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With a growing number of economic evaluations being conducted alongside trials, there is a need to address, and if necessary, investigate the generalizability of results derived from trials. This paper explores the generalizability of costs from a trial investigating the frequency of breast cancer screening in the United Kingdom.
BACKGROUND: Co-operative groups have played an important role in the advance of health-related quality of life (HRQL) research. However, definitions of the concept, criteria for selection of existing instruments and methods for data collection and interpretation remain poorly defined in the literature. A survey was conducted amongst the major cancer co-operative groups in order to gain a better understanding of their current policy and processes to ensure optimal HRQL data collection within cancer clinical trials. The topic of health economics was similarly addressed. METHODS: A written questionnaire was addressed to 16 major European and North American cancer co-operative groups. Eleven groups responded (response rate: 69%). however, one group could not provide information for the survey, thus ten questionnaires were available for analysis. RESULTS: The results from this survey among co-operative groups show that HRQL (more than health economics) is recognized as an important, although usually secondary, outcome measure in oncology trials. On the whole, co-operative groups have a rather flexible policy towards the inclusion of HRQL (and HE) into their clinical trials, and practice is very much on a case-by-case basis, but use standard practice guidelines and internal procedures is to ensure well-defined study protocols and enhance good quality studies.
BACKGROUND: To ensure the internal validity of a trial it is recommended to undertake a validation study of the method measuring the outcome. AIMS: To validate a self-administered, postal questionnaire (http://www.gyncph.suite.dk/praes/gimbel/gihtm) used for measuring the outcomes of a randomized clinical trial of total vs. subtotal abdominal hysterectomy. METHODS: A study of the content validity (10 patients) and a combined qualitative and quantitative validation study (20 patients) were performed. RESULTS: The median kappa of the 74 questions was 0.71 (range 0.22-1.00) and the median overall agreement was 0.76 (range 0.25-1.00). Five questions (7%) had kappa values below 0.40, 11 questions (15%) between 0.40 and 0.60, and 58 questions (78%) above 0.61. Three questions with a kappa value below 0.40 had an overall agreement of 0.75 or more. Significant logical inconsistencies were found in five questions, where the operation method was expected to be known. The qualitative validation resulted in a total of 80 comments. The number of comments for any given subject ranged from 0 to 12. The comments could be grouped and processed into four categories. CONCLUSIONS: The agreement was high. Inconsistencies regarding questions on the operation methods were found. Potential problems were identified in five questions (7%). The validation studies resulted in some changes to the questionnaire and we became aware of areas in which caution should be taken in the interpretation of the results of the randomized trial.
This chapter describes dietary composition according to cigarette smoking status at baseline and changes in smoking status during follow-up for men in the special intervention (SI) and usual care (UC) groups of the Multiple Risk Factor Intervention Trial. Five patterns of smoking behavior were defined: 1) sustained nonsmoking, 2) early (years 1-2 of the trial) sustained quitting, 3) late (years 3-6 of the trial) sustained quitting, 4) recidivism, and 5) continued smoking. SI men who quit smoking showed greater favorable changes in dietary lipid composition and micronutrient intake than did continued smokers, and these changes were in many instances as great as favorable changes made by nonsmokers. On the other hand, SI men who quit smoking gained an average of 3.8 lb (1.7 kg), in contrast with nonsmokers who lost an average of 6.4 lb (2.9 kg). The gain by SI quitters was, however, less than that by UC quitters, who gained 6.5 lb (3.0 kg). Moreover, despite weight gain, net change in high-density-lipoprotein (HDL) cholesterol for SI quitters was positive. With the associated decrease in low-density-lipoprotein (LDL) cholesterol, early SI quitters had the most improvement in ratio of LDL to HDL among all subgroups. Thus, unfavorable nutritional patterns of smokers put them at double jeopardy regarding cardiovascular and other chronic diseases; additionally, long-term risks can be improved not only by smoking cessation but also by achievement of healthier eating patterns.
