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Objectives During crizotinib clinical evaluation, visual disturbances, generally of grade 1 severity, were frequently reported adverse events (AE). Consequently, ophthalmologic assessments were included in a patient subgroup enrolled in PROFILE 1001 (NCT00585195), a phase 1, open-label, single-arm trial of crizotinib in patients with advanced non-small-cell lung cancer and are reported here. Materials and methods At least 30 patients were required to undergo ophthalmologic assessments, including: best-corrected visual acuity (BCVA), refractive error, pupil size, slit-lamp anterior segment biomicroscopy, intraocular inflammation, intraocular pressure, retinal fundoscopic exams, fundus photography, ocular characteristics, and optical coherence tomography (OCT). Scheduled assessments included those at baseline, Cycle 1 Day 15, Cycle 3 Day 1 (C3D1), annually during treatment, and end of treatment (28 days after last crizotinib dose). Results Thirty-three patients completed all required ophthalmologic assessments through C3D1, and 22 (66.7 %) had abnormal findings on ≥1 ophthalmologic test. Clinically important changes were ≥2-line loss in BCVA in 10 patients (30.3 %), >±1.25-diopter change in refractive error in 3 patients (9.1 %), >±2-mm change pupillary diameter change in 3 patients (9.1 %), and >50 μm increase in OCT center point thickness in 7 patients (21.2 %). Three patients (15 %) reported clinically significant abnormalities in anterior segment biomicroscopy (grade 1 cataract [n = 2], grade 1 Visual Impairment [n = 1]). No permanent treatment discontinuations were associated with ophthalmologic findings changes. Twenty-four patients (72.7 %) reported ≥1 ocular all-causality treatment-emergent AE (TEAE); none required dose reduction or permanent discontinuation, but 2 required temporary dosing interruption. Although TEAEs and ophthalmologic findings may not have occurred concurrently, of 24 patients with ≥1 all-causality ocular TEAE, 18/24 (75.0 %) had ≥1 abnormal ophthalmologic finding and 6/24 (25 %) had none; and of 9 patients without an all-causality ocular TEAE, 4/9 (44.4 %) had ≥1 abnormal ophthalmologic finding and 5/9 (55.6 %) had none. Of the 18 patients with ≥1 abnormal ophthalmologic finding, 9 (50 %) had preexisting ocular conditions. Conclusion During crizotinib treatment, ophthalmologic changes from baseline did not appear to be associated with patient-reported ocular TEAEs. Abnormal ophthalmologic findings occurred in the context of preexisting conditions for a number of patients. No ophthalmologic changes from baseline or ocular all-causality TEAEs required permanent treatment discontinuation.

Introduction We retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase–positive advanced NSCLC across four trials (NCT00585195, NCT00932451, NCT00932893, and NCT01154140). Methods Changes from baseline data in serum creatinine and eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based equation, were assessed over time. eGFR was graded using standard chronic kidney disease criteria. Results Median serum creatinine increased from 0.79 mg/dL at baseline to 0.93 mg/dL after 2 weeks of treatment (median percentage increase from baseline, 21.2%), was stable from week 12 (0.96 mg/dL) to week 104 (1.00 mg/dL), and decreased to 0.90 mg/dL at 28 days after last dose (median percentage increase from baseline, 13.1%). Median eGFR decreased over time (96.42, 80.23, 78.06 and 75.45 mL/min/1.73 m2 at baseline, week 2, week 12, and week 104, respectively) and increased to 83.02 mL/min/1.73 m2 at 28 days after the last dose. Median percentage decrease from baseline was 14.9%, 17.0%, and 10.4% at week 2, week 12, and 28 days after last dose of crizotinib, respectively. Overall, 12.6% of patients had a shift from eGFR grade less than or equal to 3a (≥45 mL/min/1.73 m2) at baseline to greater than or equal to 3b ( Conclusions Crizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity.

Aim: We analyzed cardiac function in two Phase III studies of previously treated (PROFILE 1007) or untreated (PROFILE 1014) ALK-positive advanced non-small-cell lung cancer. Patients & methods: Adverse events associated with cardiac failure were compared between treatment arms in each study separately. Cardiac function was assessed prospectively by multigated acquisition scans or echocardiograms. Results: In PROFILE 1007 and 1014, incidence of cardiac failure adverse events was 0% (crizotinib) versus 0.6% (chemotherapy) and 2.3% versus 0.6%, respectively. In crizotinib versus chemotherapy arms, respectively, >20% left ventricular ejection fraction decreases occurred in 0/19 (0%) versus 1/16 (6.3%) patients from PROFILE 1007 and 4/150 (2.7%) versus 10/150 (6.7%) patients from PROFILE 1014. Conclusion: These analyses did not reveal any clinically meaningful changes in myocardial function with crizotinib in patients with ALK-positive non-small-cell lung cancer. Clinicaltrials.gov identifier: PROFILE 1007, NCT00932893; PROFILE 1014, NCT01154140.

