Bias and precision in early phase adaptive oncology studies and its consequences for confirmatory trials

The need for a more efficient drug development process led to migration from the traditional fixed-sample clinical trial designs to group-sequential and adaptive designs, especially in early phases of clinical drug development. This, however, came with challenges in inference, since many of these newly proposed designs come without respective methods for statistical inference. In this dissertation, we study the estimation methods for oncology phase II group-sequential and adaptive designs in terms of bias and precision, and we propose new estimation methods for a new class of adaptive designs. We then evaluate the consequences, in terms of power, of using estimates from these designs to plan phase III trial. We also study and propose new approaches to adjust these estimates, based on the observed data, before employing them in planning of phase III sample size, in order to reach the desired power. Literature review showed that many estimation methods have been proposed for the classical single-arm two-stage group-sequential designs with a binary endpoint, which are the most commonly used designs in oncology trials of phase II. Simulation studies showed that the uniformly minimum variance unbiased estimator is the best amongst them in terms of bias and mean square error. However, for the adaptive group-sequential designs, these estimation methods have poor performance. Our proposed estimation methods in oncology phase II adaptive designs showed better performance as compared to the naive maximum likelihood estimator. A direct use of estimates from phase II adaptive designs to plan phase III results in underpowered phase III trials. Therefore, adjusting (discounting) these estimates beforehand is necessary. The amount of discounting, however, depends on the estimator, with our proposed estimators requiring less discounting as compared to the naive maximum likelihood estimator. Our proposed adjustment approaches show power improvements, which are similar across different estimators and design scenarios

Maternal HIV infection is an important health determinant in non-HIV-infected infants

OBJECTIVE: To assess morbidity and mortality in HIV-exposed uninfected (HEU) children to help guiding appropriate clinical care and effective preventive interventions. DESIGN: This is a longitudinal study comparing two cohorts of children; one born to HIV-infected women and the other born to HIV-uninfected women. METHODS: We have analyzed prospectively obtained information on nutritional status, morbidity and mortality from 966 HEU and 909 HIV-unexposed infants followed up until their first 18 months of life at a referral health facility in southern Mozambique. Determinants for adverse health outcomes in HEU children were also assessed using multivariate logistic regression. RESULTS: Increased incidence of hospital admissions (P = 0.0015), shorter survival in the first 18 months of life (P = 0.0510) and moderate and severe malnutrition (P = 0.0006 and 0.0014, respectively) were observed among HEU children compared with HIV-unexposed children. Incidence of outpatient attendance in HEU children was associated with being men, older age and the mother being on antiretroviral treatment. Among HEU children, those who were never breastfed, or who were weaned or were partially breastfed, had an increased incidence of hospital admissions compared with children who were exclusively breastfed. CONCLUSION: Maternal HIV infection has important health consequences in non-HIV-infected children. As the prevalence of HIV-infected pregnant women is maintained and the proportion of HIV-infected children declines because of the scale-up of antiretroviral treatment during pregnancy and breastfeeding, more focus should be given to the health needs of HEU children to ensure that the post-2015 sustainable development goals are met

Effects of HIV infection on maternal and neonatal health in southern Mozambique: A prospective cohort study after a decade of antiretroviral drugs roll out

INTRODUCTION: The HIV epidemic is concentrated in sub-Saharan Africa. However, limited information exists on its impact on women and infant's health since the introduction of antiretroviral drugs in this region, where health resources are often scarce. METHODS: The effect of HIV infection on maternal health, birth outcomes and infant health was analysed in two contemporary cohorts of HIV-uninfected and HIV-infected pregnant women from southern Mozambique. Pregnant women attending the first antenatal care visit were followed until one month after delivery. Antiretroviral therapy was administered based on CD4+T cell count and clinical stage. Maternal and neonatal morbidity and mortality, as well as pregnancy outcomes were assessed by mother's HIV status. RESULTS: A total of 1183 HIV-uninfected and 561 HIV-infected pregnant women were enrolled. HIV-infected women were more likely to have anaemia both at the first antenatal care visit and at delivery than HIV-uninfected women (71.5% versus 54.8% and 49.4% versus 40.6%, respectively, p<0.001). Incidence of hospital admissions during pregnancy was increased among HIV-infected women (RR, 2.04, [95%CI, 1.45; 2.86]; p<0.001). At delivery, 21% of HIV-infected women reported being on antiretroviral therapy, and 70% having received antiretroviral drugs for prevention of mother to child transmission of HIV. The risk of stillbirths was doubled in HIV-infected women (RR, 2.16 [95%CI 1.17; 3.96], p = 0.013). Foetal anaemia was also increased among infants born to HIV-infected women (10.6% versus 7.3%, p = 0.022). No differences were found in mean birth weight, malaria, prematurity and maternal and neonatal deaths between groups. CONCLUSIONS: HIV infection continues to be associated with significant maternal morbidity and poor neonatal health outcomes. Efforts should urgently be made to identify the barriers that impede improvements on the devastating effects of HIV in African women and their infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00811421