Any discussion of practical issues in clinical trials should take into account both the perspective of the 'Doers of Research'--the investigators and also the 'Consumers of Research'--such as the clinicians who will use the results. This paper focuses on five important prerequisites for any successful clinical trial (1) as applied to rheumatology trials.
Differences in overall survival and response rates are often noted when promising single-institution phase II treatment regimens are evaluated in a cooperative group setting. One reason for this discrepancy may be the differences in patient characteristics at the time of registration. In the metastatic melanoma literature, the prognostic factors for survival that are most frequently identified are the number of metastatic sites, visceral involvement, performance status, liver involvement, and possibly the disease-free interval and gender. A prognostic factor for response appears to be sites of involvement. A comparison of patient characteristics and outcome was conducted for patients entered in similar phase II melanoma trials at a single institution versus those in a cooperative group. Sixty-four patients at Wayne State University (WSU) were compared with 96 patients who had nearly identical eligibility criteria and were registered in the Southwest Oncology Group (SWOG). All patients were receiving comparable phase II treatments for metastatic melanoma. Southwest Oncology Group patients were significantly older (p < 0.001), had worse performance status (p = 0.03), had more visceral involvement (p = 0.001), and were more likely to have two or more metastatic sites (p = 0.02). No significant differences in gender (p = 0.55), absence or presence of liver involvement (p = 0.12), or disease-free interval were noted. These disparities, despite similar eligibility, may partly explain the observed differences in survival (WSU median = 10 months, SWOG median = 7 months; p = 0.13) and response rates (WSU = 31%, SWOG = 15%; p = 0.02) between the two groups of patients. Investigators should report these important patient characteristics in treatment reports. These differences highlight the difficulty in comparing single-institution and cooperative-group phase II trials, even with comparable patient eligibility. This serves to emphasize the need for well-designed phase III trials when comparing treatment approaches and stratification for the prognostic factors identified.
PURPOSE OF REVIEW: It has been common practice in randomized trials of HIV medicines to classify switches away from the original therapy as failures in analyses of virological effect, in line with an HIV-RNA measurement above a given level of quantification. This approach precludes the ability to identify the possible effects of a given therapy on those of a subsequent therapy. This review explores whether there have been changes in the reporting of randomized trials since the importance of continuous follow-up throughout the study period was initially raised 2 years ago. RECENT FINDINGS: Follow-up is still likely to be discontinued at a premature switch from study medication in a large number of the randomized trials published in 2002-2003. However, some studies, all initiated by investigators, did follow patients throughout the study period. In three of the studies, the proportions of patients with virological failure assessed with and without data after the premature discontinuation of randomized therapy could be elicited. Substantial differences were seen in the comparisons of two highly active antiretroviral therapy regimens according to the choice of analytical approach. In all three studies significant differences were observed between the regimens according to one approach, but not to the other. SUMMARY: The notation of treatment switch equals failure leads to an imprecise measurement of virological effect, and complete follow-up throughout the study period should be strongly encouraged, thus enabling several supplementary analyses of the virological effect of the treatment strategies being compared.