Aims To assess the prevalence and determine predictors of Sjogren9s syndrome (SS) in patients with clinically significant aqueous-deficient dry eye. Methods Patients enrolled in an industry-sponsored, multicentre clinical trial (NCT00784719) were assessed prospectively for the presence of SS. Ocular testing included Schirmer test, corneal fluorescein staining, conjunctival lissamine green staining, and tear-film breakup time. Review of systems questionnaire, medical history, dry eye questionnaire and laboratory work-up (Sjogren-specific antibody A (SSA), Sjogren-specific antibody B (SSB), rheumatoid factor (RF) and antinuclear antibody (ANA)) were obtained. Results Of 327 patients, 38 (11.6%) had SS: 21 (6.4%) with primary SS (pSS), and 17 (5.2%) with secondary SS. Nine patients (3%) were newly diagnosed using the applied diagnostic criteria based on American–European consensus criteria. Patients with SS had significantly worse conjunctival and corneal staining, Schirmer test (with and without anaesthesia), and symptoms compared with patients without SS. pSS Was significantly more likely to occur in patients with positive ANA (OR: 13.9) and RF (OR: 4.8). Conclusions Ophthalmologists caring for patients with clinically significant dry eye should have a high index of suspicion for underlying SS and low threshold for serological work-up. RF and ANA are recommended as useful tests in SSA/SSB-negative patients for further diagnostic referral.

Purpose. To evaluate the efficacy and safety of fixed combination latanoprost/timolol versus latanoprost or timolol monotherapy. Methods. This 12-week, randomized, double-masked study was designed to overcome potential shortcomings of previous trials. We enrolled 788 subjects with open-angle glaucoma or ocular hypertension treated with a beta-blocker for ≥4 weeks before screening. After washout, 500 subjects with a baseline mean intraocular pressure (IOP) ≥26 and Results. The statistical superiority of the fixed combination was demonstrated at 7/9 time points versus latanoprost and 9/9 time points versus timolol. Mean diurnal IOP levels were similar at baseline but significantly lower with the fixed combination than with either monotherapy at weeks 6 and 12 (each pConclusions. Fixed combination latanoprost/timolol safely reduces IOP levels in patients with glaucoma or ocular hypertension, though only slightly more than does latanoprost monotherapy.

Uninterrupted use of ocular hypotensive medication by glaucoma patients is important to prevent vision loss, but medication persistence is poor. Efficacy and tolerability influence physicians' decisions and patient persistence, and differences between medications may impact persistence.To examine differences in physician's decisions to continue, switch, or discontinue therapy across three prostaglandin analogs (PGAs) latanoprost, bimatoprost, and travoprost using claims data supplemented by evaluation of physicians' charted therapeutic decisions.A year of pharmacy claims data for 6271 patients with a first (index) fill between 5/1/2001 and 11/30/2004 for PGA monotherapy were classified as 'persistent', 'switched', 'restarted', or 'discontinued' with initial PGA use. An analysis of index therapy continuation during the first 2 years reflected chart reviews for 223 patients with PGA monotherapy as the index prescription.Ten percent of patients had uninterrupted use of the initial PGA alone or in combination for a year. More than half (56%) stopped and then restarted, 16% switched, and 19% discontinued the initial PGA. Patients using latanoprost were more likely to be persistent (11%) compared to bimatoprost (9%) or travoprost (5%; p0.0001 overall comparison). Overall, 68% of patients on latanoprost persisted or restarted after a gap compared to 61% for bimatoprost and 58% for travoprost (p0.0001). Patient charts demonstrated a parallel pattern in physicians' decisions to continue latanoprost (56%), bimatoprost (45%), and travoprost (40%). Study limitations included the inability to establish causal links between variables, to account for sample use, or to document reasons for patient-driven changes in therapy. The study should be replicated in a more recent database including a larger population.Uninterrupted use of ocular hypotensive therapy for a full year is relatively rare. Differences in physicians' decisions to continue, switch, or discontinue PGAs were observed in claims data, and parallel trends were observed in patient medical records.

