OTO-201 for the Treatment of Acute Otitis Externa: Results from a Phase 3 Randomized Clinical Study.

OBJECTIVES: OTO-201 is a ciprofloxacin otic suspension previously approved by the US Food and Drug Administration to treat children with bilateral otitis media with effusion requiring tympanostomy tube placement. In this phase 3, double-blind, randomized, prospective, sham-controlled, multicenter study, a single dose of OTO-201 was administered to the external auditory canal in subjects with unilateral or bilateral acute otitis externa. METHODS: Two hundred sixty-two subjects, 3 to 83 years of age, were randomized, and 260 subjects were included in the intent-to-treat analysis population: OTO-201 (0.2 mL, 12 mg, n = 130) or sham (air injection, n = 130). The primary efficacy measure was clinical cure (CC) on day 8, judged by blinded assessor for erythema, edema, otorrhea, and tenderness. Subjects were monitored over 28 days for efficacy and safety. RESULTS: OTO-201 demonstrated a significant increase in CC compared with sham at day 8 (69.2% vs 46.1%, P < .001). Higher CC was also noted on day 4 ( P = .028), day 15 ( P < .001), and day 29 ( P < .001). A similar effect was observed in the pathogen-positive population. Single OTO-201 administration in the office setting was well tolerated by subjects. CONCLUSIONS: In this study in subjects with acute otitis externa, a single administration of 12 mg OTO-201 to the external auditory canal demonstrated a significantly higher proportion of subjects with CC and bacterial eradication compared with sham starting on day 4 and on all other observation days through day 29, with no safety or tolerability concerns identified. OTO-201 is the first agent in a randomized phase 3 study to demonstrate the efficacy and safety of a single-dose, health care professional-administered topical antibiotic for the treatment of acute otitis externa.

Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40-70 years of age.

BACKGROUND: The currently licensed hepatitis B vaccines have limitations including hyporesponsiveness in older adults, poor compliance, and the extended time for most persons to develop seroprotection (e.g. >6months). A vaccine containing HBsAg combined with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) has been developed to overcome these limitations. METHODS: A Phase 3, multicenter, randomized, subject- and observer-blinded, active-controlled trial was conducted among healthy subjects 40-70years of age comparing the immunogenicity and safety of two doses of HBsAg-1018 at 0 and 4weeks to three doses of licensed hepatitis B vaccine, HBsAg-Eng, at 0, 4, and 24weeks. The primary immunogenicity endpoint was noninferiority of the seroprotection rate (SPR; % with anti-HBs≥10mIU/mL) of HBsAg-1018 compared to the SPR of HBsAg-Eng at 8 weeks following the last dose of vaccine. Conditional upon meeting noninferiority, superiority of HBsAg-1018 over HBsAg-Eng was assessed. Safety was compared between the two vaccines. RESULTS: At the primary endpoint, the SPR for the HBsAg-1018 group (90.0%) was superior to the SPR for the HBsAg-Eng group (70.5%) with an SPR difference of 19.5% (95% CI, 14.7%, 24.7%). At week 28 when the SPR peaked in the HBsAg-Eng group (72.8%), the SPR in the HBsAg-1018 group (94.8%) was significantly higher than in the HBsAg-Eng group. The SPR in the HBsAg-1018 group was significantly higher than in the HBsAg-Eng group at each study visit from week 4 through week 52. The safety profiles for the two vaccines were similar. CONCLUSION: When compared to the HBsAg-Eng three-dose regimen given at 0, 1, and 6months, HBsAg-1018 demonstrated superior seroprotection with only two doses at 0 and 1month. The safety profile of HBsAg-1018 was comparable to that of the licensed vaccine, HBsAg-Eng. HBsAg-1018 would provide a significant public health contribution toward the prevention of hepatitis B infection.

Immunogenicity and safety of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in patients with chronic kidney disease.

