Laurence Moore

Process evaluation of complex interventions: Medical Research Council guidance

Process evaluation is an essential part of designing and testing complex interventions. New MRC guidance provides a framework for conducting and reporting process evaluation studies

Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

PURPOSE Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigators choice single-agent therapy in relapsed or refractory disease. PATIENTS AND METHODS In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigators choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment. RESULTS Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigators choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigators choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigators choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigators choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. CONCLUSION Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigators choice therapy in patients with relapsed or refractory MCL.

Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer

PURPOSE In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. PATIENTS AND METHODS Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. RESULTS Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). CONCLUSION In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy.

The mammalian target of rapamycin (mTOR) pathway is up‐regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).

An informal school-based peer-led intervention for smoking prevention in adolescence (ASSIST): a cluster randomised trial

Summary Background Schools in many countries undertake programmes for smoking prevention, but systematic reviews have shown mixed evidence of their effectiveness. Most peer-led approaches have been classroom-based, and rigorous assessments are scarce. We assessed the effectiveness of a peer-led intervention that aimed to prevent smoking uptake in secondary schools. Methods We undertook a cluster randomised controlled trial of 10 730 students aged 12–13 years in 59 schools in England and Wales. 29 schools (5372 students) were randomly assigned by stratified block randomisation to the control group to continue their usual smoking education and 30 (5358 students) to the intervention group. The intervention (ASSIST [A Stop Smoking In Schools Trial] programme) consisted of training influential students to act as peer supporters during informal interactions outside the classroom to encourage their peers not to smoke. Follow-up was immediately after the intervention and at 1 and 2 years. Primary outcomes were smoking in the past week in both the school year group and in a group at high risk of regular smoking uptake, which was identified at baseline as occasional, experimental, or ex-smokers. Analysis was by intention to treat. This study is registered, number ISRCTN55572965. Findings The odds ratio of being a smoker in intervention compared with control schools was 0·75 (95% CI 0·55–1·01) immediately after the intervention (n=9349 students), 0·77 (0·59–0·99) at 1-year follow-up (n=9147), and 0·85 (0·72–1·01) at 2-year follow-up (n=8756). The corresponding odds ratios for the high-risk group were 0·79 (0·55–1·13 [n=3561]), 0·75 (0·56–0·99 [n=3483]), and 0·85 (0·70–1·02 [n=3294]), respectively. In a three-tier multilevel model with data from all three follow-ups, the odds of being a smoker in intervention compared with control schools was 0·78 (0·64–0·96). Interpretation The results suggest that, if implemented on a population basis, the ASSIST intervention could lead to a reduction in adolescent smoking prevalence of public-health importance. Funding MRC (UK).

Effectiveness of multifaceted educational programme to reduce antibiotic dispensing in primary care: Practice based randomised controlled trial

Objective To evaluate the effectiveness and costs of a multifaceted flexible educational programme aimed at reducing antibiotic dispensing at the practice level in primary care. Design Randomised controlled trial with general practices as the unit of randomisation and analysis. Clinicians and researchers were blinded to group allocation until after randomisation. Setting 68 general practices with about 480 000 patients in Wales, United Kingdom. Participants 34 practices were randomised to receive the educational programme and 34 practices to be controls. 139 clinicians from the intervention practices and 124 from control practices had agreed to participate before randomisation. Practice level data covering all the clinicians in the 68 practices were analysed. Interventions Intervention practices followed the Stemming the Tide of Antibiotic Resistance (STAR) educational programme, which included a practice based seminar reflecting on the practices’ own dispensing and resistance data, online educational elements, and practising consulting skills in routine care. Control practices provided usual care. Main outcome measures Total numbers of oral antibiotic items dispensed for all causes per 1000 practice patients in the year after the intervention, adjusted for the previous year’s dispensing. Secondary outcomes included reconsultations, admissions to hospital for selected causes, and costs. Results The rate of oral antibiotic dispensing (items per 1000 registered patients) decreased by 14.1 in the intervention group but increased by 12.1 in the control group, a net difference of 26.1. After adjustment for baseline dispensing rate, this amounted to a 4.2% (95% confidence interval 0.6% to 7.7%) reduction in total oral antibiotic dispensing for the year in the intervention group relative to the control group (P=0.02). Reductions were found for all classes of antibiotics other than penicillinase-resistant penicillins but were largest and significant individually for phenoxymethylpenicillins (penicillin V) (7.3%, 0.4% to 13.7%) and macrolides (7.7%, 1.1% to 13.8%). There were no significant differences between intervention and control practices in the number of admissions to hospital or in reconsultations for a respiratory tract infection within seven days of an index consultation. The mean cost of the programme was £2923 (€3491,

