Clinical evaluation of safety and efficacy of a new topical treatment for onychomycosis.

OBJECTIVE: This clinical study assessed the safety and efficacy of an investigational topical product for the treatment of onychomycosis (nail fungus). METHOD: A prospective, multi-center, single-arm, self-controlled clinical investigation was done with adult subjects that met the inclusion criteria, primarily culture-confirmed dermatophyte infection of at least one great toe. Subjects self-treated in a weekly regimen of topical application for six months, with clinical assessment at one, three, and six months. Primary efficacy endpoint was clearance of fungal nail infection after six months of weekly treatment. Primary safety endpoint was freedom from product-related adverse events for the duration of the treatment term. RESULTS: Fifty males and 13 females, ages 24 to 65, infected with Trichophyton (n=62) or Epidermophyton (n=1) were enrolled; 53 completed six months of assessment. Sixty percent showed improvement in clinical parameters (nail color, nail plate involvement, onycholysis, thickness, and hyperkeratosis) at six months. Cumulative rates of dermatophyte-negative culture results (test of cure) were 28, 36, and 62 percent of subjects after one, three, and six months of treatment, respectively. Three minor adverse events were device-related, with no unanticipated or serious adverse events. LIMITATIONS: This study was single-arm and self-controlled; 53 of 63 enrolled subjects completed the study. CONCLUSION: This study describes a new topical medical device with safety and efficacy profiles that compare favorably to results reported for topically applied onychomycosis drug treatments.

Persistence of antibodies 1 year after sequential administration of the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine in adults.

Vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) followed ≥ 1 year by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for immunocompetent adults ≥ 65 years of age in the United States. This study assessed antipneumococcal opsonophagocytic activity (OPA) geometric mean titers (GMTs) to PCV13 in PPSV23-naive and PPSV23-preimmunized adults 1 year after a second vaccine dose. Two parent studies were conducted previously: (1) PPSV23 vaccine-naive subjects (60-64 years of age at enrollment) received PCV13 followed by PCV13 or PPSV23 1 year later or PPSV23 followed by PCV13 1 year later; and (2) subjects (≥ 70 years of age at enrollment) vaccinated with PPSV23 ≥ 5 years before study entry received PCV13 or PPSV23 followed by PCV13 1 year later. Overall, 962 subjects (PPSV23-naive, n = 519; PPSV23-preimmunized, n = 443) who received both vaccinations in the parent studies were enrolled. Numerically higher OPA GMTs persisted for at least 1 year after administration of PCV13 as the initial vaccine (PCV13/PPSV23 or PCV13/PCV13) compared with those who received PPSV23 either 1 or 5 years prior (PPSV23/PCV13). This impairment in antibody responses to subsequent PCV13 vaccination produced by initial PPSV23 vaccination persisted for at least 1 year. OPA GMTs were numerically higher for most serotypes 1 year after 2 doses of PCV13 compared with 1 year after the first PCV13 dose. These data suggest PCV13 should be given first if both vaccines are to be administered, higher immune responses were achieved when PCV13 was given first and persisted at least 1 year (ClinicalTrials.gov Identifier: NCT01025336).

Immunogenicity and safety of a second administration of 13-valent pneumococcal conjugate vaccine 5 years after initial vaccination in adults 50 years and older.

BACKGROUND: Vaccination effectively reduces invasive disease and pneumonia caused by Streptococcus pneumoniae. However, waning antibody titers and the ability of revaccination to boost titers in older adults have been concerns. A study to describe antibody persistence after vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) and response to revaccination 5 years after the initial dose was conducted. METHODS: Pneumococcal vaccine-naive subjects aged 50-59 years were randomized and vaccinated with PCV13 plus trivalent inactivated influenza vaccine concomitantly or 1 month apart, then revaccinated with PCV13 five years later. Antipneumococcal polysaccharide opsonophagocytic activity (OPA) geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs) were determined before and approximately 1 month after each vaccination. Targeted local reactions and systemic events were collected for 14 days, adverse events (AEs) for 1 month, and serious AEs (SAEs) for 6 months after each vaccination. RESULTS: Of 1116 randomized subjects, 727 were revaccinated at year 5. Between the time of initial vaccination and revaccination, OPA GMTs and IgG GMCs declined but remained higher than levels before initial vaccination for 12 of the 13 vaccine serotypes. One month after revaccination, OPA GMTs and IgG GMCs were comparable with, or higher than, levels observed 1 month after initial vaccination for most vaccine serotypes. Local reactions were mostly mild. AEs were reported by <5% and SAEs by <1% of subjects at 1 and 6 months after revaccination, respectively. No SAEs were vaccine-related. CONCLUSIONS: Revaccination of adults ≥50 years with PCV13 five years after primary vaccination was safe and immunogenic. Additionally, antibody titers were maintained for at least 5 years after vaccination. The vaccine stimulated a memory response as shown by enhanced responses that were maintained or enhanced by revaccination. CLINICALTRIALS. GOV REGISTRATION: NCT00521586.

Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial.

BACKGROUND: Clostridium difficile, a major cause of nosocomial and antibiotic-associated diarrhea, carries a significant disease and cost burden. This study aimed to select an optimal formulation and schedule for a candidate toxoid vaccine against C. difficile toxins A and B. METHODS: Randomized, placebo-controlled, two-stage, Phase 2 study in a total of 661 adults aged 40-75 years. Stage I: low (50 µg antigen) or high (100 µg antigen) dose with or without aluminum hydroxide (AlOH) adjuvant, or placebo, administered on Days 0-7-30. Stage II: Days 0-7-30, 0-7-180, and 0-30-180, using the formulation selected in Stage I through a decision tree defined a priori and based principally on a bootstrap ranking approach. Administration was intramuscular. Blood samples were obtained on Days 0, 7, 14, 30, 60 (Stage I and II), 180, and 210 (Stage II); IgG to toxins A and B was measured by ELISA and in vitro functional activity was measured by toxin neutralizing assay (TNA). Safety data were collected using diary cards. RESULTS: In Stage I the composite immune response against toxins A and B (percentage of participants who seroconverted for both toxins) was highest in the high dose+adjuvant group (97% and 92% for Toxins A and B, respectively) and was chosen for Stage II. In Stage II the immune response profile for this formulation through Day 180 given on Days 0-7-30 ranked above the other two administration schedules. There were no safety issues. CONCLUSIONS: The high dose+adjuvant (100 µg antigen+AlOH) formulation administered at 0-7-30 days elicited the best immune response profile, including functional antibody responses, through Day 180 and was selected for use in subsequent clinical trials.

Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older.

BACKGROUND: Unlike free polysaccharide vaccines, pneumococcal polysaccharide conjugate vaccines (PCVs) induce a T cell-dependent immune response and have the potential to provide an extended duration of protection with repeated vaccinations. METHODS: This was an extension of a previous study in pneumococcal vaccine-naïve adults aged 50-64 years in which adults 60-64 years of age were given 13-valent PCV (PCV13) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) and adults aged 50-59 were given PCV13. In this follow up study conducted about 4 years later, the 60-64 year olds initially given PCV13 received PCV13 or PPSV23, and those initially given PPSV23 received another PPSV23. All adults aged 50-59 years were re-vaccinated with PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after vaccination. RESULTS: A second PCV13 given about 4 years after a first vaccination induced OPA titers that were significantly higher than those following the initial vaccination for 7 of 13 serotypes in the older group, and 6 of 13 serotypes in the younger group, and responses to the remaining serotypes were largely non-inferior. In contrast, OPA titers following revaccination with PPSV23 were statistically significantly lower for 9 of the 13 serotypes, and non-inferior for the remaining serotypes, when compared to the responses to the first PPSV23. OPA titers in the older adults who received PPSV23 after initial PCV13 were significantly higher than those following a first PPSV23 for 10 of the 13 serotypes. CONCLUSION: In adults 50 to 64 years of age, initial vaccination with PCV13 establishes an immune state that results in recall anti-pneumococcal responses upon subsequent vaccination with either conjugated or free polysaccharide vaccine. In contrast, initial vaccination with PPSV23 results in an immune state in which subsequent PPSV23 administration yields generally lower responses compared with the initial responses.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults.

BACKGROUND: Streptococcus pneumoniae is a major cause of morbidity and mortality among adults 50 years of age and older in the United States. Pneumococcal conjugate vaccines are efficacious against pneumococcal disease in children and may also offer advantages in adults. METHODS: We performed a randomized, modified double-blind trial that compared a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 831 pneumococcal vaccine naive adults 60-64 years of age. An additional group of 403 adults 50-59 years of age received open-label PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured at baseline, and at 1 month and 1 year after vaccination. RESULTS: In the randomized trial, the month 1 post-vaccination OPA geometric mean titers in the PCV13 group were statistically significantly higher than in the PPSV23 group for 8 of the 12 serotypes common to both vaccines and for serotype 6A, a serotype unique to PCV13, and were comparable for the other 4 common serotypes. The immune response to PCV13 was generally greater in adults 50-59 years of age compared to adults 60-64 years of age. OPA titers declined from 1 month to 1 year after PCV13 administration but remained higher than pre-vaccination baseline titers. CONCLUSIONS: PCV13 induces a greater functional immune response than PPSV23 for the majority of serotypes covered by PCV13, suggesting that PCV13 could offer immunological advantages over PPSV23 for prevention of vaccine-type pneumococcal infection.

Randomized, controlled trial of a 13-valent pneumococcal conjugate vaccine administered concomitantly with an influenza vaccine in healthy adults.

A randomized, double-blind, phase 3 trial evaluated the immunogenicity, safety, and tolerability of a 13-valent pneumococcal conjugate vaccine (PCV13) coadministered with trivalent inactivated influenza vaccine (TIV) in pneumococcal vaccine-naive adults. Participants ages 50 to 59 years (n = 1,116) received TIV with PCV13 (group 1) or placebo (group 2) (1:1 randomization); 1 month later, group 1 received placebo and group 2 received PCV13. A hemagglutination inhibition (HAI) assay for TIV and a standardized enzyme-linked immunosorbent assay for pneumococcal serotype-specific immunoglobulin G (IgG) were performed and opsonophagocytic activity (OPA) titers (assessed post hoc) were measured at baseline and 1 and 2 months postvaccination. The rises in HAI assay geometric mean titer (GMT) and percentage of participants in groups 1 and 2 with ≥ 4-fold increases in HAI responses (A/H1N1, 84.0% and 81.2%, respectively; A/H3N2, 71.1% and 69.5%, respectively; and B, 60.6% and 60.3%, respectively) were similar. In group 1, all serotypes met the predefined IgG geometric mean concentration (GMC) ratio noninferiority criterion relative to group 2, but GMCs were lower in group 1 than group 2. When comparing group 1 with group 2, 5 serotypes did not meet the OPA GMT ratio noninferiority criterion, and OPA GMTs were significantly lower for 10 serotypes. PCV13 injection site reactions were similar and mostly mild in both groups. Systemic events were more frequent in group 1 (86.2%) than group 2 (76.7%; P < 0.001); no vaccine-related serious adverse events occurred. Coadministration of PCV13 and TIV was well tolerated but associated with lower PCV13 antibody responses and is of unknown clinical significance. Given the positive immunologic attributes of PCV13, concomitant administration with TIV should be dictated by clinical circumstances.