Field Study and Correlative Studies of Factor IX Variant FIX-R338L in Participants Treated with Fidanacogene Elaparvovec.

BACKGROUND: Fidanacogene elaparvovec, an adeno-associated virus-based gene therapy vector expressing the high-activity factor IX (FIX) variant FIX-R338L, is in development for hemophilia B. One-stage clotting (OS) assays and chromogenic substrate (CS) assays are commonly used to measure FIX-R338L variant activity. Data from ongoing trials suggest FIX activity varies between different OS and CS assays. MATERIAL AND METHODS: To better understand FIX-R338L activity in clinical samples, an international multisite field study was conducted across a central laboratory and 18 local laboratories, using standard protocols, reagents, and instrumentation, with individual participant samples from a phase 1/2a study of fidanacogene elaparvovec. RESULTS: Unlike the wild-type FIX control, FIX-R338L activity was higher with the OS silica-based assay versus OS ellagic acid-based and CS assays. Variation in FIX activity was greater at the lowest activity levels. Activated FIX (FIXa) in plasma could result in higher OS assay activity or increased thrombin generation, which could overestimate FIX activity. However, FIXa was not detected in the participant samples, indicating that it was not contributing to the OS assay differences. Since individuals on gene therapy may receive exogenous replacement FIX products, replacement products were spiked into patient plasma samples to target a therapeutic concentration. Exogenous FIX was additive to endogenous FIX-R338L, with no interference from FIX-R338L. CONCLUSION: These results demonstrate FIX-R338L activity can be measured with OS and CS assays in clinical laboratories and provide insight into assay variability when measuring FIX with endogenously produced FIX-R338L. The findings may help establish best practices for measuring FIX-R338L activity (Clinicaltrials.gov identifier: NCT02484092).

Immunogenicity and Safety of the 13-Valent Pneumococcal Conjugate Vaccine Administered in a 3 + 1 versus 2 + 1 Dose Schedule Among Infants in China.

BACKGROUND: 13-valent pneumococcal conjugate vaccine (PCV13) was licensed in China based on immunologic noninferiority to 7-valent PCV (PCV7). As part of the noninferiority study, immunogenicity and safety of PCV13 administered as a 3- or 2-dose infant series followed by a toddler dose were examined in healthy Chinese infants. METHODS: Infants (42- to 77-days-old) were randomized to a 3-dose PCV13 or PCV7 infant series administered double-blind at 3, 4 and 5 months or PCV13 administered open-label at 2, 4 and 6 months and a 2-dose open-label series at 3 and 5 months; all subjects received a toddler dose (12 months). Serotype-specific immunoglobulin G (IgG) concentrations were measured 1 month after the infant series and before and after the toddler dose. Opsonophagocytic activity (OPA) was measured in a subset of subjects at each time point. Safety was evaluated. RESULTS: One month after the infant series, serotype-specific immune responses (IgG ≥ 0.35 µg/mL) were similar for the 2- versus 3-dose schedules, except for serotype 6B, which was significantly lower in the 2-dose group [70.1% in the PCV13 (3, 5 + 12 mo) group vs. 93.2% in the PCV13 (3, 4, 5 + 12 mo) group and 94.7% in the PCV13 (2, 4, 6 + 12 mo) group]. IgG geometric mean concentrations and OPA geometric mean titers trended numerically higher with 3- versus 2-dose schedules. No significant differences in immunogenicity were observed between the 3- versus 2-dose schedules after the toddler dose. PCV13 was well-tolerated across all schedules. CONCLUSIONS: PCV13 administered as a 3- or 2-dose infant series followed by a toddler dose was immunogenic and well tolerated in healthy Chinese infants and likely protective against PCV13 serotypes; immune responses with a 2-dose schedule were lower for some serotypes.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) formulated with 2-phenoxyethanol in multidose vials given with routine vaccination in healthy infants: An open-label randomized controlled trial.