BACKGROUND: Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and patients with chronic kidney disease (CKD) are commonly hyporesponsive to HBV vaccines. Current recommendations for CKD patients are to utilize 4 double-doses (2×20 mcg HBsAg) of a licensed hepatitis B vaccine (HBsAg-Eng). METHODS: An observer-blind, randomized, active-controlled, parallel group, multicenter trial was conducted among 521 patients 18-75 years of age with CKD, comparing 3 single doses of an investigational hepatitis B vaccine (20 mcg rHBsAg+3000 mcg 1018, a toll-like receptor 9 agonist) given at 0, 4, and 24 weeks to 4 double-doses of HBsAg-Eng (2×20 mcg rHBsAg+500 mcg alum) given at 0, 4, 8, and 24 weeks (total of 8 injections). Participants were followed for 1 year. RESULTS: Among 467 participants in the modified intent-to-treat population, at the primary endpoint at week 28, the seroprotection rate (SPR: % with anti-HBs≥10mIU/mL) in the HBsAg-1018 group (89.9%) met criteria for noninferiority and superiority to the SPR in the HBsAg-Eng group (81.8%). At week 28, the percentage of participants with anti-HBs≥100mIU/mL in the HBsAg-1018 group (73.6%) was significantly higher than in the HBsAg-Eng group (63.2%). In addition, the geometric mean concentration of anti-HBs in the HBsAg-1018 group (587.1mIU/mL) was significantly higher than in the HBsAg-Eng group (156.5mIU/mL). At weeks 8 and 12 after the first study injection, SPRs in the HBsAg-1018 group were significantly higher than in the HBsAg-Eng group. At 52 weeks, the immune response to HBsAg-1018 remained higher than to HBsAg-Eng. HBsAg-1018 was generally well tolerated and had a similar safety profile to HBsAg-Eng. CONCLUSION: In CKD patients, 3 doses of HBsAg-1018 induced significantly higher seroprotection, earlier seroprotection, and more durable seroprotection than 4 double doses of HBsAg-Eng.

Demonstration of safety and enhanced seroprotection against hepatitis B with investigational HBsAg-1018 ISS vaccine compared to a licensed hepatitis B vaccine.

Adults 40 years of age and older have been shown to be hypo-responsive immunologically to the currently available hepatitis B virus (HBV) vaccines. Three intramuscular doses of a Toll-like receptor 9 agonist, 1018 immunostimulatory sequence (1018 ISS) adjuvant, combined with recombinant hepatitis B surface antigen (HBsAg) demonstrated faster, superior, and more durable seroprotection than three doses of a licensed comparator HBV vaccine (Engerix-B(®)). This investigational vaccine, HBsAg-1018 ISS, was well tolerated with a safety profile similar to the comparator vaccine. These results suggest that HBsAg-1018 may be more effective in this hypo-responsive population.

Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery.

OBJECTIVE: The PREVENT III study was a prospective, randomized, double-blinded, multicenter phase III trial of a novel molecular therapy (edifoligide; E2F decoy) for the prevention of vein graft failure in patients undergoing infrainguinal revascularization for critical limb ischemia (CLI). METHODS: From November 2001 through October 2003, 1404 patients with CLI were randomized to a single intraoperative ex vivo vein graft treatment with edifoligide or placebo. After surgery, patients underwent graft surveillance by duplex ultrasonography and were followed up for index graft and limb end points to 1 year. A blinded Clinical Events Classification committee reviewed all index graft end points. The primary study end point was the time to nontechnical index graft reintervention or major amputation due to index graft failure. Secondary end points included all-cause graft failure, clinically significant graft stenosis (>70% by angiography or severe stenosis by ultrasonography), amputation/reintervention-free survival, and nontechnical primary graft patency. Event rates were based on Kaplan-Meier estimates. Time-to-event end points were compared by using the log-rank test. RESULTS: Demographics, comorbidities, and procedural details reflected a population with CLI and diffuse atherosclerosis. Tissue loss was the presenting symptom in 75% of patients. High-risk conduits were used in 24% of cases, including an alternative vein in 20% (15% spliced vein and 5% non-great saphenous vein) and 6% less than 3 mm in diameter; 14% of the cases were reoperative bypass grafts. Most (65%) grafts were placed to infrapopliteal targets. Perioperative (30-day) mortality occurred in 2.7% of patients. Major morbidity included myocardial infarction in 4.7% and early graft occlusion in 5.2% of patients. Ex vivo treatment with edifoligide was well tolerated. There was no significant difference between the treatment groups in the primary or secondary trial end points, primary graft patency, or limb salvage. A statistically significant improvement was observed in secondary graft patency (estimated Kaplan-Meier rates were 83% edifoligide and 78% placebo; P = .016) within 1 year. The reduction in secondary patency events was manifest within 30 days of surgery (the relative risk for a 30-day event for edifoligide was 0.45; 95% confidence interval, 0.27-0.76; P = .005). For the overall cohort at 1 year, the estimated Kaplan-Meier rate for survival was 84%, that for primary patency was 61%, that for primary assisted patency was 77%, that for secondary patency was 80%, and that for limb salvage was 88%. CONCLUSIONS: In this prospective, randomized, placebo-controlled clinical trial, ex vivo treatment of lower extremity vein grafts with edifoligide did not confer protection from reintervention for graft failure.

