Glaucoma Clinical Trials Research Articles

Mechanism - Based Translational Pharmacokinetic - Pharmacodynamic Model to Predict Intraocular Pressure Lowering Effect of Drugs in Patients with Glaucoma or Ocular Hypertension

To develop a mechanism based translational pharmacokinetic-pharmacodynamic (PKPD) model in preclinical species and to predict the intraocular pressure (IOP) following drug treatment in patients with glaucoma or ocular hypertension (OHT). Baseline diurnal IOP of normotensive albino rabbits, beagle dogs and patients with glaucoma or OHT was collected from literature. In addition, diurnal IOP of patients treated with brimonidine or Xalatan® were also obtained from literature. Healthy normotensive New Zealand rabbits were topically treated with a single drop of 0.15% brimonidine tartrate and normotensive beagle dogs were treated with a single drop of Xalatan®. At pre-determined time intervals, IOP was measured and aqueous humor samples were obtained from a satellite group of animals. Population based PKPD modeling was performed to describe the IOP data and the chosen model was extended to predict the IOP in patients. Baseline IOP clearly depicts a distinctive circadian rhythm in rabbits versus human. An aqueous humor dynamics based physiological model was developed to describe the baseline diurnal IOP across species. Model was extended to incorporate the effect of drug administration on baseline IOP in rabbits and dogs. The translational model with substituted human aqueous humor dynamic parameters predicted IOP in patients following drug treatment. A physiology based mechanistic PKPD model was developed to describe the baseline and post-treatment IOP in animals. The preclinical PKPD model was successfully translated to predict IOP in patients with glaucoma or OHT and can be applied in assisting dose and treatment selection and predicting outcome of glaucoma clinical trials.

Lower Limits of Intraocular Pressure in Glaucoma Clinical Trials

To determine the association of the lower limit of intraocular pressure (IOP) specified in the inclusion criteria to baseline and active treatment visit IOPs for monotherapy treatments. A review of clinical trial articles evaluating currently used topical glaucoma medicines. Articles were published between January 1995 and December 2011. This study included 37 monotherapy treatment arms from 15 studies. There were 18 prostaglandin analogs, 8 β-blockers, 8 carbonic anhydrase inhibitors, 2 α-agonists, and 1 unoprostone. For all studies included generally there was a stepwise increase in the baseline 8 AM and diurnal IOP of approximately 1 mm Hg for each 1 mm Hg increase in entry criteria. This was true for all treatment arms together, with or without a PM entry criterion (P<0.0001). However, the inclusion of an afternoon entry criterion time point did not seem to affect average IOP at baseline for the 8 AM and diurnal IOP. The treated reductions from baseline were not statistically different based on morning or afternoon entry criteria for either the 8 AM or diurnal IOPs (P≥0.07). Progressively higher 8 AM entry criteria IOPs at untreated baseline may influence, depending on design, in a linear manner the 8 AM and diurnal baseline IOPs of glaucoma studies at baseline. However, this effect was not observed in the treated reductions from baseline. Further, the addition of an afternoon entry criterion time point does not seem to change baseline 8 AM and diurnal IOPs.

Glaucoma clinical trial design: A review of the literature.

The purpose of this article is to review the prior research evaluating design techniques for glaucoma clinical trials to help ophthalmologists and pharmaceutical sponsors better develop literature-based studies that are cost- and time-efficient. We performed this study using known published articles by the authors and literature found on Pub Med. We included 24 articles that analyzed specifically the results of clinical trial methods and/or interpretation. This review found that studies have evaluated glaucoma specific aspects of glaucoma clinical trials including: Predicting the results of later phase clinical trials based on early phase clinical trials and animal studies; protocol design parameters such as intraocular pressure, inclusion criteria, method of pressure measurement, study population, and side effect evaluation; and study planning issues such as number of clinical sites as well as subjects, dropout rates, estimated serious adverse events, and protocol violations. This review suggests that the medical literature supports some aspects of glaucoma clinical trial study design. Additional design features might be derived from government regulations, guidance, as well as agency contacts, consultants, and clinical community standards. Study design decisions that must be made beyond the aforementioned resources should be made carefully, with appropriate consultation as needed, considering the risk/benefit ratio to the study. However, more research is needed to better evaluate the design procedures and methods involved in glaucoma clinical trials to best provide a cost- and time-efficient study while achieving quality efficacy and safety results.

