Participant characteristics and exclusion from trials: a meta-analysis of individual participant-level data from phase 3/4 industry-funded trials in chronic medical conditions

Objectives Trials often do not represent their target populations, threatening external validity. The aim was to assess whether age, sex, comorbidity count and/or race/ethnicity are associated with likelihood of screen failure (i.e., failure to be enrolled in the trial for any reason) among potential trial participants.Design Bayesian meta-analysis of individual participant-level data (IPD).SettingIndustry-funded phase 3/4 trials in chronic medical conditions. Participants were identified as “enrolled” or “screen failure” using trial IPD.Participants Data were available for 52 trials involving 72,178 screened individuals of whom 24,733 (34%) failed screening.Main outcome measures For each trial, logistic regression models were constructed to assess likelihood of screen failure in people who had been invited to screening, regressed on age (per 10-year increment), sex (male versus female), comorbidity count (per one additional comorbidity) and race/ethnicity. Trial-level analyses were combined in Bayesian hierarchical models with pooling across condition.ResultsIn age- and sex-adjusted models across all trials, neither age nor sex was associated with increased odds of screen failure, though weak associations were detected after additionally adjusting for comorbidity (age, per 10-year increment: odds ratio [OR] 1.02; 95% credibility interval [CI] 1.01 to 1.04 and male sex: OR 0.95; 95% CI 0.91 to 1.00). Comorbidity count was weakly associated with screen failure, but in an unexpected direction (OR 0.97 per additional comorbidity, 95% CI 0.94 to 1.00, adjusted for age and sex). Those who self-reported as Black were slightly more likely to fail screening (OR 1.04; 95% CI 0.99 to 1.09); an effect which persisted after adjustment for age, sex and comorbidity count (OR 1.05; 95% CI 0.98 to 1.12). The between-trial heterogeneity was generally low, but there was evidence of heterogeneity by sex across conditions (variation in odds ratios on log-scale of 0.01-0.13).Conclusions Though the conclusions are limited by uncertainty about the completeness or accuracy of data collection among non-randomised participants, we identified mostly weak associations between age, sex, comorbidity count and Black race/ethnicity and increased likelihood of screen failure. Proportionate increases in screening these underserved populations may improve representation in trials. Trial registration Relevant trials in chronic medical conditions were identified according to pre-specified criteria (PROSPERO CRD42018048202) then analysed according to availability of IPD. <br/

Prostate cancer treated with brachytherapy; an exploratory study of dose-dependent biomarkers and quality of life

BACKGROUND: Low-dose-rate permanent prostate brachytherapy (PPB) is an attractive treatment option for patients with localised prostate cancer with excellent outcomes. As standard CT-based post-implant dosimetry often correlates poorly with late treatment-related toxicity, this exploratory (proof of concept) study was conducted to investigate correlations between radiation − induced DNA damage biomarker levels, and acute and late bowel, urinary, and sexual toxicity. METHODS: Twelve patients treated with (125)I PPB monotherapy (145Gy) for prostate cancer were included in this prospective study. Post-implant CT based dosimetry assessed the minimum dose encompassing 90% (D(90%)) of the whole prostate volume (global), sub-regions of the prostate (12 sectors) and the near maximum doses (D(0.1cc), D(2cc)) for the rectum and bladder. Six blood samples were collected from each patient; pre-treatment, 1 h (h), 4 h, 24 h post-implant, at 4 weeks (w) and at 3 months (m). DNA double strand breaks were investigated by staining the blood samples with immunofluorescence antibodies to γH2AX and 53BP1 proteins (γH2AX/53BP1). Patient self-scored quality of life from the Expanded Prostate Cancer Index Composite (EPIC) were obtained at baseline, 1 m, 3 m, 6 m, 9 m, 1 year (y), 2y and 3y post-treatment. Spearman’s correlation coefficients were used to evaluate correlations between temporal changes in γH2AX/53BP1, dose and toxicity. RESULTS: The minimum follow up was 2 years. Population mean prostate D(90%) was 144.6 ± 12.1 Gy and rectal near maximum dose D(0.1cc) = 153.0 ± 30.8 Gy and D(2cc) = 62.7 ± 12.1 Gy and for the bladder D(0.1cc) = 123.1 ± 27.0 Gy and D(2cc) = 70.9 ± 11.9 Gy. Changes in EPIC scores from baseline showed high positive correlation between acute toxicity and late toxicity for both urinary and bowel symptoms. Increased production of γH2AX/53BP1 at 24 h relative to baseline positively correlated with late bowel symptoms. Overall, no correlations were observed between dose metrics (prostate global or sector doses) and γH2AX/53BP1 foci counts. CONCLUSIONS: Our results show that a prompt increase in γH2AX/53BP1foci at 24 h post-implant relative to baseline may be a useful measure to assess elevated risk of late RT − related toxicities for PPB patients. A subsequent investigation recruiting a larger cohort of patients is warranted to verify our findings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13014-017-0792-1) contains supplementary material, which is available to authorized users

