Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration.

PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections. METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

A systematic review and meta-analysis to compare the efficacy of acyclovir 3% ophthalmic ointment to idoxuridine in curing herpetic keratitis by Day 7 of treatment.

BACKGROUND: This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis (HK) presenting as dendritic and geographic ulcer sub-types. DATA SOURCES: Publications in human subjects were identified by searching the Ovid MEDLINE database through April 2011, combining medical subject headings (MESH) "Keratitis, Herpetic/" AND "Acyclovir/" limiting by the key words "topical" OR "ointment" and also restricted to MESH "Administration, Topical/" OR "Ointments/". The results were cross checked with the references used in the Cochrane Database Syst Rev. 1:1-134, 2009 and GlaxoSmithKline clinical documents related to acyclovir. STUDY SELECTION: Randomized, double-masked studies in subjects diagnosed with HK with head to head comparator arms of ACV ophthalmic ointment and topical IDU that had actual or calculable healing rates at Day seven. DATA EXTRACTION: Data independently extracted from identified articles by two authors of this manuscript. DATA SYNTHESIS: Data from seven randomized, controlled trials (RCT) evaluating 432 subjects that met inclusion criteria (214 were treated with ACV and 218 were treated with IDU) and had Day seven healing rates calculable. All sub-classified lesions were identified as either dendritic ulcers (n = 185) or geographic ulcers (n = 35). The Cochran-Mantel-Haenszel (CMH) method in Biometrics 10:417-51, 1954 and JNCI 22:719-48, 1959, controlling for study, was performed as the primary analysis using SAS v9. Homogeneity was assessed using Breslow-Day-Tarone (BDT) test in IARC 1:1-32, 1980 and Biometrika 72:91-5, 1985. The analysis was performed with outliers removed to assess their impact. RESULTS: ACV showed statistically significant greater odds of healing HK at Day seven in all subjects (Odds Ratio 3.95, 95% CI2.60, 6.00, p < 0.0001), in dendritic ulcers (Odds Ratio 4.22, 95% CI: 2.14, 8.32; p < 0.0001) and geographic ulcers (Odds Ratio 5.31, 95% CI: 1.09, 25.93; p = 0.0244). CONCLUSION: ACV 3% ophthalmic ointment is a valuable intervention for dendritic and geographic corneal ulcers. ACV and IDU were generally well tolerated in the studies reviewed.

Predictive models of choroidal neovascularization and geographic atrophy incidence applied to clinical trial design.

PURPOSE: To develop comprehensive predictive models for choroidal neovascularization (CNV) and geographic atrophy (GA) incidence within 3 years that can be applied realistically to clinical practice. DESIGN: Retrospective evaluation of data from a longitudinal study to develop and validate predictive models of CNV and GA. METHODS: The predictive performance of clinical, environmental, demographic, and genetic risk factors was explored in regression models, using data from both eyes of 2011 subjects from the Age-Related Eye Disease Study (AREDS). The performance of predictive models was compared using 10-fold cross-validated receiver operating characteristic curves in the training data, followed by comparisons in an independent validation dataset (1410 AREDS subjects). Bayesian trial simulations were used to compare the usefulness of predictive models to screen patients for inclusion in prevention clinical trials. RESULTS: Logistic regression models that included clinical, demographic, and environmental factors had better predictive performance for 3-year CNV and GA incidence (area under the receiver operating characteristic curve of 0.87 and 0.89, respectively), compared with simple clinical criteria (AREDS simplified severity scale). Although genetic markers were associated significantly with 3-year CNV (CFH: Y402H; ARMS2: A69S) and GA incidence (CFH: Y402H), the inclusion of genetic factors in the models provided only marginal improvements in predictive performance. CONCLUSIONS: The logistic regression models combine good predictive performance with greater flexibility to optimize clinical trial design compared with simple clinical models (AREDS simplified severity scale). The benefit of including genetic factors to screen patients for recruitment to CNV prevention studies is marginal and is dependent on individual clinical trial economics.

Ronacaleret, a calcium-sensing receptor antagonist, has no significant effect on radial fracture healing time: results of a randomized, double-blinded, placebo-controlled Phase II clinical trial.

