A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats.

BACKGROUND: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines. METHODS: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units. RESULTS: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm. CONCLUSION: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Accounting for confounding by time, early intervention adoption, and time-varying effect modification in the design and analysis of stepped-wedge designs: application to a proposed study design to reduce opioid-related mortality.

BACKGROUND: Beginning in 2019, stepped-wedge designs (SWDs) were being used in the investigation of interventions to reduce opioid-related deaths in communities across the United States. However, these interventions are competing with external factors such as newly initiated public policies limiting opioid prescriptions, media awareness campaigns, and the COVID-19 pandemic. Furthermore, control communities may prematurely adopt components of the intervention as they become available. The presence of time-varying external factors that impact study outcomes is a well-known limitation of SWDs; common approaches to adjusting for them make use of a mixed effects modeling framework. However, these models have several shortcomings when external factors differentially impact intervention and control clusters. METHODS: We discuss limitations of commonly used mixed effects models in the context of proposed SWDs to investigate interventions intended to reduce opioid-related mortality, and propose extensions of these models to address these limitations. We conduct an extensive simulation study of anticipated data from SWD trials targeting the current opioid epidemic in order to examine the performance of these models in the presence of external factors. We consider confounding by time, premature adoption of intervention components, and time-varying effect modification- in which external factors differentially impact intervention and control clusters. RESULTS: In the presence of confounding by time, commonly used mixed effects models yield unbiased intervention effect estimates, but can have inflated Type 1 error and result in under coverage of confidence intervals. These models yield biased intervention effect estimates when premature intervention adoption or effect modification are present. In such scenarios, models incorporating fixed intervention-by-time interactions with an unstructured covariance for intervention-by-cluster-by-time random effects result in unbiased intervention effect estimates, reach nominal confidence interval coverage, and preserve Type 1 error. CONCLUSIONS: Mixed effects models can adjust for different combinations of external factors through correct specification of fixed and random time effects. Since model choice has considerable impact on validity of results and study power, careful consideration must be given to how these external factors impact study endpoints and what estimands are most appropriate in the presence of such factors.

Sexual behavior patterns and HIV risks in bisexual men compared to exclusively heterosexual and homosexual men

OBJETIVO: Comparar los patrones de comportamiento sexual entre hombres bisexuales, heterosexuales y homosexuales. MATERIAL Y MÉTODOS: Se llevó a cabo una encuesta probabilística en hogares de la Ciudad de México en 1992-1993, utilizando el marco muestral de las Encuestas Nacionales de Salud; se obtuvo información de 8 068 hombres entre 15 y 60 años de edad. El análisis principal de este trabajo se centra en hombres sexualmente activos en los cinco años previos a la encuesta. RESULTADOS: Los hombres bisexuales notificaron con mayor frecuencia relaciones sexuales anales con mujeres (16% vs. 3%, p=0.01), y mayor frecuencia de relaciones sexuales con trabajadoras sexuales que los heterosexuales exclusivos (10% vs. 4%, p=0.04). Los bisexuales usaron condones más frecuentemente con trabajadoras sexuales que los heterosexuales (p=0.01). La mayoría de los bisexuales (79%) no mantuvieron relaciones sexuales anales (receptivas o insertivas) con otros hombres en el año previo al estudio; en su lugar, llevaron a cabo sexo oral insertivo o sólo masturbación; 35% de los homosexuales exclusivos no reportó llevar a cabo ninguna práctica anal durante sus relaciones sexuales. Los bisexuales que mantuvieron coito anal tuvieron comportamientos receptivos con menor frecuencia que los homosexuales exclusivos (13% vs. 60%, p<0.01); de éstos, debido al uso de condón, sólo 7% de los bisexuales y 18% de los homosexuales tuvieron coito anal receptivo no protegido en la última relación sexual con otro hombre. CONCLUSIONES: Los bisexuales mantuvieron comportamientos sexuales con otros hombres de menor riesgo que los homosexuales exclusivos. Este hallazgo podría implicar que los hombres bisexuales en México no son un puente epidemiológico efectivo para la transmisión del VIH.