Economizing comparative Poisson clinical trials of multiple experimental treatments by testing against the same control.

Comparative Poisson trials of an experimental treatment versus a control typically condition on the total number of events that occur across both arms (Design A). Inference is based on the binomial distribution. Recently, an approach termed Design C to compare K experimental treatments to the same control was introduced. Under Design C without curtailment, the trial continues until a prespecified number of events occur in the control arm, leading to inference based on the negative multinomial distribution. The question remains of how advantageous it is to conduct one Design C trial comparing K experimental treatment arms to the same control arm as opposed to conducting K separate Design A trials each comparing one experimental treatment arm to a different control arm. This paper, therefore, compares the expected number of subjects to enroll for the two designs under uncurtailed and curtailed settings. The designs are evaluated when the null hypothesis and various assumptions for the alternative hypothesis hold. We simulate a variety of combinations for the Type 1 error, power, and ratio of the incidence rate of events in the experimental treatment to control arms. Design C frequently offers significant savings in terms of sample size relative to Design A.

A phase 3 study of safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, followed by 23-valent pneumococcal polysaccharide vaccine, in children with HIV.

OBJECTIVES: To evaluate the safety and immunogenicity of V114 [15-valent pneumococcal conjugate vaccine (PCV) containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 14, 18C, 19A, 19F, 22F, 23F, 33F], followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 8 weeks later, in children with HIV. DESIGN: This phase 3 study (NCT03921424) randomized participants 6-17 years of age with HIV (CD4 + T-cell count ≥200 cells/µl, plasma HIV RNA <50 000 copies/ml) to receive V114 or 13-valent PCV (PCV13) in a double-blind manner on Day 1, followed by PPSV23 at Week 8. METHODS: Adverse events (AEs), pneumococcal serotype-specific immunoglobulin G (IgG), and opsonophagocytic activity (OPA) were evaluated 30 days after each vaccination. RESULTS: The proportion of participants experiencing at least one AE post-PCV was 78.8% in the V114 group ( n  = 203) and 69.6% in the PCV13 group ( n  = 204); respective proportions post-PPSV23 were 75.4% ( n  = 203) and 77.2% ( n  = 202). There were no vaccine-related serious AEs. IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were generally comparable between V114 and PCV13 for shared serotypes at Day 30, and were higher for V114 compared with PCV13 for the additional V114 serotypes 22F and 33F. Approximately 30 days after PPSV23, IgG GMCs and OPA GMTs were generally comparable between the V114 and PCV13 groups for all 15 serotypes in V114. CONCLUSIONS: In children with HIV, a sequential administration of V114 followed 8 weeks later with PPSV23 is well tolerated and induces immune responses for all 15 pneumococcal serotypes included in V114.

Safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, followed by sequential PPSV23 vaccination in healthy adults aged ≥50 years: A randomized phase III trial (PNEU-PATH).

BACKGROUND: Streptococcus pneumoniae causes pneumococcal disease, and older adults are at an increased risk. Sequential vaccination of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for broad protection against pneumococcal disease in some countries. METHODS: This phase III trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 12 months later by PPSV23, in healthy adults aged ≥50 years (NCT03480763). A total of 652 participants were randomized 1:1 to receive either V114 or PCV13, followed by PPSV23. RESULTS: The most common solicited adverse events (AEs) following PCV vaccination included injection-site pain and fatigue. Higher proportions of participants with these events were observed in the V114 group following PCV; however, these differences were not clinically significant. Following PPSV23 vaccination, the most common solicited AEs were injection-site pain and injection-site swelling; the proportions of participants with these events were comparable between both groups. Incidence of serious AEs was low in both groups following PCV and PPSV23, and none were related to study vaccines. No deaths occurred during the study. Serum opsonophagocytic activity geometric mean titers and immunoglobulin G geometric mean concentrations were comparable between both groups for all 15 serotypes in V114 following PPSV23. Immune responses elicited by V114 persisted for at least 12 months. Immune responses at 30 days and 12 months post-vaccination with PCV were comparable between both groups for the 13 shared serotypes and higher in the V114 group for the V114-unique serotypes (22F and 33F). CONCLUSION: Administration of V114 followed by PPSV23 was well tolerated and induced comparable antibody levels to PCV13 followed by PPSV23 in healthy adults aged ≥50 years.

Comparative poisson clinical trials of multiple experimental treatments vs a single control using the negative multinomial distribution.