Evaluation of Progressive Neuroretinal Rim Loss as a Surrogate End Point for Development of Visual Field Loss in Glaucoma

To evaluate the validity of using progressive loss of neuroretinal rim area as a surrogate end point for the development of visual field loss in glaucoma. Prospective, observational cohort study. The study group included 492 eyes of 328 patients classified with suspected glaucoma at the baseline visit. These eyes had an average of 7.4±2.8 confocal scanning laser ophthalmoscopy (CSLO) images during a mean follow-up time of 6.6±1.6 years. Rim area measurements were acquired with CSLO during follow-up. The visual field end point was considered the development of 3 consecutive abnormal visual fields on standard automated perimetry. Strong predictive ability and large proportion of treatment effect (PTE) explained are requisites for a suitable surrogate end point. A joint longitudinal survival model was used to evaluate the ability of rates of rim area loss in predicting visual field development, adjusting for confounding variables (baseline age, race, and corneal thickness and follow-up measurements of intraocular pressure [IOP] and pattern standard deviation). The PTE was calculated by comparing the effect of IOP on the risk of development of visual field loss when incorporating rim area loss in the same model with the effect of IOP in the model excluding rim area measurements. Predictive strength was measured by survival-adapted R(2) and PTE. Sixty-two of 492 eyes (13%) developed visual field loss during follow-up. The mean rate of rim area change in eyes that developed visual field loss was-0.011 mm(2)/year versus-0.003 mm(2)/year in eyes that did not (P<0.001). In the multivariable model, each 0.01 mm(2)/year faster rate of rim area loss was associated with a 2.94 higher risk of visual field loss (hazard ratio, 2.94; 95% confidence interval, 1.38-6.23; P= 0.005). R(2) values were 62% and 81% for univariable and multivariable models, respectively. The PTE was 65%. Progressive rim area loss was highly predictive of the development of visual field loss in glaucoma and explained a significant PTE on the clinically relevant outcome. These findings suggest that rim area measurements may be suitable surrogate end points in glaucoma clinical trials.

Assessment of rates of structural change in glaucoma using imaging technologies

To review the ability of current imaging technologies to provide estimates of rates of structural change in glaucoma patients. Review of literature. Imaging technologies, such as confocal scanning laser ophthalmoscopy (CSLO), scanning laser polarimetry (SLP), and optical coherence tomography (OCT), provide quantifiable and reproducible measurements of the optic disc and parapapillary retinal nerve fibre layer (RNFL). Rates of change as quantified by the rim area (RA) (for CSLO) and RNFL thickness (for SLP and OCT) are related to glaucoma progression as detected by conventional methods (eg, visual fields and optic disc photography). Evidence shows that rates of RNFL and RA loss are significantly faster in progressing compared with non-progressing glaucoma patients. Measurements of rates of optic disc and RNFL change are becoming increasingly precise and individualized. Currently available imaging technologies have the ability to detect and quantify progression in glaucoma, and their measurements may be suitable end points in glaucoma clinical trials.