INTRODUCTION: Single-injection and continuous brachial plexus block techniques are used widely for postoperative analgesia in patients undergoing shoulder surgery. Although patient-reported outcomes are described in individual studies, their effects have not been synthesised comprehensively using a patient-centred framework. We sought to compare the effects of single-injection vs. continuous brachial plexus block techniques on patient-reported outcomes in adult patients following elective shoulder surgery. METHODS: Databases were searched from inception to October 2025 and randomised controlled trials reporting patient-reported outcomes were included. Co-primary outcomes were postoperative patient-reported pain intensity at rest and during movement at 12 h, 24 h and 48 h post-surgery. Secondary outcomes included nausea and vomiting; sleep quality; patient satisfaction; opioid requests; and functional scores. Random-effects meta-analysis and trial sequential analysis were performed, with risk of bias and quality of patient-reported outcome reporting assessed. RESULTS: Twenty randomised controlled trials that included 1198 patients were analysed. Continuous brachial plexus blocks were associated with lower pain at rest at 12 h, 24 h and 48 h, with mean differences (MD) of -1.96 (95%CI -2.81 to -1.11, p < 0.001), -1.66 (95%CI -2.27 to -1.05, p < 0.001) and - 1.18 (95%CI -1.84 to -0.53, p < 0.001), respectively. Pain on movement could only be pooled at 24 h and 48 h and showed MD -2.04 (95%CI -4.26-0.19, p = 0.07) and - 1.30 (95%CI -3.67-1.07, p = 0.28) respectively. The co-primary outcomes approached or exceeded the predefined minimal clinically important difference for pain scores after shoulder surgery, in favour of continuous techniques. DISCUSSION: Continuous brachial plexus blocks are associated with better pain at rest and other patient-centred outcomes following shoulder surgery, while effects on dynamic pain and long-term functional recovery remain uncertain.
The Ottawa Stroke Trials Registry (OSTR) collects information on all randomized controlled trials (RCTs), in all languages, in which the primary focus is stroke. Published trials are added to the registry database once they have been identified by volunteers hand searching journals. We undertook this study to assess volunteer sensitivity, specificity, positive and negative predictive values, accuracy and reliability in identifying RCTs. Three volunteers participated in this study. The complete contents of five years of one journal were searched (n = 240) as were ten research reports from five journals. Volunteer sensitivity, specificity, positive and negative predictive values, and accuracy was 89.5%, 100%, 100%, 99.1%, and 99% respectively. Inter volunteer reliability was 0.87. Searching the published literature to identify RCTs is an enormous task. These results indicate that volunteers, with minimal training, can effectively contribute to this endeavour.
Multiple trials using antiarrhythmic drugs, pharmacologic therapy, and implantable cardioverter defibrillators have been performed in an attempt to improve survival in patients: (1) postmyocardial infarction; (2) with congestive heart failure, with and without nonsustained ventricular tachycardia; and (3) with sustained ventricular tachycardia and those who have survived an out-of-hospital cardiac arrest. This article reviews some of the key findings and limitations of completed and ongoing trials. We also make recommendations for the current treatment of such patients based on the results of these trials.
BACKGROUND: The purpose of the European PROCAR Trial was to evaluate the safety and performance of the Protégé stent in the treatment of common and/or internal carotid artery stenoses with adjunctive use of a filter embolic protection device. METHOD: The Protégé GPS stent is a self-expanding Nitinol stent system mounted on a 6 Fr 0.018'' (6-9 mm stent) or 7 Fr 0.035'' (10 mm stent) over-the-wire delivery system. Study patient assessments were conducted at baseline, periprocedure, discharge, and 1 and 6 months postprocedure. A total of 77 patients have been enrolled in the trial. RESULTS: In the 77 lesions treated (31 symptomatic, 46 asymptomatic), the procedure was technically successful in 76 (99%), with an average residual stenosis of less than 30%. One procedure failed because the embolic protection device could not be retrieved and the patient was sent to surgery. Within 30 days, there were four (5.2%) major adverse neurological events (MANEs). Three of the MANEs were major strokes (3.9%), one a minor stroke. The fifth MANE occurred prior to the 6-month follow-up visit; this patient had a major stroke 75 days after the procedure and died 36 days later. One additional death occurred because of urosepsis. CONCLUSIONS: The PROCAR trial shows that the Protégé stent with adjuvant use of a filter embolic protection device satisfies safety and performance criteria for the treatment of carotid artery stenosis. The incidence of MANEs for the Protégé stent is comparable to the incidence of these events in other recent carotid stent studies and standard carotid endarterectomy (CEA).