This paper introduces a method which conditions on the number of events that occur in the control group to determine rejection regions and power for comparative Poisson trials with multiple experimental treatment arms that are each compared to one control arm. This leads to the negative multinomial as the statistical distribution used for testing. For one experimental treatment and one control with curtailed sampling, this is equivalent to Gail's (1974) approach. We provide formulas to calculate exact one-sided overall Type I error and pointwise power for tests of treatment superiority and inferiority (vs the control). Tables of trial design parameters for combinations of one-sided overall Type I error = 0.05, 0.01 and pointwise power = 0.90, 0.80 are provided. Curtailment approaches are presented to stop follow-up of experimental treatment arms or to stop the study entirely once the final outcomes for each arm are known.

Clinical outcomes associated with pathogenic genomic instability mutations in prostate cancer: a retrospective analysis of US pharmacy and medical claims data.

Background: Prostate cancer (PC) is a clinically heterogenous disease, and genetic mutations may be useful for patient risk stratification. This retrospective cohort study compared clinical outcomes, pharmacy use, and outpatient resource use in PC patients with and without pathogenic genomic instability mutations, including DNA repair deficiency (DRD) mutations and those in TP53, PTEN, and RB1. Methods: Patients ≥18 years newly-diagnosed with PC between June 2011-March 2016 were identified in medical and prescription claims databases linked to a genomic dataset. All-cause and PC-specific pharmacy use and outpatient resource use (office visits, laboratory tests, radiology examinations, and radiation therapies) over 1, 2, and 3 years and time to evidence of disease progression after PC diagnosis, based on secondary cancer diagnosis codes and treatments received, were evaluated in mutation carriers with ≥1 of 24 gene mutations and in a sub-set of DRD gene mutation carriers, with each compared to non-mutation carriers. Results: Mutation carriers (n = 274) and non-mutation carriers (n = 74) had similar demographic and clinical features. Non-mutation carriers had lower risks of developing metastasis and castration-resistant PC than mutation carriers (hazard ratio [HR] = 0.7, 95% CI = 0.5-0.9; HR = 0.5, 95% CI = 0.3-0.9, respectively) and DRD mutation carriers (HR = 0.5, 95% CI = 0.3-0.7; HR = 0.4, 95% CI = 0.2-0.7, respectively). Compared to non-mutation carriers, mutation carriers had more all-cause pharmacy claims over 2 years of follow-up (74.4 vs 59.1, p = 0.04) and more PC-specific pharmacy claims over 2 years (11.1 vs 6.5, p = 0.01) and 3 years (17.9 vs 9.8, p = 0.01) of follow-up. No differences were observed in outpatient resource use during the follow-up period by mutation status. Conclusion: PC patients carrying ≥1 pathogenic DNA instability mutation, and DRD mutation carriers specifically, had higher clinical burden than non-mutation carriers. Targeted therapies for these patients are needed to reduce clinical burden and associated healthcare resource utilization.

Real-world evidence on adherence, persistence, switching and dose escalation with biologics in adult inflammatory bowel disease in the United States: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: The application of biologics to treat inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is well established. Our aim was to characterize the most recent five years of data on rates of adherence, persistence, switching and dose escalations with biologics used to treat IBD in the United States. METHODS: We systematically reviewed electronic databases MEDLINE, MEDLINE In-Process, EMBASE and Cochrane Library for 2012-2017 as well as conference proceedings for 2016-2017 published in English. RESULTS AND DISCUSSION: Of 449 records identified, 41 met all screening criteria. Published studies varied greatly in methodology, data sources, population studied, follow-up time and endpoint definitions, preventing meaningful comparisons across studies. Based on studies using a medication possession rate threshold of <80% or <86%, 38%-77% of patients were found non-adherent to biologics. Discontinuation within the first 3 months occurred in 0%-25% of patients in six studies; 7%-65% discontinued by 12 months in 13 studies. Among all patients who initiated an index biologic, the switch rate to another biologic ranged from 4.5% to 20% in 6 studies. Dose escalations were reported in only four studies; 8%-35% of patients had their dose escalated within the first year of therapy. WHAT IS NEW AND CONCLUSION: This study demonstrates variability in study design and methodology to assess adherence, persistence, switching and dose escalation with biologics among adults with IBD in the United States. Our findings suggest that real-world biologic use may be suboptimal and indicate new therapies and/or additional patient support may be needed.