To document patient/physician perceptions of adverse effects and their relationship to medication changes among patients prescribed prostaglandin analogs.Medical/pharmacy claims (private U.S. health network) identified patients filling initial topical ocular hypotensive prescriptions from 2001 to 2004; 300 open-angle glaucoma patients prescribed a prostaglandin analog and 103 ophthalmologists were selected by algorithm for telephone interviews. Medical charts for 225/300 interviewed and 75 non-interviewed patients were abstracted. Medication patterns were assessed in pharmacy claims data. Frequency of adverse effects noted by physicians and associations with medication change decisions were examined in charted data. Patients' experiences with adverse effects were compiled from surveys.In patients treated with latanoprost (N = 4,071), bimatoprost (N = 1,199), or travoprost (N = 1,001), continuous refill of medication through 1 year was seen in 11%, 9%, and 5% of patients, respectively (P = 0.0001; retrospective pharmacy claims). Adverse effects were the second most common reasons noted by physicians for switching medications after lack of efficacy (19% vs. 43%, respectively). Adverse effects were noted in 65% of patient charts. Hyperemia was the most common adverse effect occurring with at least one other adverse effect in 48% of patients with the condition.Ocular adverse effects, particularly hyperemia, negatively affect patient continuation with therapy and switching.

Patient adherence with topical glaucoma therapy is recognized as suboptimal. Though some studies have associated physician/patient interaction with adherence, little systematic research has explored the ophthalmologist's perspective of this interaction. Telephone interviews with physicians treating glaucoma were conducted to ascertain the extent to which multivariate analysis of physician demographics, beliefs, and behaviors could reveal differences potentially relevant to future adherence with topical glaucoma therapy for primary open-angle glaucoma, in conjunction with other phases of the Glaucoma Adherence and Persistency Study (GAPS).Structured interviews were conducted with 103 ophthalmologists treating significant numbers of primary open-angle glaucoma patients in a national managed care network. To the maximum extent possible, eligible patients of physicians interviewed were included in the other GAPS phases (claims analysis, patient surveys, and medical chart reviews).Physicians reported a wide range of beliefs and behaviors regarding patients' medication adherence, but beliefs and behaviors were linked. The segmentation analysis yielded 3 clusters of physicians, which we have described on the basis of their predominant beliefs as "reactives," "skeptics," and "idealists." The "idealists," though the smallest group, more often reported beliefs and behaviors that may be more positively associated with patient adherence, especially in the context of other GAPS findings.Physician vigilance for opportunities to detect and address nonadherence is suggested, as is interventional research on the basis of the constructs identified.

Objective To assess the efficacy and safety of fixed-combination latanoprost-timolol (FCLT) vs latanoprost or timolol monotherapy. Methods This 12-week, randomized, double-masked, parallel-group study included patients with open-angle glaucoma or ocular hypertension treated with a β-blocker and with baseline intraocular pressure (IOP) of 26 through 36 mm Hg. Following washout, eligible patients were randomized to once-daily FCLT in the evening, latanoprost in the evening, or timolol in the morning. Main Outcome Measures Postbaseline IOP assessments at 8AM, 10AM, and 4PMat weeks 2, 6, and 12; statistical superiority of FCLT for the 18 pairwise comparisons between FCLT and the 2 monotherapies, using analysis of variance. Results All therapies resulted in significant IOP reductions from baseline. Pairwise comparisons favored FCLT at all time points. When the 18 comparisons were tested simultaneously, FCLT was statistically superior to latanoprost at 7 of 9 time points and at all 9 time points when compared with timolol. In addition, FCLT was associated with greater percentage reductions in diurnal IOP levels and a greater likelihood of achieving lower mean diurnal IOP levels. Diurnal IOP reductions of 30% or more from baseline to week 12 were achieved by 73.5%, 57.5%, and 32.8% of those treated with FCLT, latanoprost, and timolol, respectively ( P = .007 for FCLT vs timolol; P Conclusions Fixed-combination latanoprost-timolol therapy is as safe and effective in lowering IOP in patients with either ocular hypertension or glaucoma as monotherapy with latanoprost or timolol. Combination therapy can be used to treat patients for whom monotherapy does not provide sufficient IOP reduction. Application to Clinical Practice The simplicity, efficacy, and tolerability of FCLT contribute to its utility in clinical practice. Trial Registration clinicaltrials.gov IdentifierNCT00277498