Infant mortality and morbidity associated with preterm and small-for-gestational-age births in Southern Mozambique: A retrospective cohort study

BACKGROUND: Preterm and small for gestational age (SGA) births have been associated with adverse outcomes during the first stages of life. We evaluated the morbidity and mortality associated with preterm and SGA births during the first year of life in a rural area of Southern Mozambique. METHODS: This is a retrospective cohort study using previously collected data from children born at the Manhica District Hospital in two different periods (2003-2005 and 2010-2012). Newborns were classified as being preterm and/or SGA or as babies not fulfilling any of the previous conditions (term non-SGA). All children were followed up for a year for morbidity and mortality outcomes. RESULTS: A total of 5574 live babies were included in the analysis. The prevalence of preterm delivery was 6.2% (345/5574); the prevalence of SGA was 14.0% (776/5542) and 2.2% (114/5542) of the children presented both conditions. During the neonatal period, preterm delivery and SGA were associated with 13 (HR: 13.0, 95% CI 4.0-42.2) and 5 times (HR: 4.5, 95% CI: 1.6-12.6) higher mortality compared to term non SGA babies. Risk of hospitalization was only increased when both conditions were present (IRR: 3.5, 95%CI: 1.5-8.1). Mortality is also increased during the entire first year, although at a lower rate. CONCLUSIONS: Neonatal and infant mortality rates are remarkably high among preterm and SGA babies in southern Mozambique. These increased rates are concentrated within the neonatal period. Prompt identification of these conditions is needed to implement interventions aimed at increasing survival of these high-risk newborns

Impact of rotavirus vaccination on diarrheal hospitalizations in children younger than 5 years of age in a rural southern Mozambique

Funding Information: We thank the participants in this study and their parents for allowing the collection of samples and data. The authors would also like to thank all Centro de Investigação em Saúde de Manhiça (CISM) staff particularly those supporting Diarrheal Disease Research Area and Manhiça District Hospital. Core funding for CISM is provided by the Spanish Agency for International Cooperation and Development (AECID). ISGlobal receives support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. The GEMS study was supported by the Bill & Melinda Gates Foundation (Project OPP 38874). The impact of rotavirus study was supported by GAVI funds through Centers for Disease Control and Prevention Foundation (CDCF), Atlanta & World Health Organization, Regional Offices for Africa (WHO AFRO). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention and World Health Organization. The authors declare no conflict of interest. Funding Information: We thank the participants in this study and their parents for allowing the collection of samples and data. The authors would also like to thank all Centro de Investigação em Saúde de Manhiça (CISM) staff particularly those supporting Diarrheal Disease Research Area and Manhiça District Hospital. Core funding for CISM is provided by the Spanish Agency for International Cooperation and Development (AECID). ISGlobal receives support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. The GEMS study was supported by the Bill & Melinda Gates Foundation (Project OPP 38874). The impact of rotavirus study was supported by GAVI funds through Centers for Disease Control and Prevention Foundation (CDCF), Atlanta & World Health Organization, Regional Offices for Africa (WHO AFRO). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2022Background: Rotavirus vaccine (Rotarix®) was introduced in Mozambique through its Expanded Program of Immunization in September 2015. We assessed the impact of rotavirus vaccination on childhood gastroenteritis-associated hospitalizations post-vaccine introduction in a high HIV prevalence rural setting of southern Mozambique. Methods: We reviewed and compared the trend of hospitalizations (prevalence) and incidence rates of acute gastroenteritis (AGE), and rotavirus associated-diarrhea (laboratory confirmed rotavirus) in pre- (January 2008–August 2015) and post-rotavirus vaccine introduction periods (September 2015–December 2020), among children <5 years of age admitted to Manhiça District Hospital. Results: From January 2008 to December 2020, rotavirus vaccination was found to contribute to the decline of the prevalence of AGE from 19% (95% CI: 18.14–20.44) prior to the vaccine introduction to 10% (95% CI: 8.89–11.48) in the post-introduction period, preventing 40% (95 % IE: 38–42) and 84% (95 % IE: 80–87) of the expected AGE and laboratory confirmed rotavirus cases, respectively, among infants. Similarly, the overall incidence of rotavirus was 11.8-fold lower in the post-vaccine introduction period (0.4/1000 child-years-at-risk [CYAR]; 95% CI: 0.3–0.6) compared with the pre-vaccination period (4.7/1000 CYAR; 95% CI: 4.2–5.1) with the highest reduction being observed among infants (16.8-fold lower from the 15.1/1000 CYAR in the pre-vaccine to 0.9/1000 CYAR in the post-vaccine eras). Conclusions: We documented a significant reduction in all-cause diarrhea hospitalizations and rotavirus positivity after vaccine introduction demonstrating the beneficial impact of rotavirus vaccination in a highly vulnerable population.publishersversionpublishe

Concordance of three alternative gestational age assessments for pregnant women from four African countries: A secondary analysis of the MIPPAD trial

Background: At times, ultrasound is not readily available in low resource countries in Africa for accurate determination of gestational age, so using alternative methods is pivotal during pregnancy. These assessments are used to aid the risk analysis for an infant and management strategies for premature delivery, if necessary. Currently, date of last menstrual period, fundal height measurements, and the New Ballard Score are commonly used in resource-limited settings. However, concordance of these measures is unknown for sub-Saharan Africa. We obtained data from an open-label randomized controlled trial, to assess the concordance of these alternative assessment methods. The purpose of our study was to determine the agreement between these alternative methods when used in sub-Saharan African populations. Methods: A total of 4,390 pregnant women from Benin, Gabon, Mozambique and Tanzania were included in our analysis. The assessment methods compared were: 1) reported last menstrual period, 2) symphysis-fundal height measurement, and 3) the New Ballard Score. The Bland-Altman method and intraclass correlation coefficient (ICC) were used to test the degree of agreement. Survival range gestational age, used as an inclusion criterion for further analysis, was from 22 to 44 weeks. Findings: Plots showed a lack of agreement between methods and the 95% limits of agreement too wide to be clinically useful. ICC = 0.25 indicated poor agreement. A post-hoc analysis, restricted from 32 to 42 weeks, was done to check for better agreement in this near-term population. The plots and ICC = 0.16 still confirmed poor agreement. Conclusion: The alternative assessments do not result in comparable outcomes and discrepancies are far beyond the clinically acceptable range. Last menstrual period should not be used as the only estimator of gestational age. In the absence of reliable early ultrasound, symphysis-fundal height measurements may be most useful during pregnancy for fetal risk assessment and the New Ballard Score after delivery as a confirmation of these estimations and for further neonatal management. However, promotion of portable ultrasound devices is required for accurate assessment of gestational age in sub-Sahara Africa

Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy

Background Prevention of reinfection and resurgence is an integral component of the goal to eradicate malaria. However, the adverse effects of malaria resurgences are not known. Methods We assessed the prevalence of Plasmodium falciparum infection among 1819 Mozambican women who delivered infants between 2003 and 2012. We used microscopic and histologic examination and a quantitative polymerase-chain-reaction (qPCR) assay, as well as flow-cytometric analysis of IgG antibody responses against two parasite lines. Results Positive qPCR tests for P. falciparum decreased from 33% in 2003 to 2% in 2010 and increased to 6% in 2012, with antimalarial IgG antibody responses mirroring these trends. Parasite densities in peripheral blood on qPCR assay were higher in 2010-2012 (geometric mean [+/-SD], 409+/-1569 genomes per microliter) than in 2003-2005 (44+/-169 genomes per microliter, P=0.02), as were parasite densities in placental blood on histologic assessment (50+/-39% of infected erythrocytes vs. 4+/-6%, P<0.001). The malaria-associated reduction in maternal hemoglobin levels was larger in 2010-2012 (10.1+/-1.8 g per deciliter in infected women vs. 10.9+/-1.7 g per deciliter in uninfected women; mean difference, -0.82 g per deciliter; 95% confidence interval [CI], -1.39 to -0.25) than in 2003-2005 (10.5+/-1.1 g per deciliter vs. 10.6+/-1.5 g per deciliter; difference, -0.12 g per deciliter; 95% CI, -0.67 to 0.43), as was the reduction in birth weight (2863+/-440 g in women with past or chronic infections vs. 3070+/-482 g in uninfected women in 2010-2012; mean difference, -164.5 g; 95% CI, -289.7 to -39.4; and 2994+/-487 g vs. 3117+/-455 g in 2003-2005; difference, -44.8 g; 95% CI, -139.1 to 49.5). Conclusions Antimalarial antibodies were reduced and the adverse consequences of P. falciparum infections were increased in pregnant women after 5 years of a decline in the prevalence of malaria. (Funded by Malaria Eradication Scientific Alliance and others.)

