Background: International Council for Harmonisation (ICH) E9 Statistical Principles for Clinical Trials was developed as a consensus guidance document to encourage worldwide harmonization of the principles of statistical methodology in clinical trials. Addendum E9 (R1) clarified and extended ICH E9 with a focus on estimands and sensitivity analyses. Since the release of E9 (R1), clinical trial protocols have included estimands, but there is variation in how they are presented. Statistical analysis plans (SAPs) are increasingly becoming publicly available (e.g. posting on ClinicalTrials.gov) and present an opportunity to link estimands with planned analyses to present the alignment of trial objectives, design, conduct, and analysis. Methods: A table format was used to create a template for inclusion in SAPs that satisfies ICH E9 (R1) guidance to align statistical analysis to the estimand. The template provides a consistent structure for presentation of estimands and the associated analysis, and is applicable to a wide range of trial designs. We illustrate use of the template with a hypothetical clinical trial in HIV-1. Results: The estimand-to-analysis table template starts with the study objective describing the clinical question of interest as written in the trial protocol. The remainder of the table describes each attribute of the estimand (treatment, target population, variable, intercurrent events, and population-level summary) in the left column (ESTIMAND), while the right column describes how each attribute will be handled using the data collected in the clinical trial (ANALYSIS). The template was applied to a hypothetical, early-phase single-arm trial, modeled after a pediatric trial in HIV, where the objective was to determine the safety of a new antiretroviral drug as part of a combination antiretroviral treatment regimen in the pediatric population. Three intercurrent events were illustrated in the table: death, premature treatment discontinuation before 24 weeks, and pregnancy. An estimand-to-analysis table from a grant application that addresses the primary objective of a placebo-controlled randomized trial is also presented to demonstrate an alternative usage. Conclusion: We found the template to be useful in study design, providing a snapshot of the objective, target population, potential intercurrent events, analysis plan, and considerations for missing data in one place and facilitating discussion among stakeholders. The proposed standardized presentation of estimand attributes and analysis considerations in SAPs will provide guidance to SAP authors and consistency across studies to facilitate reviews.
In this international, multicenter open-label study (ACTG A5379) of HepB-CpG vaccine in people with HIV without prior Hepatitis B Virus (HBV) vaccination, all 68 participants achieved HBV seroprotective titers after the 3-dose series in the primary analysis. No unexpected safety issues were observed.
Background Long-term outcome data after HCV treatment are limited, particularly for comparisons between persons with and without HIV. Methods A5320, a prospective cohort study that enrolled participants within 12 months of completing HCV DAA therapy, with or without sustained virologic response (SVR). The primary endpoint was composite: time to death or development of a targeted diagnosis. Component outcomes (death and targeted diagnosis) and liver-related events were also analyzed. The effects of HIV serostatus and HIV RNA and CD4, and liver disease stage on the outcomes were assessed. Follow-up was designated for 5 years. Results 332 participants enrolled: 184 with HIV/HCV (130 SVR) and 148 with HCV (125 SVR). The primary analysis was dominated by targeted diagnoses. Increased rates of targeted diagnoses were seen in HCV-HIV/SVR compared to HCV/SVR (p=0.016) with an incidence rate of 6.7 and 3.4 per 100 person-years, respectively. Among persons without HIV, higher rates of targeted diagnoses were observed in NonSVRs (p=0.007), 10.8 vs 3.4/100 person-years. No significant difference was seen by SVR status among those with HIV. There were 15 deaths; all liver-related deaths (n=4) occurred in NonSVR groups. Conclusions HCV cure following therapy reduces subsequent development of new clinical events, supporting the use of SVR as a predictor for clinical outcomes. Despite HIV control, a significant decrease in incident events or mortality was not demonstrated for PWH who achieved SVR, suggesting co-infection attenuates the beneficial impact of SVR. Research is needed to better define mechanisms accounting for the long-term negative impact of controlled HIV infection.
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