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BackgroundSubstantial amounts of public funds are invested in health research worldwide. Publicly funded randomised controlled trials (RCTs) often recruit participants at a slower than anticipated rate. Many trials fail to reach their planned sample size within the envisaged trial timescale and trial funding envelope.ObjectivesTo review the consent, recruitment and retention rates for single and multicentre randomised control trials funded and published by the UK's National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme.Data sources and study selectionHTA reports of individually randomised single or multicentre RCTs published from the start of 2004 to the end of April 2016 were reviewed.Data extractionInformation was extracted, relating to the trial characteristics, sample size, recruitment and retention by two independent reviewers.Main outcome measuresTarget sample size and whether it was achieved; recruitment rates (number of participants recruited per centre per month) and retention rates (randomised participants retained and assessed with valid primary outcome data).ResultsThis review identified 151 individually RCTs from 787 NIHR HTA reports. The final recruitment target sample size was achieved in 56% (85/151) of the RCTs and more than 80% of the final target sample size was achieved for 79% of the RCTs (119/151). The median recruitment rate (participants per centre per month) was found to be 0.92 (IQR 0.43–2.79) and the median retention rate (proportion of participants with valid primary outcome data at follow-up) was estimated at 89% (IQR 79–97%).ConclusionsThere is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.

Background Randomised controlled trials (RCTs) are the gold standard assessment for health technologies. A key aspect of the design of any clinical trial is the target sample size. However, many publicly-funded trials fail to reach their target sample size. This study seeks to assess the current state of recruitment success and grant extensions in trials funded by the Health Technology Assessment (HTA) program and the UK Medical Research Council (MRC). Methods Data were gathered from two sources: the National Institute for Health Research (NIHR) HTA Journal Archive and the MRC subset of the International Standard Randomised Controlled Trial Number (ISRCTN) register. A total of 440 trials recruiting between 2002 and 2008 were assessed for eligibility, of which 73 met the inclusion criteria. Where data were unavailable from the reports, members of the trial team were contacted to ensure completeness. Results Over half (55%) of trials recruited their originally specified target sample size, with over three-quarters (78%) recruiting 80% of their target. There was no evidence of this improving over the time of the assessment. Nearly half (45%) of trials received an extension of some kind. Those that did were no more likely to successfully recruit. Trials with 80% power were less likely to successfully recruit compared to studies with 90% power. Conclusions While recruitment appears to have improved since 1994 to 2002, publicly-funded trials in the UK still struggle to recruit to their target sample size, and both time and financial extensions are often requested. Strategies to cope with such problems should be more widely applied. It is recommended that where possible studies are planned with 90% power.

Background In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone. Methods All patients, including retrospective training ( n  = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n  = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts. Results Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25–0.74, p  = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups ( p  = 0.063), with a significant treatment interaction ( p interaction  <  0.001). This trend was also found in the validation cohort with high ( n  = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06–0.51, p  <  0.001) and low ICTOS ( n  = 175, p  = 0.31), with a significant treatment interaction ( p interaction  = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors. Conclusion An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment. Trial registration ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.

Nivolumab is a fully human monoclonal antibody that inhibits programmed death‐1 activation. The clinical pharmacology profile of nivolumab was analyzed by a population pharmacokinetics model that assessed covariate effects on nivolumab concentrations in 1,895 patients who received 0.3–10.0 mg/kg nivolumab in 11 clinical trials. Nivolumab pharmacokinetics is linear with a time‐varying clearance. A full covariate model was developed to assess covariate effects on pharmacokinetic parameters. Nivolumab clearance and volume of distribution increase with body weight. The final model included the effects of baseline performance status (PS), baseline body weight, and baseline estimated glomerular filtration rate (eGFR), sex, and race on clearance, and effects of baseline body weight and sex on volume of distribution in the central compartment. Sex, PS, baseline eGFR, age, race, baseline lactate dehydrogenase, mild hepatic impairment, tumor type, tumor burden, and programmed death ligand‐1 expression had a significant but not clinically relevant (<20%) effect on nivolumab clearance.