BACKGROUND: This open-label randomized controlled trial in infants compared safety, tolerability, and immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) formulated with the preservative 2-phenoxyethanol (2-PE) in a multidose vial (MDV) to the current PCV13 without 2-PE in a single-dose syringe (SDS). METHODS: Gambian infants were randomized 1:1 to receive PCV13 as either MDV or SDS at ages 2, 3, and 4months. Serotype-specific antipneumococcal antibody responses and opsonophagocytic activity ([OPA]; subset) were measured at age 5months. Noninferiority was declared if the lower bound of the 97.5% CI for the difference (MDV-SDS) in proportions of subjects achieving IgG concentrations ≥0.35µg/mL (primary endpoint) was greater than -10%. IgG geometric mean concentrations (GMCs) were noninferior if the lower limit of the two-sided 97.5% CI of the geometric mean ratio (MDV vs SDS) was greater than 0.5. Reactogenicity and other adverse events were collected. RESULTS: 500 participants were randomized and vaccinated; 489 (MDV: n=245; SDS: n=244) completed the trial. Noninferiority of MDV was demonstrated for all serotypes as measured by percentage of subjects achieving antibody responses above ≥0.35µg/mL. IgG GMCs (coprimary endpoint) also demonstrated noninferiority of MDV; OPA results supported these findings. Safety and tolerability were comparable between groups. CONCLUSIONS: PCV13 in MDV was safe and immunogenic when administered according to the routine schedule to infants. MDV was noninferior to SDS for all 13 pneumococcal serotypes. Comparable immunogenicity and safety profiles of PCV13 MDV and SDS suggest PCV13 MDV can help optimize vaccination in resource-limited settings. ClinicalTrials.gov NCT01964716 https://clinicaltrials.gov/ct2/show/NCT01964716.

Long-term antibody persistence study (3 years after last dose) of the 7-valent pneumococcal conjugate vaccine in young children in China.

BACKGROUND: In a previous study, Chinese infants were vaccinated with 7-valent pneumococcal conjugate vaccine (PCV7) ⩾7days before routine diphtheria, tetanus, and acellular pertussis vaccine (DTaP); PCV7 administered concomitantly with DTaP (PCV7+DTaP); or DTaP alone. This study examined antibody persistence at a single time point 3years after the last vaccination. METHODS: Children who participated in the prior PCV7 study were eligible to participate. A single blood sample was drawn at enrollment. Immunoglobulin G (IgG) geometric mean concentrations (GMCs) specific to the PCV7 serotypes and percentages of subjects with IgG ⩾0.35µg/mL were compared for subjects receiving PCV7 versus PCV7+DTaP (concomitant) and for PCV7 or PCV7+DTaP (concomitant) versus DTaP alone. IgG concentrations at 3years after the last vaccination were also compared with those after the infant series and toddler dose. RESULTS: Three years after the last vaccination with PCV7 or PCV7+DTaP (concomitant), IgG GMCs for most PCV7 serotypes were lower than after the infant series or toddler dose but remained above prevaccination concentrations. IgG GMC were similar between the PCV7 and PCV7+DTaP (concomitant) groups for 5 out of 7 serotypes but serotypes 4 and 19F were significantly lower in the PCV7+DTaP (concomitant) recipients. Three years after the last vaccination, IgG GMCs were significantly higher for 6 of 7 PCV7 serotypes among those receiving PCV7 or PCV7+DTaP (concomitant) compared with recipients of DTaP alone. Among subjects receiving DTaP alone, serotype-specific antibody concentrations were significantly higher for all serotypes 3years after the last vaccination compared with after the infant series. CONCLUSION: Three years after PCV7 vaccination, serotype-specific antibodies were lower than after the primary infant series but higher than prevaccination levels and higher among subjects who received PCV7 compared with those who did not. The immune response was comparable in children who received PCV7 with and without concomitant DTaP. CLINICAL TRIAL REGISTRATION: NCT01298544.

Immunogenicity and Safety of 13-valent Pneumococcal Conjugate Vaccine Compared With 7-valent Pneumococcal Conjugate Vaccine Among Healthy Infants in China.