U.S. scientists are gearing up for a major clinical trial intended to measure the effects of a popular but controversial drug used to treat attention deficit hyperactivity disorder, methylphenidate (Ritalin), on a previously untested population--children aged 3 to 6. But in doing so, they are running up against ethical concerns about using young subjects in clinical trials. The scientists involved in the study admit that they are concerned about the drug's effect on the children's still-developing personalities and brains, as well as their inability to give informed consent. But they believe that such trials are the only way to answer concerns about rising use of the drug among this population.
OBJECTIVE: To compare the effectiveness of four commercial weight loss diets available to adults in the United Kingdom. DESIGN: Six month multicentre randomised unblinded controlled trial. SETTING: Community based sample of otherwise healthy overweight and obese adults. INTERVENTIONS: Dr Atkins' new diet revolution, Slim-Fast plan, Weight Watchers pure points programme, and Rosemary Conley's eat yourself slim diet and fitness plan. MAIN OUTCOME MEASURES: Weight and body fat changes over six months. RESULTS: All diets resulted in significant loss of body fat and weight over six months. Groups did not differ significantly but loss of body fat and weight was greater in all groups compared with the control group. In an intention to treat analysis, average weight loss was 5.9 kg and average fat loss was 4.4 kg over six months. The Atkins diet resulted in significantly higher weight loss during the first four weeks, but by the end was no more or less effective than the other diets. CONCLUSIONS: Clinically useful weight loss and fat loss can be achieved in adults who are motivated to follow commercial diets for a substantial period. Given the limited resources for weight management in the NHS, healthcare practitioners should discuss with their patients programmes known to be effective. TRIAL REGISTRATION: Clinical trials NCT00327821.
BACKGROUND AND PURPOSE: The CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial proved the effectiveness of the combination of clopidogrel and aspirin compared with aspirin alone in reducing presence and number of microembolic signals (MES) in patients with recently symptomatic carotid stenosis. The present study aimed at installing primary and secondary quality control measures in CARESS because MES evaluation relies on subjective judgment by human experts. METHODS: As primary quality control, centers participating in CARESS evaluated a reference digital audio tape (DAT) before the study containing both MES and artifacts. Interobserver agreement of classifying signals as MES was expressed as proportions of specific agreement of positive ratings (ps+/-values). For all DATs included in CARESS (n=300), online number of MES and off-line number of MES read by the central reader were compared using correlation coefficients. As secondary control, a sample of 16 of 300 DATs was cross-validated by another independent reader (post-trial validator). RESULTS: For the reference tape, the cumulative ps+/-value was 0.894 based on 12 of 14 observers. Two observers with very different results improved after a training procedure. Agreement between post-trial validator and central reader was ps+=0.805, indicating very good agreement. Correlation between online evaluation and off-line evaluation of DATs was very good overall (cumulative rho=0.84; P<0.001). CONCLUSIONS: Multicenter studies using MES as outcome parameter are feasible. However, primary and secondary quality control procedures are important.
The most reliable information about treatment effects comes from randomized controlled trials (RCTs). However, the possibility of subtle interactions--for example, between treatment preferences and treatment effects--is generally subordinated in the quest for evidence about main treatment effects. If patient preferences can influence the effectiveness of treatments through poorly understood (psychological) pathways, then RCTs, particularly when unblinded, may wrongly attribute effects solely to a treatment's physiological/pharmacological properties. To interpret the RCT evidence base it is important to know whether any preference effects exist and, if so, by how much they affect outcome. Reliable measurement of these effects is difficult and will require new approaches to the conduct of trials. In view of the fanciful image with which such effects are portrayed and the uncertainties about their true nature and biological mechanisms, existing evidence is unlikely to provide sufficient justification for investment in trials. This is a Catch 22. Until an escape is found we might never know, even approximately, how much of modern medicine is attributable to psychological processes.
