Medical Research Council Clinical Trials Research Articles

P72 Development of a novel platform trial evaluating systemic therapies in adult atopic eczema with parallel mechanistic studies (BEACON and BEACONomics): a UK-wide interdisciplinary collaboration

Abstract Atopic eczema is common and profoundly impacts on the quality of life, and psychological and social function. More severe disease often requires systemic (standard or targeted) immune-modifying therapy; however, drug response and tolerability vary in practice. As the molecular effects of the drugs used have not been characterized in detail, the causes of such variability remain poorly understood. There remains equipoise as to which drug is best, with no active comparator data for standard vs. targeted therapies. We have designed a global first trial in atopic eczema to directly compare the effectiveness and tolerability of standard and targeted drugs. The platform design, building on expertise in cancer and COVID (Medical Research Council Clinical Trials Unit), allows incorporation of additional comparator arms as new treatments emerge. We used multistakeholder input from patients [partnership with National Eczema Society, patient coapplicants, national patient survey (> 90 participants), public and patient involvement webinar feedback], clinicians [UK Dermatology Clinical Trials Network, national surveys (> 50 clinicians)], health economics and qualitative researchers. We partnered with experts in skin biology and single-cell methods, exploiting high-throughput analytic pipelines of the Human Cell Atlas, to design embedded studies to dissect mechanisms underlying drug effects. The trial (BEACON), which commenced in February 2023, is funded through the NIHR Health Technology Assessment programme. This 12-month multiarm trial involves > 400 adults with moderate-to-severe eczema requiring systemic therapy from > 30 UK sites. It is designed around real-world practice and incorporates inclusive recruitment strategies and remote data capture. BEACON will establish the comparative clinical effectiveness, tolerability and cost-effectiveness of methotrexate, ciclosporin and dupilumab. It will transition to a multiarm, multistage platform trial, enabling additional treatment arms. The primary outcome is EASI at 6 months, with key Harmonising Outcome Measures for Eczema outcome measures incorporated. Dose increases and treatment switching (6 months) are possible, mirroring standard practice. BEACON-omics is funded through the National Institute for Health and Care Research Efficacy and Mechanism Evaluation and Open Targets (public–private partnership). This longitudinal cohort study will profile serial skin and blood samples at scale (150 participants) using single-cell multiome and spatial transcriptome approaches, to investigate mechanisms of treatment effects and provide a foundational resource for new target discovery. This world-first platform trial for systemic therapies in adult atopic eczema, and one of the first in chronic inflammatory disease, will provide comparative data on commonly used systemic treatments and incorporate novel therapies as they emerge. Integrated cutting-edge discovery science will maximize the potential of the platform.

RR-TB treatments, testing bedaquiline and injectable kanamycin

RR-TB treatments, testing bedaquiline and injectable kanamycin Here, Professor Andre Nunn from Medical Research Council Clinical Trials Unit at UCL, explores tuberculosis with a focus on RR-TB treatments (rifampicin-resistant) and their drug combinations. Tuberculosis (TB) is one of the oldest diseases known to man and its management remains a challenge to public health worldwide. According to the most recent World Health Organisation (WHO) report over 10 million persons fell ill with tuberculosis in 2021. It occurs within all the countries of the world but is most prevalent in low and middle income countries. A total of 1.6 million people died from TB world-wide in 2021 making it the 13th leading cause of death and the second leading infectious disease killer after COVID-19.

Tuberculosis drug regimens and their efficacies

Tuberculosis drug regimens and their efficacies Andrew Nunn, Professor of Epidemiology in the Medical Research Council Clinical Trials Unit at UCL conducts two stages of drug treatment for those with tuberculosis called 'STREAM'. In this clinical trial, stage 1 demonstrated that a 9-month regimen was non-inferior to the 20-month regimen that was currently recommended by the World Health Organisation (WHO), and stage 2 investigated two new shortened regimens; one a fully oral 9-month regimen in which bedaquiline is substituted for the injectable tuberculosis drug, kanamycin, and a 6-month regimen in which both bedaquiline and a shortened intensive phase with kanamycin. After assessing the results of patient data from the trials, as well as from observational studies using bedaquiline, pretomanid and linezolid, the World Health Organisation informed key stakeholders in National TB Programmes of detailed recommendations which will be presented later this year in a 2022 update of the WHO consolidated guidelines, to better TB care and treatment.

FOCUS4 biomarker laboratories: from the benefits to the practical and logistical issues faced during 6 years of centralised testing

AimsFOCUS4 was a phase II/III umbrella trial, recruiting patients with advanced or metastatic colorectal cancer, between 2014 and 2020. Molecular profiling of patients’ formalin-fixed, paraffin-embedded tumour blocks was undertaken at...

Formalising the induction of patient and public involvement contributors on trial oversight committees

BackgroundClinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of trial design, running and oversight. This research explored the induction and training of PPI Contributors joining trial oversight committees and was used to update the Medical Research Council Clinical Trials Unit at University College London’s (MRC CTU at UCL) induction pack for new PPI Contributors.MethodsPublished and unpublished materials provided by other CTUs and research organisations on training for PPI Contributors on oversight committees were reviewed, with themes then triangulated to identify the most common topics covered in induction training. A face-to-face workshop with PPI Contributors from the MRC CTU at UCL reviewed a draft updated Induction Pack. Findings from these discussions were incorporated into a revised induction pack which was then re-reviewed by the workshop attendees.ResultsNo published literature on this subject was found. However, several common themes were identified from unpublished materials. Workshop attendees agreed with most of the themes suggested in the initial draft pack based on the literature search and also provided a number of additional topics for discussion.ConclusionsThere is very little consistency in the induction of PPI Contributors on oversight committees. Whilst most local guidance explains the general role of a PPI Contributor, more context and background of the particular trial needs to be provided to allow for adequate induction of new committee members. The Induction Pack created provides a framework upon which trial managers can build a full picture of their study.

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme

Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 μg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis.

Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis.

Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons

BackgroundThere is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management.MethodsWe held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began.DiscussionWe found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time.ConclusionsAdaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks.

Knowing thyself: an audit of cell therapy manufacturing in Australia and New Zealand

Background & Aim We conducted a survey to assess cell therapy manufacturing capacity in Australia and New Zealand. We examined the number and types of cell therapy manufacturing facilities; the number of projects, parallel processes and clinical trials; the types of products; and manufacturing and quality staffing levels. We identified participant cell therapy manufacturing facilities by contacting individuals working in the field of cell therapy in Australia and New Zealand and inviting submissions on a one per cell manufacturing facility basis. Methods, Results & Conclusion The overall response rate was 59% (23 of 38 eligible facilities). Of the 23 responding facilities, 21 are in Australia and 2 are in New Zealand. Eighteen are run by public organisations and five by private organisations and a diverse range of accreditations were represented. There were 43 GMP laboratories across 14 of 22 facilities that reported on this parameter and approximately 4.6 manufacturing staff and 1.7 quality staff per facility. Products included hematopoietic progenitor cells, mononuclear cells, T-cells, peripheral blood mononuclear cells, CD34+ cells, mesenchymal stem cells and chimeric antigen receptor T-cells, therapeutic T-cell subsets, cell banks, autologous serum eye drops, keratinocytes, human amnion epithelial cells, pancreatic islets, dendritic cells and chondrocytes. Research interests were processing and storage optimization; the effect of methodologies on engraftment; gene and cell therapy; the biology of manufactured cell types; cell tracking and imaging; cell culture platforms; bioscaffolds; 3-D bioprinting; transplantation and the diseases treated. Reported collaborations included within Australia and with groups in Basel, Busan, Boston, Cambridge MA, Hong Kong, Los Angeles, Montreal, Nagoya, New York, Philadelphia, Stockholm and Toronto. Other national manufacturing-relevant assets are the Centre of Research Excellence in MedTech in New Zealand, the Cooperative Research Centre for Cell Therapy Manufacturing in Australia, the Australian National Health and Medical Research Council Clinical Trials Centre and Advanced Health Research and Translation Centres and Therapeutic Innovation Australia. Australian and New Zealand provide a platform for cell therapy manufacturing, infrastructure and capacity building. These form the foundation to enable both countries to meet the growing need for cell and gene therapy and regenerative medicine in our region.

Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis

Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis

Exploring Data Quality Management within Clinical Trials.

Clinical trials are an important research method for improving medical knowledge and patient care. Multiple international and national guidelines stipulate the need for data quality and assurance. Many strategies and interventions are developed to reduce error in trials, including standard operating procedures, personnel training, data monitoring, and design of case report forms. However, guidelines are nonspecific in the nature and extent of necessary methods. This article gathers information about current data quality tools and procedures used within Australian clinical trial sites, with the aim to develop standard data quality monitoring procedures to ensure data integrity. Relevant information about data quality management methods and procedures, error levels, data monitoring, staff training, and development were collected. Staff members from 142 clinical trials listed on the National Health and Medical Research Council (NHMRC) clinical trials Web site were invited to complete a short self-reported semiquantitative anonymous online survey. Twenty (14%) clinical trials completed the survey. Results from the survey indicate that procedures to ensure data quality varies among clinical trial sites. Centralized monitoring (65%) was the most common procedure to ensure high-quality data. Ten (50%) trials reported having a data management plan in place and two sites utilized an error acceptance level to minimize discrepancy, set at <5% and 5 to 10%, respectively. The quantity of data variables checked (10-100%), the frequency of visits (once-a-month to annually), and types of variables (100%, critical data or critical and noncritical data audits) for data monitoring varied among respondents. The average time spent on staff training per person was 11.58 hours over a 12-month period and the type of training was diverse. Clinical trial sites are implementing ad hoc methods pragmatically to ensure data quality. Findings highlight the necessity for further research into "standard practice" focusing on developing and implementing publically available data quality monitoring procedures.

929O_PR - ICON8: A GCIG phase III randomised trial evaluating weekly dose- dense chemotherapy integration in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment: Results of primary progression- free survival (PFS) analysis

Background: For several decades, standard first-line chemotherapy for EOC has been carboplatin (C) and paclitaxel (T), administered 3-weekly (q3w). The JGOG3016 trial reported clinically significant lengthening of PFS and overall survival in Japanese women using dose-dense weekly (q1w) T but with increased toxicity. ICON8 is a 3-arm trial, comparing standard q3w CT with dose-dense q1w regimens in a predominantly European patient group. Methods: Eligible women with FIGO stage IcG3- IV EOC were randomised 1:1:1 to Arm 1 (standard) - q3w C AUC5/6 + q3w T 175mg/m2; Arm 2 - q3w C AUC5/6 + q1w T 80mg/m2; Arm 3 - q1w C AUC2 + q1w T 80 mg/m2. Patients entered ICON8 after immediate primary surgery (IPS), or received neo-adjuvant chemotherapy with planned delayed primary surgery (DPS). Primary intention to treat analysis compared arm 2v1 and arm 3v1 using methods for data with non-proportional hazards. Results: 1566 women were randomised Jun 2011-Nov 2014. Median age- 62 years, 72% serous histology, 93% ECOG performance status 0/1. 48% had IPS, 50% planned DPS, 2% inoperable. 72%, 60%, 63% completed 6 cycles protocol-defined treatment in arms 1, 2, 3. Completion rate for 6 cycles platinum was 88% (90%; 89%; 85%). Paclitaxel dose-intensification was achieved (median total dose T (mg/m2)-1011; 1234; 1274). Grade (G) 3/4 toxicity (predominantly uncomplicated low neutrophils) was seen in 42%; 63%; 53% patients. Incidence of G3/4 febrile neutropenia (4%; 6%; 3%) and ≥G2 sensory neuropathy (28%; 25%; 23%) were similar across arms. At Feb 2017, 64% patients had experienced disease progression. No significant increase in PFS was observed with either weekly treatment (log-rank arm 2v1 p = 0.45; arm 3v1 p = 0.56, non-proportionality p = 0.02, restricted mean survival time=24.4; 24.9; 25.3 months in arms 1, 2, 3, median PFS- 17.9; 20.6; 21.1months, HR = 0.92 arm 2v1, HR = 0.94 arm 3v1). Conclusions: Although weekly dose-dense chemotherapy can be delivered successfully as first-line EOC treatment without substantial toxicity increase, it does not significantly improve PFS compared to standard 3-weekly CT. Clinical trial identification: ISRCTN: ISRCTN10356387 EUDRACT: 2010-022209-16 CTA: 2010-022209-16 ENGOT: OV-13 MREC: 11/LO/0043 Legal entity responsible for the study: Medical Research Council Clinical Trials Unit at University College London Funding: Cancer Research UK; Medical Research Council Disclosure: All authors have declared no conflicts of interest.

Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial

SummaryBackgroundNeoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen.MethodsOE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1–4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4–6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed.FindingsBetween Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6–26·3) with CF and 26·1 months (22·5–29·7) with ECX (hazard ratio 0·90 (95% CI 0·77–1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis.InterpretationFour cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma.FundingCancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial

SummaryBackgroundPeri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma.MethodsIn this multicentre, randomised, open-label phase 2–3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1–21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203.FindingsBetween Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5–54·9) in the chemotherapy alone group and 48·1% (43·2–52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91–1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53).InterpretationThe results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing.FundingCancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.

Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study

Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov, NCT01292291. Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88-96%) than TRUS-biopsy (48%, 42-55%; p<0·0001) and less specific (41%, 36-46% for MP-MRI vs 96%, 94-98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer. PROMIS is funded by the UK Government Department of Health, National Institute of Health Research-Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).

Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial

SummaryBackgroundWhole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life.MethodsThe Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered non-inferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% [one-sided] significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061.FindingsBetween March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38–85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1·06, 95% CI 0·90–1·26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4·7 days (46·4 QALY days for the OSC plus WBRT group vs 41·7 QALY days for the OSC group), with two-sided 90% CI of −12·7 to 3·3.InterpretationAlthough the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group.FundingCancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia.

Models and impact of patient and public involvement in studies carried out by the Medical Research Council Clinical Trials Unit at University College London: findings from ten case studies

BackgroundPatient and public involvement (PPI) in studies carried out by the UK Medical Research Council Clinical Trials Unit (MRC CTU) at University College London varies by research type and setting. We developed a series of case studies of PPI to document and share good practice.MethodsWe used purposive sampling to identify studies representing the scope of research at the MRC CTU and different approaches to PPI. We carried out semi-structured interviews with staff and patient representatives. Interview notes were analysed descriptively to categorise the main aims and motivations for involvement; activities undertaken; their impact on the studies and lessons learned.ResultsWe conducted 19 interviews about ten case studies, comprising one systematic review, one observational study and 8 randomised controlled trials in HIV and cancer. Studies were either open or completed, with start dates between 2003 and 2011. Interviews took place between March and November 2014 and were updated in summer 2015 where there had been significant developments in the study (i.e. if the study had presented results subsequent to the interview taking place). A wide range of PPI models, including representation on trial committees or management groups, community engagement, one-off task-focused activities, patient research partners and participant involvement had been used. Overall, interviewees felt that PPI had a positive impact, leading to improvements, for example in the research question; study design; communication with potential participants; study recruitment; confidence to carry out or complete a study; interpretation and communication of results; and influence on future research.ConclusionsA range of models of PPI can benefit clinical studies. Researchers should consider different approaches to PPI, based on the desired impact and the people they want to involve. Use of multiple models may increase the potential impacts of PPI in clinical research.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1488-9) contains supplementary material, which is available to authorized users.

Monitoring randomized clinical trials in Africa; pragmatic approaches and experiences from HIV trials

The Medical Research Council Clinical Trials Unit has coordinated HIV clinical trials in Africa for almost 15 years. Approaches to monitoring trial data have been developed using a combination of on-site and central (database) monitoring. Tools and templates have been designed to supplement trial protocols and help standardize trial processes. Local monitors supplement infrequent visits from the sponsor, enabling monitoring at the required intensity and allowing for capacity building. Database strategies have evolved to complement on-site visits, allowing more effective monitoring of data quality, and providing functionality in a cost-effective manner. Ongoing training and support of monitors and site staff is given via teleconferences, emails and meetings. Mentoring of site staff by monitors is encouraged, including cross-site visits where resources allow.

Measuring the impact of methodological research: a framework and methods to identify evidence of impact.

BackgroundProviding evidence of impact highlights the benefits of medical research to society. Such evidence is increasingly requested by research funders and commonly relies on citation analysis. However, other indicators may be more informative. Although frameworks to demonstrate the impact of clinical research have been reported, no complementary framework exists for methodological research. Therefore, we assessed the impact of methodological research projects conducted or completed between 2009 and 2012 at the UK Medical Research Council Clinical Trials Unit Hub for Trials Methodology Research Hub, with a view to developing an appropriate framework.MethodsVarious approaches to the collection of data on research impact were employed. Citation rates were obtained using Web of Science (http://www.webofknowledge.com/) and analyzed descriptively. Semistructured interviews were conducted to obtain information on the rates of different types of research output that indicated impact for each project. Results were then pooled across all projects. Finally, email queries pertaining to methodology projects were collected retrospectively and their content analyzed.ResultsSimple citation analysis established the citation rates per year since publication for 74 methodological publications; however, further detailed analysis revealed more about the potential influence of these citations. Interviews that spanned 20 individual research projects demonstrated a variety of types of impact not otherwise collated, for example, applications and further developments of the research; release of software and provision of guidance materials to facilitate uptake; formation of new collaborations and broad dissemination. Finally, 194 email queries relating to 6 methodological projects were received from 170 individuals across 23 countries. They provided further evidence that the methodologies were impacting on research and research practice, both nationally and internationally. We have used the information gathered in this study to adapt an existing framework for impact of clinical research for use in methodological research.ConclusionsGathering evidence on research impact of methodological research from a variety of sources has enabled us to obtain multiple indicators and thus to demonstrate broad impacts of methodological research. The adapted framework developed can be applied to future methodological research and thus provides a tool for methodologists to better assess and report research impacts.Electronic supplementary materialThe online version of this article (doi:10.1186/1745-6215-15-464) contains supplementary material, which is available to authorized users.

Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial

The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap. This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927. Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p<0·0001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2·0 points (-2·8 to -1·2; p<0·0001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0·01 (95% CI -0·03 to 0·04; p=0·787) and health-care costs were marginally reduced with CPAP (-£35, -390 to 321; p=0·847). CPAP improved objective sleepiness (p=0·024), mobility (p=0·029), total cholesterol (p=0·048), and LDL cholesterol (p=0·042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use. In older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome. National Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.