BACKGROUND: Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) were compared with 7-valent pneumococcal conjugate vaccine (PCV7) in Chinese infants. METHODS: Healthy infants aged 2 months were randomized to a double-blind 3-dose infant series plus 1 toddler dose of PCV7 or PCV13 at 3, 4, 5 and 12 months or open-label PCV13 at 2, 4, 6 and 12 months. Serotype-specific immunoglobulin G (IgG) binding and functionality were measured 1 month after the infant series and after the toddler dose. Local reactions, systemic events and adverse events were assessed postvaccination. RESULTS: For the 7 common serotypes, serotype-specific binding IgGs elicited by PCV13 were noninferior to PCV7 after the 3-dose infant series; functional antibodies were comparable. For the 6 additional serotypes, PCV13 recipients had significantly higher serotype-specific IgGs and functional antibodies than PCV7 recipients after the infant series. The toddler dose boosted the immune response. Local reactions and systemic events were mild in severity and similar across groups. No new safety signals were identified. CONCLUSIONS: For the 7 common serotypes, serotype-specific binding IgG after 2 different 3-dose regimens of PCV13 were noninferior to PCV7 responses. PCV13 recipients had significantly higher immune responses to the 6 additional serotypes. PCV13 is expected to provide pneumococcal disease protection comparable to PCV7 for the common serotypes and further protection against disease caused by the 6 additional serotypes. Safety of PCV7 and PCV13 was comparable.

Safety and tolerability of 13-valent pneumococcal conjugate vaccine in healthy Chinese adults, children and infants.

OBJECTIVE: Pneumococcal disease is a global problem, including in China. The objective of this study was to provide safety data for single-dose 13-valent pneumococcal conjugate vaccine (PCV13) in Chinese subjects, needed to begin a phase III safety and immunogenicity study in Chinese infants. METHODS: Healthy Chinese adults (18-55 years), children (3-5 years), and infants (42-98 days) received a single dose of PCV13 in this open-label safety study. Local reactions and systemic events were collected for 7 days via an electronic diary; adverse events were recorded for 1 month after vaccination. RESULTS: All 72 (24 per group) screened subjects (58.3% males; mean ± standard deviation [SD] age: 43.3 ± 9.1 years [adults], 4.5 ± 0.7 years [children], and 79.6 ± 15.2 days [infants]) were enrolled, received vaccine, and completed the study. The most frequently reported local reactions per group were pain at the injection site (n = 23 adults [95.8%]), tenderness (n = 18 children [75%]), and swelling (n = 6 infants [25%]), none of which were severe. The mean duration of each local reaction was ⩽2.0 days in infants and ⩽2.4 days in children but in adults was 3.3 days for pain at the injection site and 9 days each for redness and swelling. Systemic events in adults were muscle pain (n = 5), fatigue (n = 3), and headache and joint pain (n = 1 each). One child and seven infants had disturbed sleep (increased or decreased). One adult and one child had mild fever (37.7-38.5°C, as per China Food and Drug Administration guidelines). No subject used antipyretic medication. One adverse event (bronchopneumonia in an infant) was reported, which was serious, severe, and unrelated to vaccination. There were no deaths. CONCLUSIONS: A single dose of PCV13 was safe and well tolerated in healthy Chinese adults, children, and infants. This study provided the safety data to enable a phase III safety and immunogenicity registration trial in Chinese infants to proceed.

Evaluation of 13-valent pneumococcal conjugate vaccine and concomitant meningococcal group C conjugate vaccine in healthy infants and toddlers in Spain.