To assess communication about adherence and to determine the impact of communication skills training on physicians' approach to nonadherence.Sociolinguistic analysis of videotaped community ophthalmologists' encounters with patients with glaucoma before and after training. Patients in both phases and physicians in phase I knew communication was being studied but not what the focus of the study was. In phase II, physicians knew the targeted communication behaviors.Twenty-three ophthalmologists and 100 regularly scheduled patients with glaucoma (50 per phase).An educational program with videotaped vignettes of simulated patient encounters using audience response and role play to teach patient-centered communication skills, including a 4-step adherence assessment and the use of open-ended questions in ask-tell-ask sequences.Physician eliciting an acknowledgment of nonadherence during a clinical encounter compared with acknowledgment of nonadherence during a postvisit research interview (primary outcome), and performance of targeted communication and substantive discussion of adherence.After intervention, physicians increased the proportion of open-ended questions (15% vs 6%; P = 0.001) and specifically about medication taking (82% compared with 18% of encounters; P0.001). Compared with the absence of ask-tell-ask communication, 32% of phase II encounters included a complete ask-tell-ask sequence, 78% included an ask-tell sequence, and 32% a tell-ask sequence (P0.001). Three of 4 steps for assessment of adherence were more common in phase II, and substantial discussions of adherence occurred in 86% versus 30% of encounters (P0.001). In phase II, physicians elicited acknowledgment of nonadherence in 78% (7/9) of those who acknowledged nonadherence in the postvisit interview compared with 25% in phase I (3/12; P = 0.03).This study demonstrates that experienced community physicians significantly improved their communication strategies and ability to detect and address nonadherence after a 3-hour educational program.Proprietary or commercial disclosure may be found after the references.

PURPOSE. To develop methods for investigating adherence to glaucoma medications by using a modified claims data-based measure of adherence, validation by chart review, and patient and physician interviews. METHODS. Data from administrative claims of 13,956 subjects receiving an initial glaucoma medication, and data from overlapping samples of 300 patients' charts, 300 interviews of patients, and 103 interviews of physicians were analyzed and compared. RESULTS. The mean medication possession ratio (MPR) was 0.64 (median 0.57) for the 13,956 subjects. Although 59% potentially had an ocular hypotensive agent at 12 months, only 10% had such medication available continuously. Chart review revealed that 31% of subjects "new to therapy" in claims data had actually been previously treated; and that 90% of the 17% who had medication added to initial monotherapy were misclassified by claims-based algorithms as medication switches or no change. Twenty percent of surveyed patients received samples on a regular basis and had lower MPR than those who did not (P < 0.05). CONCLUSIONS. Large pharmacy databases offer insight into medication usage but are vulnerable to errors from sampling (since patients who receive samples will be considered to have poor adherence), misidentification of newly treated patients, and misclassification of added versus switched medications. That a large proportion of patients stop and restart medications makes MPR a robust measure of adherence over time that reflects the resumption of medication after a gap in adherence. The data confirm that adherence to treatment with glaucoma medications is poor, similar to adherence in patients with other chronic diseases.

To use multiple data sources to determine drivers of patient adherence to topical ocular hypotensive therapy.Retrospective database and chart reviews in combination with prospective patient surveys. Diverse medical environments where insured patients in the research database seek care.Three hundred patients with a new claim diagnosis for open-angle glaucoma who initially were prescribed one of three prostaglandins and 103 physicians participating in the same medical plans.A structured interview addressing self-reported adherence, experiences with medication, communication with the physician, and health-related beliefs associated with adherence behavior was administered to surveyed patients. Phone interviews were conducted with participating ophthalmologists.Of adherence, medication possession ratio.Eight variables were associated independently with a lower medication possession ratio: (1) hearing all of what you know about glaucoma from your doctor (compared with some or nothing); (2) not believing that reduced vision is a risk of not taking medication as recommended; (3) having a problem paying for medications; (4) difficulty while traveling or away from home; (5) not acknowledging stinging and burning; (6) being nonwhite; (7) receiving samples; and (8) not receiving a phone call visit reminder. The multivariate model explained 21% of the variance.These findings indicate that doctor-patient communications and health-related beliefs of patients contribute to patient adherence. Patient learning styles that are associated with less concern about the future effects of glaucoma and the risks of not taking medications are associated with lower adherence. Specifically, knowledge about potential vision loss from glaucoma is a critical element that tends to be missed by more passive doctor-dependent patients who tend to be poorly adherent. These findings suggest that educational efforts in the office may improve patient adherence to medical therapies.