Bridging the Major Prospective National Eye Institute-sponsored Glaucoma Clinical Trials and Clinical Practice

De Moraes, Carlos Gustavo MD*,†; Ritch, Robert MD*,‡; Liebmann, Jeffrey M. MD*,† Author Information

Predicting treatment effects using biomarker data in a meta‐analysis of clinical trials

A biomarker (S) measured after randomization in a clinical trial can often provide information about the true endpoint (T) and hence the effect of treatment (Z). It can usually be measured earlier and more easily than T and as such may be useful to shorten the trial length. A potential use of S is to completely replace T as a surrogate endpoint to evaluate whether the treatment is effective. Another potential use of S is to serve as an auxiliary variable to help provide information and improve the inference on the treatment effect prediction when T is not completely observed. The objective of this report is to focus on its role as an auxiliary variable and to identify situations when S can be useful to increase efficiency in predicting the treatment effect in a new trial in a multiple-trial setting. Both S and T are continuous. We find that higher efficiency gain is associated with higher trial-level correlation but not individual-level correlation when only S, but not T is measured in a new trial; but, the amount of information recovery from S is usually negligible. However, when T is partially observed in the new trial and the individual-level correlation is relatively high, there is substantial efficiency gain by using S. For design purposes, our results suggest that it is often important to collect markers that have high adjusted individual-level correlation with T and at least a small amount of data on T. The results are illustrated using simulations and an example from a glaucoma clinical trial.

Primary Congenital Glaucoma

Glaucomas of the childhood are devastatinly deceptive in their presentations because of an insidious onset and late recognition. Primary congenital glaucomas (PCG) which serve as a prototype for glaucomas in the young Subtleties of diagnosis may lie in simple symptoms of watering and photophobia. This article is aimed to summarize all common manifestations and basics of surgical treatment, conventional and contemporary. Parameters of diagnosis and success have been undergoing modifications from time to time, hence the need to take stalk. How we look at childhood glaucomas in the light of conclusions drawn from glaucoma clinical trials in adults, evolving concepts of risk factors like central corneal thickness at the first and subsequent visits are of practical concern.

Factors associated with site requirement for glaucoma clinical trials

Factors associated with site requirement for glaucoma clinical trials

Mixed treatment comparison and meta-regression of the efficacy and safety of prostaglandin analogues and comparators for primary open-angle glaucoma and ocular hypertension

Objectives:Primary open-angle glaucoma (POAG) is a chronic condition characterised by optic neuropathy and vision loss. Elevated intraocular pressure (IOP) can damage the optic nerve and is a risk factor for glaucoma, thus treatment usually comprises topical hypotensives. This analysis aims to address methodological issues associated with the synthesis of glaucoma clinical trial data, given variations in study methodology and IOP measurement.Methods:Meta-regression was used to estimate how IOP varies over time for patients receiving treatment. Relative treatment effects were assessed using a random-effects mixed treatment comparison (MTC) in order to preserve randomisation and avoid selection bias. To produce clinically meaningful outputs, these analyses were combined to obtain the mean on-treatment IOP and the proportion of patients achieving different IOP targets at different time points. A further MTC estimated the probability of hyperaemia events.Results:The analysis showed that after 3 months’ treatment, between 58 and 83% of patients will have a ≥20% reduction in IOP and 70–93% of patients will have an absolute IOP <20 mmHg. Latanoprost and bimatoprost were found to produce significantly lower on-treatment IOP compared with timolol (p < 0.05); the difference between latanoprost and bimatoprost was not significant. Travoprost produced a lower mean IOP compared with timolol (not significant). Latanoprost-timolol was found to produce significantly lower IOP than latanoprost alone or β-blockers. The probability of hyperaemia-type events varied between treatments from 14.8 to 63.03%. Latanoprost had significantly lower odds of hyperaemia than travoprost, bimatoprost, travoprost-timolol, or bimatoprost-timolol.Conclusion:This analysis suggests that latanoprost and bimatoprost produce a statistically significant reduction in IOP compared with timolol, but are associated with a higher risk of hyperaemia. Out of all the prostaglandins, latanoprost may achieve a good balance between tolerability and IOP efficacy. As with all forms of meta-analysis, the results are based on the assumption that the studies and intervention groupings are sufficiently similar to be compared.

