Darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in diabetic macular edema: a 3-month placebo-controlled study.

PURPOSE: To investigate the potential of lipoprotein-associated phospholipase A2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME). DESIGN: Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study. PARTICIPANTS: Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18). METHODS: Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months. MAIN OUTCOME MEASURES: Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography. RESULTS: Five patients in the study received intravitreal anti-vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3-5.8) and of 57 µm in central subfield thickness (95% CI, -84 to -30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, -1.0 to 4.4) and a decrease in center subfield thickness of 34 µm (95% CI, -75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups. CONCLUSIONS: Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A2 inhibitory mechanism for the treatment of DME.

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.

Clinical evaluation of pazopanib eye drops in healthy subjects and in subjects with neovascular age-related macular degeneration.

PURPOSE: To evaluate pazopanib 10 mg/mL eye drops (pazopanib) in healthy subjects and in subjects with previously untreated subfoveal choroidal neovascularization secondary to age-related macular degeneration. METHODS: Study 1 (single center, randomized, placebo-controlled, double-masked) included 3 cohorts of 12 to 13 healthy subjects each who instilled pazopanib or placebo 4 times daily for 2 weeks. Study 2 (multicenter open-label) included 19 subjects with neovascular age-related macular degeneration who instilled pazopanib 4 times daily for 12 weeks. Both studies evaluated pharmacokinetics and safety. Study 2 also evaluated efficacy. RESULTS: Steady-state concentrations of pazopanib in plasma seemed to be reached by Week 2. At Week 4 (Study 2), there were no meaningful changes from baseline in the mean central retinal thickness (37.9 µm) or best-corrected visual acuity (0.1 letters) (primary endpoint), retinal morphology, choroidal neovascularization size, or total lesion size. Complement Factor H genotype had no effect on changes from baseline in the best-corrected visual acuity or central retinal thickness. The most common pazopanib-related ocular adverse events included eye irritation (Study 1, n = 7) and instillation site pain (Study 2, n = 3). No serious adverse events were reported. CONCLUSION: Pazopanib was well tolerated. In subjects with previously untreated neovascular age-related macular degeneration, pazopanib instilled 4 times daily as monothereapy did not seem to improve the best-corrected visual acuity or decrease the central retinal thickness.

Coronary heart disease outcomes among chronic opioid and cyclooxygenase-2 users compared with a general population cohort.

BACKGROUND: We estimated the incidence of myocardial infarction (MI) and coronary revascularization (CR) among users of chronic opioid therapy (COT) and compared risks across categories of morphine-equivalent doses of COT and comparator cohorts. METHODS: We conducted a retrospective claims-based study using de-identified data from a commercially insured population. A cohort of 148,657 adult users of COT, a matched cohort of the general population, and three cohorts of users of chronic cyclooxygenase-2 (COX-2) inhibitor therapy totaling 122,810 were identified. Incidence rates and incidence rate ratios (IRRs) of MI and MI/CR were estimated. RESULTS: Adjusted IRRs for MI ranged from 1.21 (95% confidence interval [95%CI], 1.02-1.45) among those receiving low COT doses to 1.89 (95%CI, 1.54-2.33) among those receiving high doses compared with those receiving very low doses, averaging <15 mg/day. Similar patterns were shown for MI/CR. IRRs standardized to the age-sex distribution of the general cohort and adjusted for coronary heart disease risk factors showed 2.7 times the rate of MI and 2.4 times the rate of MI/CR in the COT cohort compared with the general population. Using the same analysis, COX-2 users had 1.7-1.9 times the rate of MI and MI/CR compared with the general cohort. CONCLUSIONS: Chronic analgesic use with either COT or COX-2 was associated with an increased risk of cardiovascular outcomes. These findings suggest either a selection of high-risk patients to chronic analgesic treatment, coupled with unmeasured or residual confounding, or a potential cardiovascular effect of these medications. Further research is warranted to evaluate causes for this association.

Understanding the drug development process.

In the United States, new drug development is a complex, highly regulated process that often involves academic institutions, the pharmaceutical industry, and government agencies. Much of the primary and clinical research conducted in the United States is funded by the National Institutes of Health. The Food and Drug Administration (FDA) provides regulatory review and oversight of the drug development process. The Investigational New Drug application is the primary mechanism that the FDA uses to regulate clinical testing in humans. A New Drug Application summarizing all of the data necessary to perform risk/benefit analysis of the new drug is submitted to the FDA for review and approval once sufficient testing has been completed. Recent research into the pathogenesis of inflammatory bowel disease has yielded numerous drug targets resulting in a multitude of molecules and biologic agents under varying stages of development and a consequent need for clinical testing. A thorough understanding of the regulatory development process and the National Institutes of Health funding process is necessary for any investigator involved in clinical trials.

Ethical issues, safety, and data integrity in clinical trials.

Published in 1974, the Belmont Report established the ethical principles for conducting clinical research in the United States. The essential concepts are respect for the research participant, beneficence for society at large, and justice (equal access to participation and equal treatment) toward subjects in a research study. These principles are applied through the use of informed consent, risk/benefit assessment, and the impartial selection of study subjects. Strict adherence to these criteria often results in conflicts of interest, which the investigator must anticipate and manage. Investigators must also be thoroughly acquainted with the principles of Good Clinical Practice and regulatory requirements. Recent implementation of the Privacy Rule now requires the investigator to protect not only the safety but the privacy of the research subject. While the regulatory obligations can appear onerous, strict compliance results in clinical research that is safe, scientifically sound, and ethical.

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.

A randomized, placebo-controlled phase 3 trial (Study SB-767905/012) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain.

UNLABELLED: Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ∼40% of patients. Such symptoms considerably impair patients' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of ≥ 1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated. PERSPECTIVE: These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia.

A randomized, placebo-controlled phase 3 trial (Study SB-767905/013) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain.

UNLABELLED: The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo, for 12 weeks. The primary efficacy endpoint was the proportion of patients who experienced ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period, and an average increase from baseline of ≥ 1 SBM per week. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia. PERSPECTIVE: Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC.

Epidemiology of opioid pharmacy claims in the United States.

OBJECTIVE: To describe opioid pharmacy claims patterns in the United States among an insured population. DESIGN: Information was obtained from the US insurance claims database, IMS Lifelink, between 1997 and 2002. Descriptive statistics of opioid claims patterns were described with stratification by gender, age, and year of use. RESULTS: The prevalence of insured people with opioid claims increased from 17.1 percent in 1997 to 18.4 percent in 2002. Among people with an opioid claim, 24 percent had > or =30 days and 10 percent had > or =90 days of days supplied based on the insurance claims. Prevalence varied by type of opioid; 56 percent of people with a claim received propoxyphene, 43 percent received codeine, 23 percent received oxycodone, and 17 percent received hydrocodone. Sustained-release opioids were found among 6 percent of those with a claim. With respect to the dose of opioids in the pharmacy claims (expressed as morphine equivalent total daily dose), 71 percent had claims for <50 mg, 55 percent had claims for 50-99 mg, and 24 percent had claims for > or =100 mg. Women, individuals with cancer, and older patients had significantly more pharmacy claims as well as claims for higher doses of opioids (p < 0.05). Internal medicine and family practice specialists were responsible for 22.4 percent and 20.9 percent of all opioid claims. CONCLUSIONS: Opioid pharmacy claims increased slightly over time. Older patients, women and patients with a cancer diagnosis had significantly more opioid claims and claims for higher doses than the younger patients, men, and those without cancer.