Improving the reporting of public health intervention research: advancing TREND and CONSORT

4572) per practice (SD £1187). There was a 5.5% reduction in the cost of dispensed antibiotics in the intervention group compared with the control group (−0.4% to 11.4%), equivalent to a reduction of about £830 a year for an average intervention practice. Conclusion The STAR educational programme led to reductions in all cause oral antibiotic dispensing over the subsequent year with no significant change in admissions to hospital, reconsultations, or costs. Trial registration ISRCT No 63355948.

Attitudes and behaviour of general practitioners and their prescribing costs: a national cross sectional survey

BACKGROUND Evidence-based public health decision-making depends on high quality and transparent accounts of what interventions are effective, for whom, how and at what cost. Improving the quality of reporting of randomized and non-randomized study designs through the CONSORT and TREND statements has had a marked impact on the quality of study designs. However, public health users of systematic reviews have been concerned with the paucity of synthesized information on context, development and rationale, implementation processes and sustainability factors. METHODS This paper examines the existing reporting frameworks for research against information sought by users of systematic reviews of public health interventions and suggests additional items that should be considered in future recommendations on the reporting of public health interventions. RESULTS Intervention model, theoretical and ethical considerations, study design choice, integrity of intervention/process evaluation, context, differential effects and inequalities and sustainability are often overlooked in reports of public health interventions. CONCLUSION Population health policy makers need synthesized, detailed and high quality a priori accounts of effective interventions in order to make better progress in tackling population morbidities and inequalities. Adding simple criteria to reporting standards will significantly improve the quality and usefulness of published evidence and increase its impact on public health program planning.

Phase I/II Trial of Temsirolimus Combined With Interferon Alfa for Advanced Renal Cell Carcinoma

Background: General practitioner (GP) prescribing accounts for about 10% of NHS expenditure. GPs at the top of the range have annual prescribing costs that are almost twice as much as those at the bottom of the range. This variation cannot be accounted for purely in terms of differences in underlying need for health care. Objectives: To describe the relationship between GPs’ prescribing costs and their attitudes towards prescribing decisions and prescribing information sources, and to identify potentially modifiable attitudinal and behavioural factors associated with high cost prescribing. Design: A postal questionnaire was designed on the basis of hypotheses developed from a literature search and an earlier qualitative survey. This questionnaire was sent to a national sample of GPs with equal numbers of practices in the upper, middle, and lowest quintile of prescribing costs. Setting: GP practices in England. Participants: 1714 GPs in NHS practice. Outcome measures: GPs’ self-reported practices, attitudes and personal characteristics. Results: There was a 64% response rate. Responders were more likely to be from larger practices, in less deprived areas, and with lower prescribing costs than were non-responders. Multivariable analysis showed that GPs with high prescribing costs were significantly more likely to work in dispensing practices, in practices with low income populations, in single handed practices, and in practices without a GP trainer. They were also significantly more likely to see drug company representatives more frequently, to prescribe newly available drugs more freely, to prescribe more readily to patients who expect a prescription, to report high levels of frustration from lack of time in the consultation, to find unsatisfactory those consultations which ended in advice only, and to express dissatisfaction with their review methods for repeat prescribing. They were significantly less likely to find useful criticism of prescribing habits by colleagues, and to check the BNF rather than other sources when uncertain about an aspect of drug treatment. Conclusions: While they cannot be held to have a causal relationship, the pattern of attitudes towards prescribing of GPs in the highest quintile of prescribing costs provide the basis for developing an educational intervention which may be an acceptable method of modifying the attitudes of GPs and consequently reducing their prescribing costs.

Process evaluation in complex public health intervention studies: the need for guidance

PURPOSE Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC. PATIENTS AND METHODS Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information. RESULTS Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months. CONCLUSION The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.