The Glaucoma Research Community and FDA Look to the Future: A Report from the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium*

On March 13–14, 2008, the National Eye Institute (NEI), of the National Institutes of Health (NIH), and the Food and Drug Administration Center for Drug Evaluation and Research (FDA CDER) held the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium to discuss the possible use of new structural and functional endpoints for evaluating glaucoma therapies in clinical trials. It was an important meeting where the FDA and the glaucoma research community advanced their common understanding of glaucoma clinical trials. An appreciation was gained by researchers and others within the glaucoma community of the receptivity of the FDA to new endpoints. Glaucoma is a complex, progressive optic neuropathy. It is the leading cause of irreversible and preventable blindness, affecting an estimated 2.2 million people in the United States and 70 million worldwide. Basic and clinical research initiatives are revealing the pathobiology and clinical course of glaucoma and are setting the stage for possible new treatments. Currently, clinical drug trials are focused on intraocular pressure (IOP) measurements and/or visual field tests (a functional outcome measure) for the assessment of clinical IOPlowering efficacy and changes in optic nerve function. In some studies, stereoscopic optic disc photography (a structural outcome measure) has been used as a secondary endpoint. The FDA considers optic nerve and retinal nerve fiber layer (RNFL) structural changes and new changes in visual function to be outcome measures in clinical trials that serve as the basis for approving neuroprotective glaucoma therapies, provided those outcomes are proven predictive of function that is clinically relevant to a patient. Although there are data suggesting the early involvement of central vision, glaucoma generally affects peripheral vision first in standard clinical testing. Functional visual field tests evaluate the presence and amount of visual field loss. Clinical observation of the optic nerve and examination of optic nerve photographs can be used to determine the presence of structural changes such as narrowing of the neuroretinal rim, loss of parapapillary fibers from the RNFL, increased excavation of the optic cup, -zone parapapillary atrophy, and optic disc hemorrhage. Accurate interpretation of the structural events has traditionally been dependent on the experience and subjective judgment of the observer. New computerized imaging devices for viewing the optic nerve are used widely to detect glaucomatous changes in the optic disc and RNFL and also to quantitate these changes. Measurements generally are objective and reproducible. Among these imaging technologies are confocal scanning laser ophthalmoscopy, scanning laser polarimetry, and optical coherence tomography. The purpose of the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium was to provide a forum for discussing outcome measures— based on the newer technologies—for evaluating neuroprotective products (i.e., those that protect the optic nerve) for glaucoma in clinical trials to facilitate bringing safe and efficacious glaucoma pharmacotherapies to the U.S. market. Although there was no discussion in the Symposium directly comparing the various technologies and instruments, a future meeting on this subject is anticipated. The meeting was held in the Natcher Auditorium on the NIH campus. Participants from the glaucoma community left with a clearer understanding of FDA expectations for demonstrating the safety and efficacy of new pharmacotherapies, the relevancy of new endpoints, and the role of the FDA in providing guidance for meeting recognized standards for approval of new therapeutic agents. Symposium organizers were Robert N. Weinreb, MD, Uni

Role of Optic Nerve Imaging in Glaucoma Clinical Practice and Clinical Trials

Role of Optic Nerve Imaging in Glaucoma Clinical Practice and Clinical Trials

Role of Optic Nerve Imaging in Glaucoma Clinical Practice and Clinical Trials

To provide an update on the role of optic nerve and peripapillary retinal nerve fiber layer imaging in glaucoma clinical practice and clinical trials. Perspective. Review of recent literature and authors' clinical and laboratory studies. Imaging technologies such as confocal scanning laser ophthalmoscopy, scanning laser polarimetry, and optical coherence tomography provide objective and quantitative measurements that are highly reproducible and show very good agreement with clinical estimates of optic nerve head structure and visual function. Structural assessments provided by imaging complement optic disk photography in clinical care and have the potential to identify relevant structural efficacy endpoints in glaucoma randomized clinical trials. As with other technologies, imaging may produce false identification of glaucoma and its progression; thus, clinicians should not make management decisions based solely on the results of one single test or technology. Although optic disk stereophotography represents the standard for documentation of glaucomatous structural damage in practice and research trials, advances in computerized imaging technology provide useful measures that assist the clinician in glaucoma diagnosis and monitoring and offer considerable opportunity for use as efficacy endpoints in clinical trials.