BACKGROUND: Fractures cause significant morbidity, mortality, and use of health care resources. An oral agent that enhances fracture healing could reduce costs and prevent future disabilities. In Phase I studies, ronacaleret, a novel calcium-sensing receptor antagonist, stimulated parathyroid hormone (PTH) release and increased bone formation markers, suggesting that it may act as an effective oral anabolic agent to enhance fracture healing. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, clinical trial in 85 male and female subjects who had sustained a closed, unilateral, extra-articular fracture of the distal radius and were receiving conservative treatment. Subjects were randomly assigned in a double-blind manner to ronacaleret 200 mg twice daily, ronacaleret 400 mg once daily or matching placebo and followed for 12 weeks. Fracture healing was assessed by radiographs and quantitative computed tomography (CT), and bone turnover markers were measured. The study was terminated early for futility based on the results of an unplanned interim analysis. RESULTS: There were no significant differences between treatment groups in time to radiographic fracture healing (74, 65 and 68 days for placebo, 200 mg twice daily and 400 mg once daily dose groups, respectively), cortical bridging, grip strength, pain and swelling, time to cast removal, or range of motion. Markers of bone formation and levels of whole PTH, intact PTH and serum calcium increased following treatment with ronacaleret. CONCLUSION: Ronacaleret had no significant effect on duration of healing by radiograph or CT scan, time to cast removal, clinical symptoms, grip strength, or range of motion.

Efficacy and safety of monthly ibandronate in men with low bone density.

INTRODUCTION: Monthly oral ibandronate is indicated for the prevention and treatment of osteoporosis in postmenopausal women. The STudy Researching Osteoporosis iN Guys (STRONG) investigated the efficacy and safety of 150-mg monthly oral ibandronate in men with primary, idiopathic, or hypogonadism-related low bone density. METHODS: STRONG was a 1-year, placebo-controlled, randomized (2 ibandronate: 1 placebo), double-blind study that enrolled ambulatory men aged > or =30 years with baseline femoral neck (FN) bone mineral density (BMD) T-scores < or =-2.0 and lumbar spine (LS) BMD T-scores < or =-1.0 or LS BMD T-scores < or =-2.0, FN BMD T-scores < or =-1.0, and BMD T-scores > or =-4.0 at any site assessed by dual-energy X-ray absorptiometry. The primary endpoint was mean percent change from baseline in LS BMD at 1 year (intent-to-treat [ITT] population). Secondary endpoints included mean BMD changes from baseline at the FN, total hip (TH), and trochanter (TR) and changes in bone turnover markers (BTMs), as measured by the bone resorption marker serum C-terminal telopeptide of type 1 collagen (sCTX) and the bone formation marker bone-specific alkaline phosphatase (BSAP). All men received twice daily calcium carbonate (1000 mg/day) and vitamin D (400 IU/day). Changes in BMD for treatment groups were compared using analysis of covariance with treatment, investigative site, and baseline testosterone as factors and baseline BMD as a covariate. RESULTS: The ITT population consisted of 132 men; 47 received placebo and 85 received monthly ibandronate. Men who received ibandronate achieved greater increases in LS BMD at 12 months than those who received placebo (3.5% vs. 0.9%, respectively; difference, 2.6; p<0.001). The ibandronate group also achieved greater 12-month BMD increases than the placebo group, respectively, at the TH (1.8% vs. -0.3%; difference, 2.1; p<0.001), FN (1.2% vs. -0.2%; difference, 1.4; p=0.012), and TR (2.2% vs. 0.4%; difference, 1.7; p<0.005). In men who completed the study and adhered to the protocol (per-protocol (PP) population), percent decreases in median sCTX and BSAP levels from baseline were also greater with ibandronate versus placebo (p< or =0.001 for both comparisons). Overall, monthly ibandronate was well tolerated. CONCLUSIONS: In men with low BMD, 1 year of treatment with oral once-monthly 150-mg ibandronate significantly increased BMD at the LS and hip (TH, TR, and FN), significantly reduced BTM levels in the PP population, and was generally well tolerated.