Correlations between comorbidities in trials and the community: an individual-level participant data meta-analysis

Background: People with comorbidities are under-represented in randomised controlled trials, and it is unknown whether patterns of comorbidity are similar in trials and the community. Methods: Individual-level participant data were obtained for 83 clinical trials (54,688 participants) for 16 index conditions from two trial repositories: Yale University Open Data Access (YODA) and the Centre for Global Clinical Research Data (Vivli). Community data (860,177 individuals) were extracted from the Secure Anonymised Information Linkage (SAIL) databank for the same index conditions. Comorbidities were defined using concomitant medications. For each index condition, we estimated correlations between comorbidities separately in trials and community data. For the six commonest comorbidities we estimated all pairwise correlations using Bayesian multivariate probit models, conditioning on age and sex. Correlation estimates from trials with the same index condition were combined into a single estimate. We then compared the trial and community estimates for each index condition. Results: Despite a higher prevalence of comorbidities in the community than in trials, the correlations between comorbidities were mostly similar in both settings. On comparing correlations between the community and trials, 21% of correlations were stronger in the community, 10% were stronger in the trials and 68% were similar in both. In the community, 5% of correlations were negative, 21% were null, 56% were weakly positive and 18% were strongly positive. Equivalent results for the trials were 11%, 33%, 45% and 10% respectively. Conclusions: Comorbidity correlations are generally similar in both the trials and community, providing some evidence for the reporting of comorbidity-specific findings from clinical trials

Participant characteristics and exclusion from trials: a meta-analysis of individual participant-level data from phase 3/4 industry-funded trials in chronic medical conditions

Objectives: To assess whether age, sex, comorbidity count, and race and ethnic group are associated with the likelihood of trial participants not being enrolled in a trial for any reason (ie, screen failure). Design: Bayesian meta-analysis of individual participant level data. Setting: Industry funded phase 3/4 trials of chronic medical conditions. Participants: Participants were identified using individual participant level data to be in either the enrolled group or screen failure group. Data were available for 52 trials involving 72 178 screened individuals of whom 24 733 (34%) were excluded from the trial at the screening stage. Main outcome measures: For each trial, logistic regression models were constructed to assess likelihood of screen failure in people who had been invited to screening, and were regressed on age (per 10 year increment), sex (male v female), comorbidity count (per one additional comorbidity), and race or ethnic group. Trial level analyses were combined in Bayesian hierarchical models with pooling across condition. Results: In age and sex adjusted models across all trials, neither age nor sex was associated with increased odds of screen failure, although weak associations were detected after additionally adjusting for comorbidity (odds ratio of age, per 10 year increment was 1.02 (95% credibility interval 1.01 to 1.04) and male sex (0.95 (0.91 to 1.00)). Comorbidity count was weakly associated with screen failure, but in an unexpected direction (0.97 per additional comorbidity (0.94 to 1.00), adjusted for age and sex). People who self-reported as black seemed to be slightly more likely to fail screening than people reporting as white (1.04 (0.99 to 1.09)); a weak effect that seemed to persist after adjustment for age, sex, and comorbidity count (1.05 (0.98 to 1.12)). The between-trial heterogeneity was generally low, evidence of heterogeneity by sex was noted across conditions (variation in odds ratios on log scale of 0.01-0.13). Conclusions: Although the conclusions are limited by uncertainty about the completeness or accuracy of data collection among participants who were not randomised, we identified mostly weak associations with an increased likelihood of screen failure for age, sex, comorbidity count, and black race or ethnic group. Proportionate increases in screening these underserved populations may improve representation in trials. Trial registration number: PROSPERO CRD42018048202

Participant characteristics and exclusion from trials: a meta-analysis of individual participant-level data from phase 3/4 industry-funded trials in chronic medical conditions

