B. Bietti Foundation”. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-016-0285-x) contains supplementary material, which is available to authorized users

Health-related quality of life in patients with primary open-angle glaucoma. An Italian multicentre observational study

Purpose: As a progressive condition, glaucoma may impair health-related quality of life (HRQoL), due to vision loss and other factors. This study evaluated HRQoL in a cohort of patients treated for primary open-angle glaucoma (POAG) and assessed its association with clinical features. Methods: This was an Italian, multicentre, cross-sectional, observational study with the subgroup of newly diagnosed patients with POAG prospectively followed up for one year. Patients with previous or new diagnosis (or strong clinical suspicion) of POAG aged >18 years were considered eligible. Information was collected on demographic characteristics, medical history, clinical presentation and POAG treatments. HRQoL was measured using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and Glaucoma Symptom Scale (GSS). Subscale and total scores were obtained and a Pearson correlation coefficient between instruments’ scores calculated. Results: A total of 3227 patients were enrolled from 2012 to 2013 and 3169 were analysed. Mean age was 66.9 years. A total of 93.8% had a previous diagnosis (median duration: 8.0 years). Median values for mean deviation and pattern standard deviation were 3.9 and 3.6 dB, respectively. Mean scores on most subscales of the NEI-VFQ-25 exceeded 75.0 and mean GSS subscale scores ranged between 70.8 and 79.7 (with a total mean score of 74.8). HRQoL scores on both scales were significantly inversely associated with POAG severity. Conclusion: In this large sample of Italians treated for POAG, disease severity was limited and HRQoL scores were high. QoL decreased with advancing disease severity. These findings confirm the role of vision loss in impairing QoL in POAG, underlying the importance of timely detection and appropriate treatment

Approaches to interim analysis of cancer randomised clinical trials with time to event endpoints: A survey from the Italian National Monitoring Centre for Clinical Trials

<p>Abstract</p> <p>Background</p> <p>Although interim analysis approaches in clinical trials are widely known, information on current practice of planned monitoring is still scarce. Reports of studies rarely include details on the strategies for both data monitoring and interim analysis. The aim of this project is to investigate the forms of monitoring used in cancer clinical trials and in particular to gather information on the role of interim analyses in the data monitoring process of a clinical trial. This study focused on the prevalence of different types of interim analyses and data monitoring in cancer clinical trials.</p> <p>Methods</p> <p>Source of investigation were the protocols of cancer clinical trials included in the Italian registry of clinical trials from 2000 to 2005. Evaluation was restricted to protocols of randomised studies with a time to event endpoint, such as overall survival (OS) or progression free survival (PFS). A template data extraction form was developed and tested in a pilot phase. Selection of relevant protocols and data extraction were performed independently by two evaluators, with differences in the data assessment resolved by consensus with a third reviewer, referring back to the original protocol. Information was obtained on a) general characteristics of the protocol b) disease localization and patient setting; c) study design d) interim analyses; e) DSMC.</p> <p>Results</p> <p>The analysis of the collected protocols reveals that 70.7% of the protocols incorporate statistical interim analysis plans, but only 56% have also a DSMC and be considered adequately planned. The most concerning cases are related to lack of any form of monitoring (20.0% of the protocols), and the planning of interim analysis, without DSMC (14.7%).</p> <p>Conclusion</p> <p>The results indicate that there is still insufficient attention paid to the implementation of interim analysis.</p