Eye on the Bayou: New Concepts in Glaucoma, Cataract and Neuro-Ophthalmology

Jonathan D. Nussdorf, MD. Kugler Publishers, The Hague, Netherlands, 2006. ISBN: 978-90-6299-209-6, $108.00. Scope: This book is a collection of the lectures and roundtable discussions from the 54th Annual Symposium of the New Orleans Academy of Ophthalmology. The book is divided into four main sections: neuro-ophthalmology, glaucoma, psychophysics, and anterior segment surgery. The target reader is the comprehensive ophthalmologist. Each subspecialty section contains the text of several lectures and roundtable discussions designed to address questions introduced by the preceding lectures. The roundtable panel consists of several “experts” who discuss their philosophy on difficult management issues. The neuro-ophthalmology section contains transcripts of Andrew Lee's excellent lectures on common mistakes when examining the neuro-ophthalmology patient, double vision and pupil involvement, an update on optic neuritis, and important points to communicate to patients with nonarteritic anterior ischemic optic neuropathy. Additionally, Lee discusses MRI, CT, and optical coherence tomography (OCT) indications in neuro-ophthalmology. The second section includes lectures by Harry Quigley and Eve Higginbotham that cover epidemiological risk factors for glaucoma such as race and sex. This is followed by a discussion on low tension glaucoma and neuroprotection. Paul Palmberg critiques the commonly held belief that glaucoma structural damage precedes visual function loss. Finally, there are several succinct synopses of recent landmark glaucoma clinical trials (CNTGS, AGIS, EMGT, CIGTS, OHTS, and EGPS) followed by an interesting roundtable discussion critiquing these clinical trials. The psychophysics section is primarily a series of lectures updating visual field testing with short wavelength automated perimetry (SWAP), frequency doubling technology (FDT), Swedish interactive thresholding algorithm (SITA), zippy estimation of sequential testing (ZEST), and tendency oriented perimetry (TOP). Additionally, there is a section on interpreting visual field loss in glaucoma and a roundtable discussion on detecting and monitoring glaucoma progression. The final section consists of several lectures on anterior segment surgery and complications. The first lecture discusses the new disease entity “toxic anterior segment syndrome.” The remaining lectures are discussions of the basics of laser trabeculoplasty and clinical pearls on performing and managing trabeculectomy. Two roundtable discussions cover trabeculectomy skills by providing further pearls and suggestions for surgical infection prophylaxis. Strengths: This book contains many useful diagnostic pearls relevant to comprehensive ophthalmologists. The text is easy to follow. The neuro-ophthalmology section is especially well done and practical. The roundtable discussions are insightful. Weaknesses: The topics covered are relatively narrow. There is no index. If readers are not looking for updates on the specific topics, they may find the book focused on too little. Recommended Audience: This book is aimed to the comprehensive ophthalmologist or specialist interested in updating knowledge in a different subspecialty. Additionally, individuals who attended the 54th Annual Symposium of the New Orleans Academy of Ophthalmology can use this book to review the material. Critical Appraisal: This book provides a practical, succinct update on narrow but important topics to the practicing comprehensive ophthalmologist or resident physician. Christopher Thiagarajah, MD Karl Golnik, MD, MEd University of Cincinnati and the Cincinnati Eye Institute Cincinnati, Ohio

Choosing endpoints in clinical studies and trials

Currently, it is challenging to select endpoints for measuring disease progression in glaucoma clinical trials. The endpoints that are used are not biological, but statistical, events because there is no reference standard for progression. Progression rates depend on the criteria used to define change, and in the absence of a reference standard for progression, reasonable criteria can be determined by paying attention to specificity (ie false-positive rate). Past randomized-clinical trials (CITGS, OHTS, and CNGT) have not made a accurate estimate of specificity at the time of trial design. It is not meaningful to compare the sensitivities (or more accurately the ‘hit rate’) of different progression criteria unless their respective specificities are equivalent. The ideal approach to compare progression rates, therefore, would be to equalize the specificities with each approach. However, owing to the lack of an external standard, this is difficult to achieve with reasonable confidence. With the advancement of research in visual field and imaging, clinical endpoints will have to be reviewed to incorporate new criteria for progression detection and measurement.