Objectives: To assess whether age, sex, comorbidity count, and race and ethnic group are associated with the likelihood of trial participants not being enrolled in a trial for any reason (ie, screen failure). Design: Bayesian meta-analysis of individual participant level data. Setting: Industry funded phase 3/4 trials of chronic medical conditions. Participants: Participants were identified using individual participant level data to be in either the enrolled group or screen failure group. Data were available for 52 trials involving 72 178 screened individuals of whom 24 733 (34%) were excluded from the trial at the screening stage. Main outcome measures: For each trial, logistic regression models were constructed to assess likelihood of screen failure in people who had been invited to screening, and were regressed on age (per 10 year increment), sex (male v female), comorbidity count (per one additional comorbidity), and race or ethnic group. Trial level analyses were combined in Bayesian hierarchical models with pooling across condition. Results: In age and sex adjusted models across all trials, neither age nor sex was associated with increased odds of screen failure, although weak associations were detected after additionally adjusting for comorbidity (odds ratio of age, per 10 year increment was 1.02 (95% credibility interval 1.01 to 1.04) and male sex (0.95 (0.91 to 1.00)). Comorbidity count was weakly associated with screen failure, but in an unexpected direction (0.97 per additional comorbidity (0.94 to 1.00), adjusted for age and sex). People who self-reported as black seemed to be slightly more likely to fail screening than people reporting as white (1.04 (0.99 to 1.09)); a weak effect that seemed to persist after adjustment for age, sex, and comorbidity count (1.05 (0.98 to 1.12)). The between-trial heterogeneity was generally low, evidence of heterogeneity by sex was noted across conditions (variation in odds ratios on log scale of 0.01-0.13). Conclusions: Although the conclusions are limited by uncertainty about the completeness or accuracy of data collection among participants who were not randomised, we identified mostly weak associations with an increased likelihood of screen failure for age, sex, comorbidity count, and black race or ethnic group. Proportionate increases in screening these underserved populations may improve representation in trials. Trial registration number: PROSPERO CRD42018048202

Metal on metal hip resurfacing versus uncemented custom total hip replacement - early results

<p>Abstract</p> <p>Introduction</p> <p>There is no current consensus on the most appropriate prosthesis for treating symptomatic osteoarthritis (OA) of the hip in young, active patients. Modern metal on metal hip resurfacing arthroplasty (HR) has gained popularity as it is theoretically more stable, bone conserving and easier to revise than total hip arthroplasty. Early results of metal on metal resurfacing have been encouraging. We have compared two well matched cohorts of patients with regard to function, pain relief and patient satisfaction.</p> <p>Methods</p> <p>This prospective study compares 2 cohorts of young, active patients treated with hip resurfacing (137 patients, 141 hips) and custom uncemented (CADCAM) stems (134 patients, 141 hips). All procedures were performed by a single surgeon. Outcome measures included Oxford, WOMAC and Harris hip scores as well as an activity score. Statistical analysis was performed using the unpaired student's t-test.</p> <p>Results</p> <p>One hundred and thirty four and 137 patients were included in the hip replacement and resurfacing groups respectively. The mean age of these patients was 54.6 years. The mean duration of follow up for the hip resurfacing group was 19.2 months compared to 13.4 months for the total hip replacement group.</p> <p>Pre operative oxford, Harris and WOMAC scores in the THA group were 41.1, 46.4 and 50.9 respectively while the post operative scores were 14.8, 95.8 and 5.0. In the HR group, pre- operative scores were 37.0, 54.1 and 45.9 respectively compared to 15.0, 96.8 and 6.1 post operatively. The degree of improvement was similar in both groups.</p> <p>Conclusion</p> <p>There was no significant clinical difference between the patients treated with hip resurfacing and total hip arthroplasty in the short term.</p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Protocol for the immediate delivery versus expectant care of women with preterm prelabour rupture of the membranes close to term (PPROMT) Trial [ISRCTN44485060]

BACKGROUND: Preterm prelabour rupture of membranes (PPROM) complicates up to 2% of all pregnancies and is the cause of 40% of all preterm births. The optimal management of women with PPROM prior to 37 weeks, is not known. Furthermore, diversity in current clinical practice suggests uncertainty about the appropriate clinical management. There are two options for managing PPROM, expectant management (a wait and see approach) or early planned birth. Infection is the main risk for women in which management is expectant. This risk need to be balanced against the risk of iatrogenic prematurity if early delivery is planned. The different treatment options may also have different health care costs. Expectant management results in prolonged antenatal hospitalisation while planned early delivery may necessitate intensive care of the neonate for problems associated with prematurity. METHODS/DESIGN: We aim to evaluate the effectiveness of early planned birth compared with expectant management for women with PPROM between 34 weeks and 36(6 )weeks gestation, in a randomised controlled trial. A secondary aim is a cost analysis to establish the economic impact of the two treatment options and establish the treatment preferences of women with PPROM close to term. The early planned birth group will be delivered within 24 hours according to local management protocols. In the expectant management group birth will occur after spontaneous labour, at term or when the attending clinician feels that birth is indicated according to usual care. Approximately 1812 women with PPROM at 34–36(6 )weeks gestation will be recruited for the trial. The primary outcome of the study is neonatal sepsis. Secondary infant outcomes include respiratory distress, perinatal mortality, neonatal intensive care unit admission, assisted ventilation and early infant development. Secondary maternal outcomes include chorioamnionitis, postpartum infection treated with antibiotics, antepartum haemorrhage, induction of labour, mode of delivery, maternal satisfaction with care, duration of hospitalisation, and maternal wellbeing at four months postpartum. DISCUSSION: This trial will provide evidence on the optimal care for women with PPROM close to term (34–37 weeks gestation). Consideration of both the clinical and economic sequelae of the management of PPROM will enable informed decision making and guideline development