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The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47–1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36–0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63–3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor–targeted agents, which should be evaluated in prospective trials.\ud \ud Patient summary: \ud The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor.

Objectives AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

BackgroundAGILE is a phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection.MethodsWe undertook a dose-escalating, open-label, randomised-controlled (standard-of-care) Bayesian adaptive phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomised 2:1 in groups of 6 participants to 300mg, 600mg and 800mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was higher than 25%. Secondary outcomes included safety, clinical progression, pharmacokinetics and virologic responses.ResultsOf 103 volunteers screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 400, 600 or 800mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800mg molnupiravir respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800mg was estimated at 0.9%.ConclusionMolnupiravir was safe and well tolerated; a dose of 800mg twice-daily for 5 days was recommended for Phase II evaluation.

Background: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. Methods: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0–2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m 2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m 2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m 2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m 2 administered intravenously over 2 h and oral capecitabine 1000 mg/m 2 twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m 2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m 2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m 2 followed by a weekly infusion of 250 mg/m 2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. Findings: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0–77·5). Median progression-free survival was 22·2 months (95% CI 18·3–26·8) in the chemotherapy alone group and 15·5 months (13·8–19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87–1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5–71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02–2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3–4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). Interpretation: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. Funding: Cancer Research UK.

Objective: To compare the efficacy and cost of specialised individually-delivered parent training (PT) for preschool children with attention-deficit/ hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). Design: Multi-centre, three-arm parallel group randomised controlled trial. Research Setting: National Health Service Trusts. Participants: Preschool children (33-54 months) fulfilling ADHD research diagnostic criteria. Interventions: New Forest Parenting Programme (NFPP) – 12 week individual, home-delivered ADHD PT programme; Incredible Years (IY) – 12 week group-based, PT programme initially designed for children with behaviour problems. Main outcome measures: Primary outcome - Parent ratings of child’s ADHD symptoms (Swanson, Nolan & Pelham Questionnaire - SNAP-IV). Secondary outcomes - teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post-treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputation). Intervention and other costs were estimated using standardized approaches. Results: NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms (mean difference -0.009 95%CI [-0.191, 0.173], p=0.921) or any other measure. Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms (-0.189 95%CI [-0.380, 0.003], p=0.053). NFPP significantly reduced parent-rated conduct-problems compared to TAU across scales (p-values.05). The cost per family of providing NFPP in the trial was significantly lower than IY (£1,591 versus £2,103). \ud Conclusions: Although, there were no differences between NFPP and IY with regards clinical effectiveness, individually-delivered NFPP cost less. However, this difference may be reduced when implemented in routine clinical practice. Clinical decisions should take into account parental preferences between delivery approaches. \ud Funding: National Institute of Health Research. \ud Trial Registration: Trial name: COPPI Trial; ISRCTN39288126.

BackgroundThe addition of cetuximab to perioperative chemotherapy for operable colorectal liver metastases resulted in a shorter progression free survival. Details of disease progression are described to further inform the primary study outcome.MethodsA total of 257 KRAS wild-type patients were randomised to chemotherapy alone or chemotherapy with cetuximab. Data regarding sites and treatment of progressive disease were obtained for the 109 (chemotherapy n=48, chemotherapy and cetuximab n=61) patients with progressive disease at the cut-off date for analysis of November 2012. ResultsThe liver was the most frequent site of progression (chemotherapy 67% (32/48); chemotherapy and cetuximab 66% (40/61)). A higher proportion of patients in the cetuximab group had multi-site/other sites of progressive disease (chemotherapy 8%, 4/48; chemotherapy and cetuximab 23%, 14/61 p=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further chemotherapy, most frequently irinotecan based. Twenty two patients, 11 in each arm, received cetuximab as a further line agent. ConclusionBoth the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

The dominant discourse in research, management and teaching is one that may loosely be characterised as that of prediction and control. The objective of research is to identify causal correlations within policy, management, teaching strategies and educational outcomes that are sufficiently robust as to be able to predict outcomes and make generalisations across practice. With the construction of a cumulative bank of evidence, given clearly specified educational outcomes, we might see research as supporting the improvement of schools towards ‘effective’ or ‘best’ practice. This discourse assumes that education, though complicated, nevertheless takes place within a bounded system of relatively stable, linear and balanced causal interactions. This perspective on schooling may be understood as the ‘prediction/control’ paradigm. This paper explores the possibility of an alternative perspective, one that is based on principles derived from complexity theory and which may be referred to as the ‘complexity’ parad...