Risk factors, medical therapies and perioperative events in limb salvage surgery: observations from the PREVENT III multicenter trial.

OBJECTIVES: Patients who require infrainguinal revascularization for critical limb ischemia (CLI) are at elevated risk for cardiovascular events. The PREVENT III study was a prospective, randomized, multicenter, phase 3 trial of edifoligide for the prevention of vein graft failure in patients with CLI. We examined the baseline characteristics, perioperative medical therapies, and 30-day incidence of major cardiovascular events in the PREVENT III cohort. METHODS: Demographics, medical and surgical history, mode of presentation for the index limb, procedural details, and concomitant medications were reviewed for all patients enrolled in PREVENT III (N = 1,404). Major adverse cardiovascular events, including death, myocardial infarction, or cerebrovascular event (stroke or transient ischemic attack) were tabulated. Univariate and multivariate analyses were performed to discern factors that were associated with the utilization of medical therapies and with perioperative events. RESULTS: Demographics and comorbidities reflected a population with diffuse, advanced atherosclerosis. Perioperative mortality was 2.7%, and major morbidity included myocardial infarction in 4.7% and stroke/transient ischemic attack in 1.4%. Among this population of CLI patients, 33% were not on antiplatelet therapy at study entry, and 24% were not receiving antithrombotics of any type. In addition, 54% of patients were not receiving lipid-lowering therapy, and 52% were not prescribed beta-blocker medications at study entry. On multivariate analysis, race was a significant determinant of antithrombotic utilization, with African-American patients less frequently treated both at baseline and discharge (adjusted odd ratios, 0.5 and 0.6, P < .0001). Antithrombotic and beta-blocker drug usage increased in the overall cohort from baseline (76% and 48%) to discharge (88% and 60%; P < .0001). Patients treated in a university hospital setting were more likely to be prescribed antiplatelet, lipid-lowering, and beta-blocker medications. Advanced age (>75 years), coronary artery disease (prior myocardial infarction or revascularization), and dialysis-dependent renal failure were associated with an increased 30-day risk of death, myocardial infarction, or stroke. Protective effects of beta-blocker and lipid-lowering medications were noted in these defined subgroups. CONCLUSIONS: A significant percentage of the population that undergoes surgical revascularization for CLI is not prescribed therapies of proven benefit in reducing cardiovascular events. Utilization of antithrombotics and beta-blockers increases during hospitalization for limb salvage surgery but that of lipid-lowering therapy does not. African-American patients appear to be at greater risk for undertreatment with antithrombotics, and the data suggest that patients undergoing leg bypass surgery in a university hospital setting receive more comprehensive medical treatment of atherosclerosis. Treatment guidelines for medical therapy are needed to standardize care and improve outcomes for patients with CLI.

Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients.

Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor Monitor polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of -4.1 log(10) and -4.3 log(10) copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients. The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis). Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV.