A third trial oversight committee: Functions, benefits and issues

BACKGROUND/AIMS: Clinical trial oversight is central to the safety of participants and production of robust data. The United Kingdom Medical Research Council originally set out an oversight structure comprising three committees in 1998. The first committee, led by the trial team, is hands-on with trial conduct/operations (‘Trial Management Group’) and essential. The second committee (Data Monitoring Committee), usually completely independent of the trial, reviews accumulating trial evidence and is used by most later phase trials. The Independent Data Monitoring Committee makes recommendations to the third oversight committee. The third committee, (‘Trial Steering Committee’), facilitates in-depth interactions of independent and non-independent trial members and gives broader oversight (blinded to comparative analysis). We investigated the roles and functioning of the third oversight committee with multiple research methods. We reflect upon these findings to standardise the committee’s remit and operation and to potentially increase its usage. METHODS: We utilised findings from our recent published suite of research on the third oversight committee to inform guideline revision. In brief, we conducted a survey of 38 United Kingdom–registered Clinical Trials Units, reviewed a cohort of 264 published trials, observed 8 third oversight committee meetings and interviewed 52 trialists. We convened an expert panel to discuss third oversight committees. Subsequently, we interviewed nine patient/lay third committee members and eight committee Chairs. RESULTS: In the survey, most Clinical Trials Units required a third committee for all their trials (27/38, 71%) with independent members (ranging from 1 to 6). In the survey and interviews, the independence of the third committee was valued to make unbiased consideration of Independent Data Monitoring Committee recommendations and to advise on trial progress, protocol changes and recruitment issues in conjunction with the trial leadership. The third committee also advised funders and sponsors about trial continuation and represented patients and the public by including lay members. Of the cohort of 264 published trials, 144 reported a ‘steering’ committee (55%), but the independence of these members was not described so these may have been internal Trial Management Groups. Around two thirds of papers (60%) reported having an Independent Data Monitoring Committee and 26.9% neither a steering nor an Independent Data Monitoring Committee. However, before revising the third committee charter (Terms of Reference), greater standardisation is needed around defining member independence, composition, primacy of decision-making, interactions with other committees and the lifespan. CONCLUSION: A third oversight committee has benefits for trial oversight and conduct, and a revised charter will facilitate greater standardisation and wider adoption

Influence of Prenatal Arsenic Exposure and Newborn Sex on Global Methylation of Cord Blood DNA

Background An emerging body of evidence indicates that early-life arsenic (As) exposure may influence the trajectory of health outcomes later in life. However, the mechanisms underlying these observations are unknown. Objective The objective of this study was to investigate the influence of prenatal As exposure on global methylation of cord blood DNA in a study of mother/newborn pairs in Matlab, Bangladesh. Design Maternal and cord blood DNA were available from a convenience sample of 101 mother/newborn pairs. Measures of As exposure included maternal urinary As (uAs), maternal blood As (mbAs) and cord blood As (cbAs). Several measures of global DNA methylation were assessed, including the [3H]-methyl-incorporation assay and three Pyrosequencing assays: Alu, LINE-1 and LUMA. Results In the total sample, increasing quartiles of maternal uAs were associated with an increase in covariate-adjusted means of newborn global DNA methylation as measured by the [3H]-methyl-incorporation assay (quartile 1 (Q1) and Q2 vs. Q4; p = 0.06 and 0.04, respectively). Sex-specific linear regression analyses, while not reaching significance level of 0.05, indicated that the associations between As exposures and Alu, LINE-1 and LUMA were positive among male newborns (N = 58) but negative among female newborns (N = 43); tests for sex differences were borderline significant for the association of cbAs and mbAs with Alu (p = 0.05 and 0.09, respectively) and for the association between maternal uAs and LINE-1 (p = 0.07). Sex-specific correlations between maternal urinary creatinine and newborn methyl-incorporation, Alu and LINE-1 were also evident (p\u3c0.05). Conclusions These results suggest that prenatal As exposure is associated with global DNA methylation in cord blood DNA, possibly in a sex-specific manner. Arsenic-induced epigenetic modifications in utero may potentially influence disease outcomes later in life. Additional studies are needed to confirm these findings and to examine the persistence of DNA methylation marks over time

Levels, timing, and etiology of stillbirths in Sylhet district of Bangladesh

<p>Abstract</p> <p>Background</p> <p>Lack of data is a critical barrier to addressing the problem of stillbirth in countries with the highest stillbirth burden. Our study objective was to estimate the levels, types, and causes of stillbirth in rural Sylhet district of Bangladesh.</p> <p>Methods</p> <p>A complete pregnancy history was taken from all women (n = 39 998) who had pregnancy outcomes during 2003-2005 in the study area. Verbal autopsy data were obtained for all identified stillbirths during the period. We used pre-defined case definitions and computer programs to assign causes of stillbirth for selected causes containing specific signs and symptoms. Both non-hierarchical and hierarchical approaches were used to assign causes of stillbirths.</p> <p>Results</p> <p>A total of 1748 stillbirths were recorded during 2003-2005 from 48,192 births (stillbirth rate: 36.3 per 1000 total births). About 60% and 40% of stillbirths were categorized as antepartum and intrapartum, respectively. Maternal conditions, including infections, hypertensive disorders, and anemia, contributed to about 29% of total antepartum stillbirths. About 50% of intrapartum stillbirths were attributed to obstetric complications. Maternal infections and hypertensive disorders contributed to another 11% of stillbirths. A cause could not be assigned in nearly half (49%) of stillbirths.</p> <p>Conclusion</p> <p>The stillbirth rate is high in rural Bangladesh. Based on algorithmic approaches using verbal autopsy data, a substantial portion of stillbirths is attributable to maternal conditions and obstetric complications. Programs need to deliver community-level interventions to prevent and manage maternal complications, and to develop strategies to improve access to emergency obstetric care. Improvements in care to avert stillbirth can be accomplished in the context of existing maternal and child health programs. Methodological improvements in the measurement of stillbirths, especially causes of stillbirths, are also needed to better define the burden of stillbirths in low-resource settings.</p

Exon-Level Transcriptome Profiling in Murine Breast Cancer Reveals Splicing Changes Specific to Tumors with Different Metastatic Abilities

In breast cancer patients, tumor metastases at distant sites are the main cause of death. However, the molecular mechanisms of metastasis of breast cancer remain unclear. It is thought that changes occurring at the level of RNA processing contribute to cancer. Alternative splicing (AS) of pre-mRNA, a key post-transcriptional mechanism allowing for the production of distinct proteins from a single gene, affects over 90% of human genes. Such splicing events are responsible for generating mRNAs that encode protein isoforms that can have very different biological properties and functions. A well-studied example is the BCL-X gene, whose two major transcript isoforms produce two proteins having antagonistic functions: the short form (BCL-XS) promotes apoptosis while the long form (BCL-XL) is anti-apoptotic. Moreover, overexpression of BCL-XL has been reported to enhance the metastatic potential of breast tumor cells in patients

TIPIT: A randomised controlled trial of thyroxine in preterm infants under 28 weeks' gestation

<p>Abstract</p> <p>Background</p> <p>Infants born at extreme prematurity (below 28 weeks' gestation) are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone which is recognised to be a frequent phenomenon in these infants. At present it is unclear whether low levels of thyroid hormone are a cause of disability, or a consequence of concurrent adversity.</p> <p>Methods</p> <p>We propose an explanatory multi-centre double blind randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks' corrected gestational age. The primary outcome will be brain growth. This will be assessed by the width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks' corrected gestational. The secondary outcomes will be (a) thyroid hormone concentrations measured at increasing postnatal age, (b) status of the hypothalamic pituitary axis, (c) auxological data between birth and 36 weeks' corrected gestational age, (d) thyroid gland volume, (e) volumes of brain structures (measured by magnetic resonance imaging), (f) determination of the extent of myelination and white matter integrity (measured by diffusion weighted MRI) and brain vessel morphology (measured by magnetic resonance angiography) at expected date of delivery and (g) markers of morbidity including duration of mechanical ventilation and chronic lung disease.</p> <p>We will also examine how activity of the hypothalamic-pituitary-adrenal axis modulates the effects of thyroid supplementation. This will contribute to decisions about which confounding variables to assess in large-scale studies.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN89493983</p

Diabetes and hypertension increase the placental and transcellular permeation of the lipophilic drug diazepam in pregnant women

Background: Previous studies carried out in our laboratories have demonstrated impaired drug permeation in diabetic animals. In this study the permeation of diazepam (after a single dose of 5 mg/day, administered intramuscularly) will be investigated in diabetic and hypertensive pregnant women.Methods: A total 75 pregnant women were divided into three groups: group 1 (healthy control, n = 31), group 2 (diabetic, n = 14) and group 3 (hypertensive, n = 30). Two sets of diazepam plasma concentrations were collected and measured (after the administration of the same dose of diazepam), before, during and after delivery. The first set of blood samples was taken from the mother (maternal venous plasma). The second set of samples was taken from the fetus (fetal umbilical venous and arterial plasma). In order to assess the effect of diabetes and hypertension on diazepam placental-permeation, the ratios of fetal to maternal blood concentrations were determined. Differences were considered statistically significant if p=0.05.Results: The diabetes and hypertension groups have 2-fold increase in the fetal umbilical-venous concentrations, compared to the maternal venous concentrations. Feto: maternal plasma-concentrations ratios were higher in diabetes (2.01 ± 1.10) and hypertension (2.26 ± 1.23) groups compared with control (1.30 ± 0.48) while, there was no difference in ratios between the diabetes and hypertension groups. Umbilical-cord arterial: venous ratios (within each group) were similar among all groups (control: 0.97 ± 0.32; hypertension: 1.08 ± 0.60 and diabetes: 1.02 ± 0.77).Conclusions: On line with our previous findings which demonstrate disturbed transcellular trafficking of lipophilic drugs in diabetes, this study shows significant increase in diazepam placental-permeation in diabetic and hypertensive pregnant women suggesting poor transcellular control of drug permeation and flux, and bigger exposure of the fetus to drug-placental transport

TIPIT: A randomised controlled trial of thyroxine in preterm infants under 28 weeks gestation: Magnetic Resonance Imaging and Magnetic Resonance Angiography protocol

<p>Abstract </p> <p>Background</p> <p>Infants born at extreme prematurity are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone described as hypothyroxinaemia, which is recognised to be a frequent phenomenon in these infants. Derangements of critical thyroid function during the sensitive window in prematurity when early development occurs, may have a range of long term effects for brain development. Further research in preterm infants using neuroimaging techniques will increase our understanding of the specificity of the effects of hypothyroxinaemia on the developing foetal brain. This is an explanatory double blinded randomised controlled trial which is aimed to assess the effect of thyroid hormone supplementation on brain size, key brain structures, extent of myelination, white matter integrity and vessel morphology, somatic growth and the hypothalamic-pituitary-adrenal axis.</p> <p>Methods</p> <p>The study is a multi-centred double blinded randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks corrected gestational age. The primary outcomes will be width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks corrected gestational age. The secondary outcomes will be thyroid hormone concentrations, the hypothalamic pituitary axis status and auxological data between birth and expected date of delivery; thyroid gland volume, brain size, volumes of key brain structures, extent of myelination and brain vessel morphology at expected date of delivery and markers of morbidity which include duration of mechanical ventilation and/or oxygen requirement and chronic lung disease.</p> <p><b>Trial registration</b></p> <p>Current Controlled Trials ISRCTN89493983</p

Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide