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Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort.
No full textBACKGROUND
Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours.
METHODS
We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials.
RESULTS
Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001).
CONCLUSION
SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours.
CLINICAL TRIAL REGISTRATION
NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883
ACORN: Observational Study of Bevacizumab in Combination With First-Line Chemotherapy for Treatment of Metastatic Colorectal Cancer in the UK.
No full textINTRODUCTION
Survival in metastatic colorectal cancer is worse than expected in the United Kingdom. Real-world data are needed to better understand UK-specific treatment practices that may explain this.
PATIENTS AND METHODS
The Avastin ColORectal Non-interventional (ACORN) study is a multicenter, prospective, UK-based, observational, phase 4 study (ClinicalTrials.gov, NCT01506167) that recruited patients with metastatic colorectal cancer scheduled to receive bevacizumab in combination with first-line chemotherapy as part of routine clinical practice. Primary end points included progression-free survival, overall survival (OS), serious adverse events (AEs), and grade 3 to 5 bevacizumab-related AEs.
RESULTS
A total of 714 patients were recruited between August 30, 2012, and February 4, 2014. Median follow-up was 16.4 months. Median first-line chemotherapy duration was 5.6 months, with capecitabine/oxaliplatin (265 [37.1%]) being the most common regimen. Median total chemotherapy duration was 8.1 months and did not vary by geographic location in the UK. Median progression-free survival (95% confidence interval) was 8.7 (8.2-9.1) months, and median OS was 17.8 (16.1-19.3) months. There was no significant difference in efficacy by chemotherapy regimen administered. Ninety-nine patients (13.9%) received bevacizumab after disease progression. The safety profile of bevacizumab was consistent with previous studies.
CONCLUSION
ACORN provided evidence that there were no clear differences observed in outcomes between bevacizumab with capecitabine-based chemotherapy and fluorouracil-based regimens, and confirmed the safety profile of bevacizumab in a real-world UK-based population. The lower-than-expected OS is likely due to the short total chemotherapy duration, less frequent use of bevacizumab after disease progression, and higher rates of in-situ primary tumors
Implementation of research evidence in orthopaedics: a tale of three trials.
No full textOBJECTIVE
To examine implementation of evidence in orthopaedic practice following publication of the results of three pivotal clinical trials.
DESIGN
Case studies based on three orthopaedic trials funded in sequence by the National Institute for Health Research Health Technology Assessment (HTA) programme. These trials dealt with treatment of fractures of the humerus, radius and ankle, respectively. For each case study, we conducted time-series analyses to examine the relationship between publication of findings and the implementation (or not) of the findings.
RESULTS
The results of all three trials favoured the less expensive and less invasive option. In two cases, a change of practice, in line with the evidence that eventually emerged, preceded publication. Furthermore, the upturn in use of the intervention most supported by each of these two trials corresponded to the start of recruitment to the respective trial. The remaining trial failed to influence practice despite yielding clear-cut evidence.
CONCLUSIONS
Implementation of results of all three HTA orthopaedic trials favoured the less expensive and less invasive option. In two of the three studies, a change in practice, in line with the evidence that eventually emerged, preceded publication of that evidence. A trend or a change in practice, at around the start of the trial, indicates that the direction of causation opposes our hypothesis that publication of trial findings would lead to changes in practice. Our results provide provocative insight into the nuanced topic of research and practice, but further qualitative work is needed to fully explain what led to the pre-emptive change in practice we observed and why there was no change in the third case
Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
No full textBACKGROUND
Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.
METHODS
In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.
FINDINGS
Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group).
INTERPRETATION
Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.
FUNDING
Intercept Pharmaceuticals
Chemsex is not a barrier to self-reported daily PrEP adherence among PROUD study participants.
No full textBACKGROUND
Pre-exposure prophylaxis (PrEP) is a novel HIV prevention method whereby HIV-negative individuals take the drugs tenofovir and emtricitabine to prevent HIV acquisition. Optimal adherence is critical for PrEP efficacy. Chemsex describes sexual activity under the influence of psychoactive drugs, in the UK typically; crystal methamphetamine, gamma-hydroxybutyrate(GHB) and/or mephedrone. Chemsex drug use has been associated with increased HIV transmission risk among gay, bisexual and other men who have sex with men (GBM) and poor ART adherence among people living with HIV. This study assessed whether self-reported chemsex events affected self-reported daily PrEP adherence among PROUD study participants.
METHODS
The PROUD study was an open-label, randomised controlled trial, conducted in thirteen English sexual health clinics, assessing effectiveness of Truvada-PrEP among 544 HIV-negative GBM. The study reported an 86% risk-reduction of HIV from daily PrEP. Participants were asked about chemsex engagement at follow-up visits. Monthly self-reports of missed PrEP tablets were aggregated to assess adherence between visits. Univariable and multivariable regression analyses were performed to test for associations between chemsex and reporting less than seven out of seven intended doses(<7/7ID) in the 7 days before and/or after last condomless anal intercourse(CAI).
RESULTS
1479 follow-up visit forms and 2260 monthly adherence forms from 388 participants were included in the analyses, with 38.5% visit forms reporting chemsex since last visit and 29.9% follow-up periods reporting <7/7ID. No statistically significant associations were observed between reporting <7/7ID and chemsex (aOR=1.29 [95% CI 0.90-1.87], p = 0.168). Statistically significant associations were seen between reporting <7/7ID and participants perceiving that they would miss PrEP doses during the trial, Asian ethnicity, and reporting unemployment at baseline.
CONCLUSIONS
These analyses suggest PrEP remains a feasible and effective HIV prevention method for GBM engaging in chemsex, a practise which is prevalent in this group and has been associated with increased HIV transmission risk
Adaptive trial designs in diagnostic accuracy research.
No full textThe aim of diagnostic accuracy studies is to evaluate how accurately a diagnostic test can distinguish diseased from nondiseased individuals. Depending on the research question, different study designs and accuracy measures are appropriate. As the prior knowledge in the planning phase is often very limited, modifications of design aspects such as the sample size during the ongoing trial could increase the efficiency of diagnostic trials. In intervention studies, group sequential and adaptive designs are well established. Such designs are characterized by preplanned interim analyses, giving the opportunity to stop early for efficacy or futility or to modify elements of the study design. In contrast, in diagnostic accuracy studies, such flexible designs are less common, even if they are as important as for intervention studies. However, diagnostic accuracy studies have specific features, which may require adaptations of the statistical methods or may lead to specific advantages or limitations of sequential and adaptive designs. In this article, we summarize the current status of methodological research and applications of flexible designs in diagnostic accuracy research. Furthermore, we indicate and advocate future development of adaptive design methodology and their use in diagnostic accuracy trials from an interdisciplinary viewpoint. The term "interdisciplinary viewpoint" describes the collaboration of experts of the academic and nonacademic research
Storiform collagenoma (sclerotic fibroma) of the oral mucosa.
No full textStoriform collagenoma (also called sclerotic fibroma) is uncommon, occurs as a cutaneous fibrous neoplasm, and is particularly rare in mucosal tissue in the head and neck. We describe an unexpected diagnosis in the oral cavity. Histopathological examination showed a proliferation of fibrous tissue, which was well circumscribed but unencapsulated, with thick laminated bundles of eosinophilic collagen that exhibited a storiform or "whorled" pattern. First described by Weary et al in 1972, storiform collagenoma is a marker for Cowden's disease or PTEN hamartoma tumour syndrome. Identification of other synchronous lesions should prompt chromosomal analysis for a mutation in the PTEN gene on chromosome 10q23
The impact of patient-reported outcome (PRO) data from clinical trials: a systematic review and critical analysis.
No full textBACKGROUND
Patient-reported outcomes (PROs) are commonly collected in clinical trials and should provide impactful evidence on the effect of interventions on patient symptoms and quality of life. However, it is unclear how PRO impact is currently realised in practice. In addition, the different types of impact associated with PRO trial results, their barriers and facilitators, and appropriate impact metrics are not well defined. Therefore, our objectives were: i) to determine the range of potential impacts from PRO clinical trial data, ii) identify potential PRO impact metrics and iii) identify barriers/facilitators to maximising PRO impact; and iv) to examine real-world evidence of PRO trial data impact based on Research Excellence Framework (REF) impact case studies.
METHODS
Two independent investigators searched MEDLINE, EMBASE, CINAHL+, HMIC databases from inception until December 2018. Articles were eligible if they discussed research impact in the context of PRO clinical trial data. In addition, the REF 2014 database was systematically searched. REF impact case studies were included if they incorporated PRO data in a clinical trial.
RESULTS
Thirty-nine publications of eleven thousand four hundred eighty screened met the inclusion criteria. Nine types of PRO trial impact were identified; the most frequent of which centred around PRO data informing clinical decision-making. The included publications identified several barriers and facilitators around PRO trial design, conduct, analysis and report that can hinder or promote the impact of PRO trial data. Sixty-nine out of two hundred nine screened REF 2014 case studies were included. 12 (17%) REF case studies led to demonstrable impact including changes to international guidelines; national guidelines; influencing cost-effectiveness analysis; and influencing drug approvals.
CONCLUSIONS
PRO trial data may potentially lead to a range of benefits for patients and society, which can be measured through appropriate impact metrics. However, in practice there is relatively limited evidence demonstrating directly attributable and indirect real world PRO-related research impact. In part, this is due to the wider challenges of measuring the impact of research and PRO-specific issues around design, conduct, analysis and reporting. Adherence to guidelines and multi-stakeholder collaboration is essential to maximise the use of PRO trial data, facilitate impact and minimise research waste.
TRIAL REGISTRATION
Systematic Review registration PROSPERO CRD42017067799