Effectiveness of Monovalent Rotavirus Vaccine in Mozambique, a Country with a High Burden of Chronic Malnutrition

Funding Information: Funding: This research was funded by GAVI through the Centers for Disease Control and Prevention (CDC), Atlanta and World Health Organization, Regional Office for Africa (WHO/AFRO). African Research in Neglected Tropical Diseases (EFINTD, grant number 89539); Deutsche Forschungsge-meinschaft (DFG; grant number JO369/5-1); Fundo Nacional de Investigação (FNI); United States Agency for International Development (USAID; grant number AID-656-F-16-00002); the Calouste Gulbenkian Foundation from where A.C., F.M., and J.S. have a PhD fellowship. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Mozambique introduced monovalent rotavirus vaccine (Rotarix® ) in September 2015. We evaluated the effectiveness of Rotarix® under conditions of routine use in Mozambican children hospitalized with acute gastroenteritis (AGE). A test negative case-control analysis was performed on data collected during 2017–2019 from children <5 years old, admitted with AGE in seven sentinel hospital sites in Mozambique. Adjusted VE was calculated for ≥1 dose of vaccine vs. zero doses using unconditional logistic regression, where VE = (1 − aOR) × 100%. VE estimates were stratified by age group, AGE severity, malnutrition, and genotype. Among 689 children eligible for analysis, 23.7% were rotavirus positive (cases) and 76.3% were negative (controls). The adjusted VE of ≥1 dose in children aged 6–11 months was 52.0% (95% CI, −11, 79), and −24.0% (95% CI, −459, 62) among children aged 12–23 months. Estimated VE was lower in stunted than non-stunted children (14% (95% CI, −138, 66) vs. 59% (95% CI, −125, 91)). Rotavirus vaccination appeared moderately effective against rotavirus gastroenteritis hospitalization in young Mozambican children. VE point estimates were lower in older and stunted children, although confidence intervals were wide and overlapped across strata. These findings provide additional evidence for other high-mortality countries considering rotavirus vaccine introduction.publishersversionpublishe

Bias und Präzision in frühen Phasen adaptiven onkologische Studien und die Folgen für Bestätigungsstudien

The need for a more efficient drug development process led to migration from the traditional fixed-sample clinical trial designs to group-sequential and adaptive designs, especially in early phases of clinical drug development. This, however, came with challenges in inference, since many of these newly proposed designs come without respective methods for statistical inference. In this dissertation, we study the estimation methods for oncology phase II group-sequential and adaptive designs in terms of bias and precision, and we propose new estimation methods for a new class of adaptive designs. We then evaluate the consequences, in terms of power, of using estimates from these designs to plan phase III trial. We also study and propose new approaches to adjust these estimates, based on the observed data, before employing them in planning of phase III sample size, in order to reach the desired power. Literature review showed that many estimation methods have been proposed for the classical single-arm two-stage group-sequential designs with a binary endpoint, which are the most commonly used designs in oncology trials of phase II. Simulation studies showed that the uniformly minimum variance unbiased estimator is the best amongst them in terms of bias and mean square error. However, for the adaptive group-sequential designs, these estimation methods have poor performance. Our proposed estimation methods in oncology phase II adaptive designs showed better performance as compared to the naive maximum likelihood estimator. A direct use of estimates from phase II adaptive designs to plan phase III results in underpowered phase III trials. Therefore, adjusting (discounting) these estimates beforehand is necessary. The amount of discounting, however, depends on the estimator, with our proposed estimators requiring less discounting as compared to the naive maximum likelihood estimator. Our proposed adjustment approaches show power improvements, which are similar across different estimators and design scenarios