BackgroundThe YOMEGA study (Y-study) was a randomized trial comparing one anastomosis gastric bypass (OAGB) and Roux-en-Y gastric bypass (RYGB). Here, we aim to compare the Y-study and our pioneer trial from Taiwan (T-study).MethodsData from the Y-study and the T-study were collected and compared.ResultsThe Y-study recruited 234 patients with a mean body mass index (BMI) of 43.9 and age of 43.5 years. The T-study recruited 80 patients with a similar mean BMI of 44.3 and mean age of 31.4 years. The studies had similar findings including (1) OAGB is easier and possibly safer procedure than RYGB. Both studies showed that OAGB had a shorter operation time than RYGB, but a lower surgical complication rate was only demonstrated in T-study. (2) Both procedures have similar weight loss but OAGB features better glycemic control than RYGB. Weight loss at 2 years after surgery was similar between two procedures, but OAGB reduced HbA1c to a greater degree than RYGB at 2 years in Y-study (− 2.3% vs. − 1.3%; p = 0.025). The resolution of the metabolic syndrome was 100% for both groups in the T-study. (3) OAGB carried a higher risk of malnutrition. OAGB had more malabsorptive problems with a lower hemoglobin level than RYGB at 2 years after surgery. Adverse malnutrition events occurred in nine (7.8%) OAGB patients in the Y-study. Four (3.4%) patients of OAGB received revision surgery in Y-study but none in T-study. (4) Bile reflux was noted in OAGB patients but did not influence quality of life or revision rate. Y-study found that bile in the gastric pouch was present in 16% of patients in the OAGB group versus none in the RYGB, but no inter-group difference in quality of life was detected. There was a trend for RYGB patients to experience more abdominal pain than OAGB.ConclusionsBoth studies showed that OAGB is a technically easier procedure and features better glycemic control than RYGB, but has a mal-absorptive effect. However, the bile reflux and abdominal pain controversies persisted.

Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date. COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771). In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.

Novel cancer therapies are often approved with evidence from a single pivotal trial alone. There are concerns about the credibility of this evidence. Higher validity may be indicated by five methodological and statistical characteristics of pivotal trial evidence that were described by the U.S. Food and Drug Administration (FDA), which may corroborate the reliance on a single trial alone for approval decisions. We did a metaepidemiologic evaluation of all single pivotal trials supporting FDA approval of novel drugs and therapeutic biologicals for cancers between 2000 and 2016. For each trial, we determined the presence of these five characteristics, which we operationalized as (1) large and multicenter trial (≥200 patients; more than one center); consistent treatment benefits across (2) multiple patient subgroups (in view of FDA reviewers), (3) multiple endpoints (including overall survival, progression-free survival, response rate, health related quality of life), and (4) multiple treatment comparisons (e.g., multi-arm studies); and (5) “statistically very persuasive” results (P-values <0.00125). Thirty-five of 100 approvals were based on evidence from a single pivotal trial without any further supporting evidence on beneficial effects (20 randomized controlled trials and 15 single-arm trials). The number increased substantially from one approval before 2006 to 23 after 2011. Sixty-six percent (23/35) of the trials were large multicenter trials (median 301 patients and 63 centers). Consistent effects were demonstrated across subgroups in 66% (23/35), across endpoints in 43% (15/35), and across multiple comparisons in 3% (1/35). Very low P-values for the primary endpoint were seen in 34% (12/35). At least one of the corroborating characteristics was present in 94% (33/35) of all approvals, two or more were present in 54% (19/35), and none had all characteristics. Single pivotal trials typically have some of the corroborating characteristics, but often only one or two. These characteristics need to be better operationalized, defined, and reported and whether single trials with such characteristics provide similar evidence about benefits and harms of novel treatments as multiple trials would do needs to be shown.

Background The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC ( n = 78) or LDAC alone ( n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm ( P = 0.015). Methods This post hoc analysis determines whether the clinical benefits of glasdegib are restricted to patients who achieve CR, or if they extend to those who do not achieve CR. Results In patients who did not achieve CR, the addition of glasdegib to LDAC improved overall survival (OS) versus LDAC alone (hazard ratio = 0.63 [95% confidence interval, 0.41–0.98]; P = 0.0182; median OS, 5.0 vs 4.1 months). Additionally, more patients receiving glasdegib + LDAC achieved durable recovery of absolute neutrophil count (≥ 1000/μl, 45.6% vs 35.5%), hemoglobin (≥ 9 g/dl, 54.4% vs 38.7%), and platelets (≥ 100,000/μl, 29.8% vs 9.7%). Transfusion independence was achieved by 15.0% and 2.9% of patients receiving glasdegib + LDAC and LDAC alone, respectively. Conclusions Collectively, these data suggest that there are clinical benefits with glasdegib in the absence of CR. Trial registration ClinicalTrials.gov NCT01546038 (March 7, 2012)

Treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or escalated(e)-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) remains the international standard of care for advanced-stage classical Hodgkin lymphoma (HL). We performed a retrospective, multicentre analysis of 221 non-trial (“real-world”) patients, aged 16–59 years, diagnosed with advanced-stage HL in the Anglia Cancer Network between 2004 and 2014, treated with ABVD or eBEACOPP, and compared outcomes with 1088 patients in the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma (RATHL) trial, aged 18–59 years, with median follow-up of 87.0 and 69.5 months, respectively. Real-world ABVD patients (n=177) had highly similar 5-year progression-free survival (PFS) and overall survival (OS) compared with RATHL (PFS 79.2% vs 81.4%; OS 92.9% vs 95.2%), despite interim positron-emission tomography-computed tomography (PET/CT)-guided dose-escalation being predominantly restricted to trial patients. Real-world eBEACOPP patients (n=44) had superior PFS (95.5%) compared with real-world ABVD (HR 0.20, p=0.027) and RATHL (HR 0.21, p=0.015), and superior OS for higher-risk (international prognostic score ≥3 [IPS 3+]) patients compared with real-world IPS 3+ ABVD (100% vs 84.5%, p=0.045), but not IPS 3+ RATHL patients. Our data support a PFS, but not OS, advantage for patients with advanced-stage HL treated with eBEACOPP compared with ABVD and suggest higher-risk patients may benefit disproportionately from more intensive therapy. However, increased access to effective salvage therapies might minimise any OS benefit from reduced relapse rates after frontline therapy.

Background The appropriate level of oxygenation for extremely preterm neonates (<28 weeks' gestation) to maximise the greatest chance of survival, without incurring significant morbidity, remains unknown. Infants exposed to lower levels of oxygen (targeting oxygen saturations of <90%) in the first weeks of life are at increased risk of death, cerebral palsy, patent ductus arteriosus, pulmonary vascular resistance and apnoea, whilst those maintained in higher levels of oxygen (targeting oxygen saturations of >90%) have been reported to have greater rates of morbidity including retinopathy of prematurity and chronic lung disease. In order to answer this clinical dilemma reliably, large scale trial evidence is needed. Methods/Design To detect a small but important 4% increase in death or severe disability in survivors, over 5000 neonates would need to be recruited. As extreme prematurity affects 1% of births, such a project undertaken by one trial group would be prohibitively lengthy and expensive. Hence, the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration has been formed. A prospective meta-analysis (PMA) is one where studies are identified, evaluated, and determined to be eligible before the results of any included studies are known or published, thereby avoiding some of the potential biases inherent in standard, retrospective meta-analyses. This methodology provides the same strengths as a single large-scale multicentre randomised study whilst allowing greater pragmatic flexibility. The NeOProM Collaboration protocol (NCT01124331) has been agreed prior to the results of individual trials being available. This includes pre-specifying the hypotheses, inclusion criteria and outcome measures to be used. Each trial will first publish their respective results as they become available and the combined meta-analytic results, using individual patient data, will be published when all trials are complete. The primary outcome to be assessed is a composite outcome of death or major disability at 18 months - 2 years corrected age. Secondary outcomes include several measures of neonatal morbidity. The size of the combined dataset will allow the effect of the interventions to be explored more reliably with respect to pre-specified patient- and intervention-level characteristics. Discussion Results should be available by 2014.