BACKGROUND: Given the concurrent administration of multiple vaccines during routine pediatric immunizations, efforts to elucidate the potential interference of any vaccine on the immune response to the concomitantly administered antigens are fundamental to prelicensure clinical research. METHODS: This phase 3 randomized controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) versus 7-valent PCV (PCV7) assessed immune responses of concomitantly administered meningococcal group C conjugated to diphtheria toxin cross-reactive material 197 (MnCCV-CRM197) in a 2-dose infant series and 15-month toddler dose. RESULTS: 619 subjects were randomized, 315 to PCV13 and 304 to PCV7. MnCCV-CRM197-induced immune responses were similar between the PCV13 and PCV7 groups, with >97% of the subjects achieving a ≥1:8 meningococcal serum bactericidal assay (SBA) titer after both dose 2 and the toddler dose. Geometric mean titers were lower in the PCV13 group 191.22 (167.72, 218.02) versus 266.19 (234.86, 301.71) following dose 2 and 432.28 (361.22, 517.31) versus 730.84 (642.05, 831.91) following the toddler dose. The geometric mean (GM) meningococcal SBA titer ratios (PCV13/PCV7) were 0.72 after dose 2 and 0.59 after the toddler dose. The criteria for MnCCV-CRM197 non-inferiority for GM titers were satisfied after dose 2. Percent responders was similar up to titers of 1:128. PCV13 elicited substantial antipneumococcal responses against all 13 serotypes, with ≥90% of the subjects achieving an antibody concentration ≥0.35µg/mL after dose 3 in the infant series. Safety and tolerability were similar between the vaccine groups. CONCLUSIONS: Immunogenicity results of MnCCV-CRM197 for PCV13 compared with PCV7 included lower GMTs, but the clinical significance of this is unknown as the proportion of infants achieving protective MenC antibody titers was comparable in the two groups. Percent responders were similar up to titers of 1:128. PCV13 has an acceptable safety profile in infants and toddlers, while providing expanded coverage against pneumococcal disease.

Immunogenicity of a combination vaccine containing diphtheria toxoid, tetanus toxoid, three-component acellular pertussis, hepatitis B, inactivated polio virus, and Haemophilus influenzae type b when given concomitantly with 13-valent pneumococcal conjugate vaccine.

Two randomized trials of 13-valent pneumococcal conjugate vaccine (PCV13) relative to PCV7 evaluated the immune responses of coadministered antigens comprising Infanrix(®) hexa/Infanrix(®)-IPV+Hib (diphtheria, tetanus, 3-component acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b). After the 3-dose infant series, immunogenic noninferiority was demonstrated for all concomitantly administered antigens between the PCV13 and PCV7 groups. All antigens elicited good booster responses after the toddler dose except pertussis toxoid; however, 99.6% subjects achieved pertussis toxoid protective antibody level ≥5EU/mL in both groups. These results support the concomitant administration of PCV13 and Infanrix hexa/Infanrix-IPV+Hib as part of routine immunization schedules.

A Bayesian dose-finding trial with adaptive dose expansion to flexibly assess efficacy and safety of an investigational drug.

BACKGROUND: Adaptive dose-ranging trials are more efficient than traditional approaches and may be designed to explicitly address the goals and decisions inherent in learn-phase drug development. We report the design, implementation, and outcome of an innovative Bayesian, response-adaptive, dose-ranging trial of an investigational drug in patients with diabetes, incorporating a dose expansion approach to flexibly address both efficacy and safety. PURPOSE: The design was developed to assess whether one or more doses of an investigational drug demonstrated superior efficacy to an active control while maintaining an acceptable safety profile. METHODS: The trial used a two-stage design, in which patients were initially allocated equally to placebo, investigational drug at a low and a medium dose, and an active control. Movement to the second stage was contingent upon evidence of efficacy (measured by change in fasting blood glucose) to add a very low dose of the investigational drug and of safety (measured by weight gain) to add a high dose of the investigational drug. The design incorporated a longitudinal model to maximize use of incomplete data, predictive probabilities to guide the decisions to terminate the trial for futility or move on to Stage 2, and a dose-response model in Stage 2 to borrow information across adjacent doses. Extensive simulations were used to fine tune trial parameters, to define operating characteristics, and to determine the required sample sizes. A data monitoring committee was provided with frequent reports to aid in trial oversight. RESULTS: In Stage 1, as trial data accrued, the predictive probability that either the low or medium dose of the investigational drug was superior to the active control fell to low values. Stage 1 termination was recommended after 199 subjects were randomized, out of a maximum trial size of 500 subjects, and the final sample size was 218. Thus the trial did not progress to Stage 2. LIMITATIONS: Because of the relatively narrow dose range to be assessed, and the inability to utilize the highest dose at the beginning of the trial, a fully responsive-adaptive design incorporating dose-response modeling was not considered a viable option. This limited the efficiency gains possible with a full set of adaptive design elements. CONCLUSIONS: The two-stage dose-expansion design functioned as designed, recommending early termination based on a low probability that the tested doses had efficacy greater than the active control.