BACKGROUND: The Diabetes Manual is a type 2 diabetes self-management programme based upon the clinically effective 'Heart Manual'. The 12 week programme is a complex intervention theoretically underpinned by self-efficacy theory. It is a one to one intervention meeting United Kingdom requirements for structured diabetes-education and is delivered within routine primary care. METHODS/DESIGN: In a two-group cluster randomized controlled trial, GP practices are allocated by computer minimisation to an intervention group or a six-month deferred intervention group. We aim to recruit 250 participants from 50 practices across central England. Eligibility criteria are adults able to undertake the programme with type 2 diabetes, not taking insulin, with HbA1c over 8% (first 12 months) and following an agreed protocol change over 7% (months 13 to 18). Following randomisation, intervention nurses receive two-day training and delivered the Diabetes Manual programme to participants. Deferred intervention nurses receive the training following six-month follow-up. Primary outcome is HbA1c with total and HDL cholesterol; blood pressure, body mass index; self-efficacy and quality of life as additional outcomes. Primary analysis is between-group HbA1c differences at 6 months powered to give 80% power to detect a difference in HbA1c of 0.6%. A 12 month cohort analysis will assess maintenance of effect and assess relationship between self-efficacy and outcomes, and a qualitative study is running alongside. DISCUSSION: This trial incorporates educational and psychological diabetes interventions into a single programme and assesses both clinical and psychosocial outcomes. The trial will increase our understanding of intervention transferability between conditions, those diabetes related health behaviours that are more or less susceptible to change through efficacy enhancing mechanisms and how this impacts on clinical outcomes.
BACKGROUND: While obesity is known to have many physiological consequences, the psychopathology of this condition has not featured prominently in the literature. Cross-sectional studies have indicated that obese children have increased odds of experiencing poor quality of life and mental health. However, very limited trial evidence has examined the efficacy of exercise therapy for enhancing mental health outcomes in obese children, and the Sheffield Obesity Trial (SHOT) will provide evidence of the efficacy of supervised exercise therapy in obese young people aged 11-16 years versus usual care and an attention-control intervention. METHOD/DESIGN: SHOT is a randomised controlled trial where obese young people are randomised to receive; (1) exercise therapy, (2) attention-control intervention (involving body-conditioning exercises and games that do not involve aerobic activity), or (3) usual care. The exercise therapy and attention-control sessions will take place three times per week for eight weeks and a six-week home programme will follow this. Ninety adolescents aged between 11-16 years referred from a children's hospital for evaluation of obesity or via community advertisements will need to complete the study. Participants will be recruited according to the following criteria: (1) clinically obese and aged 11-16 years (Body Mass Index Centile > 98th UK standard) (2) no medical condition that would restrict ability to be active three times per week for eight weeks and (3) not diagnosed with insulin dependent diabetes or receiving oral steroids. Assessments of outcomes will take place at baseline, as well as four (intervention midpoint) and eight weeks (end of intervention) from baseline. Participants will be reassessed on outcome measures five and seven months from baseline. The primary endpoint is physical self-perceptions. Secondary outcomes include physical activity, self-perceptions, depression, affect, aerobic fitness and BMI.
BACKGROUND: The closure of the abdomen after median laparotomy is still a matter of debate among surgeons. Further well designed and performed randomised controlled trials determining the optimal method of abdominal fascial closure are needed. DESIGN: This is a three armed, multi-centre, intra-operatively randomised, controlled, patient blinded trial. Over 20 surgical departments will enrol 600 patients who are planned for an elective primary abdominal operation. The objective of this study is to compare the frequency of abdominal incisional hernias between two continuous suture techniques with different, slowly absorbable monofilament materials and an interrupted suture using an absorbable braided suture material at one year postoperatively. CONCLUSION: This trial will answer the question whether the continuous abdominal wall closure with a slowly absorbable material with longitudinal elasticity is superior to the continuous suture with a material lacking elasticity and to interrupted sutures with braided thread.