Glaucoma clinical trials and what they mean for our patients

PurposeTo InternetAdvance publication at ajo.com May 15, 2003. provide a perspective on the several randomized clinical trials in glaucoma, to suggest how their results can be used in clinical practice, and to look to the future of glaucoma therapy. DesignA search and review of the glaucoma clinical trials literature, the glaucoma observational studies literature, and the evidence–based medicine literature. MethodsAnalysis of the significance of glaucoma clinical trials data on patient management along with use of patient data to demonstrate how treatment decisions can be used in the practice setting. ResultsGlaucoma clinical trials and observational studies strongly support the need to reduce intraocular pressures (IOP) substantially and to maintain those pressures in patients with advanced glaucoma. Whether this aggressive therapy occurs by medications or by filtering surgery does not seem as important as that the treatment is effective and sustained. However, there is not the same strength of evidence for aggressive treatment or even any treatment for most patients with ocular hypertension and for some cases of early glaucoma. Because about half of the patients with open-angle glaucoma will have IOPs less than 21 mm Hg, these patients need to be detected through careful optic disk and visual field assessment. Once patients are detected and treated appropriately, blindness from open-angle glaucoma is unlikely. ConclusionsThe goal of managing ocular hypertension and glaucoma is not to preserve every ganglion cell, but rather to preserve a patient’s visual ability to conduct activities of daily living. Risk factors for damage need to be assessed for individual patients and each patient managed as an individual and not as the “average” patient depicted in the results of clinical trials. In the future, neuroprotective therapy other than IOP reduction will provide another means to control glaucoma damage.

Translating Research into Practice

Historically, management strategies for glaucoma have stressed reduction of IOP as the primary goal. Yet, if we question this principle, we find a deficiency of information to support it as the optimal strategy for managing glaucoma patients and those at risk of developing glaucoma. Thus, the practice of lowering IOP in glaucoma management was placed on trial by the 1987 Eddy and Billings report (D. M. Eddy and J. Billings, 1987). Although generally denounced by clinicians, this report nonetheless alerted the ophthalmologic community that success of glaucoma treatment must be measured by endpoints unrelated to IOP and that a controlled trial to demonstrate glaucoma treatment efficacy was necessary. A clinical trial is an experiment. As such, it is the best study design for inferring causality between an exposure (e.g., IOP) and an outcome (e.g., glaucoma), and it is the best methodology for demonstrating treatment efficacy. However, it is important to understand that efficacy is not the same as effectiveness. Whereas "efficacy" is the extent to which a specific intervention produces a beneficial result under ideal conditions, "effectiveness" is the extent to which a specific intervention, when deployed in the field, does what it is intended to do. The influence of study results on the practice of medicine is more a function of demonstrated effectiveness than efficacy of an intervention. All of the completed glaucoma clinica trials reviewed were well performed, and many have had a substantial influence on the philosophy and practice of glaucoma management. The glaucoma clinical trials currently being performed represent the highest standards of clinical trial methodology. This is an exciting time for clinical research on glaucoma. Well accepted dogmas are being challenged, and the ophthalmic community is aggressively addressing difficult issues. Questions being asked are of fundamental importance and addressing them is essential. Particularly exciting in these trials is the fact that IOP is not being considered as an endpoint and that consideration is being given to the previously ignored but extremely important issue of overall patient well-being. Only with time will the ultimate impact of these trials on the philosophy and practice of glaucoma management become evident.