David Carr argues that the intelligibility of spiritual development as an educational activity is dependent upon there being a framework of propositions that relates to spiritual experience and that there is a methodology for establishing their truth. These propositions and the accompanying methodology need to be constructed along the lines of a traditional but re-worked form of religious education. Michael Hand argues to the contrary that there can be no methodology for the evaluation of the truth claims in relation to ‘spiritual’ propositions since they invariably psychologically, if not logically, involve reference to a transcendental being and are therefore seen as substantially matters of faith. Since the presentation of faith-based propositional knowledge is inappropriate to the secular school, the only route for spiritual education is in terms of those emotional qualities that we identify with the human ‘spirit’, that is, generosity, magnanimity, good heartedness, etc. In this paper it is...

This article presents a critical review of complexity theory in relation to educational research. The ‘analytical reductionist’ approach is one in which the educational researcher seeks to reduce complex wholes to particular factors and to identify correlations between them and desirable outcomes. Complexity theory shows how this approach in social research is both unreliable within its own terms of reference and misdirected. Complexity theory is characterised by a number of features. These include recognition that educational systems contain multiple variables. These connect in non‐linear and dynamic ways, i.e. where factors are seen to interact in a causal relationship the effects do not necessarily relate proportionally to the cause, and few factors may interact with many and many may interact with few. The crucial point of focus is on (a) the nature of the connections that are products of previous interactions reaching into the particular history of the organisation, and (b) the constitutive nature of...

Creativity may be seen as a complex process of informational processing within a given framework, or, as Margaret Boden has termed it, "conceptual space."l It is in the context of such frameworks that the process of managing information makes sense. The framework offers the possibilities within which information can be combined and separated, grouped and regrouped, and may be seen to define the boundaries of that which makes sense both within the space and at its parameters. Boden suggests that we can, by playing around with the variables within a "conceptual space," be creative. We can generate multiple possibilities in terms of meaningful articulations. We can also aspire to a more fundamental level of creative thought or action by engaging in the high-risk process of challenging the very rules that support the coherence of the space itself. In other words we can think, hypothesize or "play" at the boundaries of sense. Such explorations might result in changing those boundaries, thus transforming the conceptual space. Such changes might be minor but at other times dramatic, constituting major transitions in human thought and expression. This account seems to explain both the gradual process of creative development in the arts and sciences as well as the dramatic transformations that we observe in the history of intellectual and cultural development. Some conceptual spaces may be clearly defined with relatively closely controlled parameters. Others might be more open, more accommodating both within and at their boundaries A number of questions arise in the context, two of which are of particular interest. First, how do novel combinations or reorganizations of information within the conceptual space come to be made and how they are recognized as sensible and of value within the system? Second and more fundamentally, how are new and original articulations that stand at the parameters or boundaries of the sense-making system constructed? How are we guided

Governments of the United Kingdom expect to get their own way in matters of domestic policy. Negotiation and a degree of compromise may be necessary but, in general, the potent mix of Parliament's legislative supremacy, an overall majority in the House of Commons and strict party discipline combine to ensure that the executive's will prevails. Moreover, should the law as enacted not achieve the desired ends, or judicial interpretation differ from the initial intention, ministers can always introduce amending legislation to effect the original purpose. Or such was the case until the United Kingdom became a member of the European Community. It is trite to observe that, so long as the European Communities Act 1972 remains in force, providing for the incorporation into UK law of European Community (EC) law (which itself embodies the principle that, where there is a conflict, it takes precedence'), Parliament's legislative supremacy, and hence the executive's autonomy, are significantly compromised in respect of those matters which fall within the Community's competence. A quarter of a century after its enactment, the implications of this situation continue to reverberate throughout the body politic. This is obvious from the passionate debate engendered by issues such as changes to the Treaty of Rome or the effect of joining a single currency but, in addition to these high-profile matters, the day-to-day business of the European Union continually gives rise to less publicised situations in which the government's perception of what is desirable conflicts with the views of Union institutions or a majority of other Member States. Historically, most of these disputes have been resolved in the political arena, but increasingly they involve a legal dimension and are falling to be determined by the courts. This development not only changes fundamentally the traditional relationship between the judiciary and other governmental institutions, it also raises new questions about what constitutes proper conduct by the executive in a situation where an entirely domestic policy to which it attaches considerable political importance is threatened by developments in EC law. Such an example is provided by the impact of the Acquired Rights Directive2 on the government's attempts to promote competition in the provision of public services. In our view, the episode raises issues of constitutional importance. At the end of the 1970s, most public services were provided 'in-house,' using staff employed directly by the relevant authority, but the election in 1979 of a

The Audit Commission for Local Authorities in England and Wales was established by Part III of the Local Government Finance Act 1982 ('the 1982 Act') to take overall responsibility for the audit of local government.' It was created with the twin objectives of emphasising the independence of the audit process and promoting greater value for money in local authority spending, the government being of the view that 'improving public sector efficiency is still in large measure a matter of improving scrutiny, monitoring and management within the context of existing institutions. 2

3556 Background: The New EPOC study randomised patients with operable or borderline operable colorectal liver metastasis to perioperative chemotherapy with or without cetuximab. Recruitment to the ...