Pre-operative parenteral nutrition in patients with oesophageal cancer: a prospective, randomised clinical trial

A prospective randomised clinical trial was conducted to examine the efficacy of 2 weeks pre-operative parenteral nutrition (PPN) for the prevention of complications following surgery for oesophageal cancer. Forty patients were studied, the diet of twenty being supplemented by pre-operative parenteral nutrition. There were no significant differences in age, nutritional status, tumour staging and histology between the two groups of patients. The use of PPN resulted in a significant gain in body weight and nitrogen but failed to produce an overall reduction in post-operative morbidity and mortality rates. However patients receiving PPN exhibited two types of changes in serum albumin levels. Those with a fall in serum albumin levels associated with an increase in body weight (indicating an expansion of extracellular volume) had a significantly higher incidence of post-operative pulmonary complications than the group exhibiting a rise in serum albumin levels concomitant with increase in body weight. These data suggested that two weeks PPN might not be adequate in certain patients and a longer period of PPN is required. They also show no clinical benefit from the routine use of pre-operative parenteral nutrition in all patients, but do not exclude benefit in selected groups.     

New perspective on the nutritional approach to cancer-related anorexia/cachexia: preliminary results of a randomised phase III clinical trial with five different arms of treatment

Cancer-related anorexia/cachexia syndrome (CACS) is a multifactorial syndrome characterised by tissue wasting, particularly lean body mass (LBM), metabolic alterations, fatigue, anorexia and reduced food intake. In April 2005 we started a phase III randomised study to establish the most effective and safest treatment for CACS addressing as primary endpoints: LBM, resting energy expenditure (REE), total daily physical activity, interleukin (IL)-6 and tumour necrosis factor (TNF)-α levels, and fatigue. According to the statistical design the sample size was 475 patients (95 per arm). Eligibility criteria: histologically confirmed tumours of any site; weight loss −5% in the last 3 months and/or abnormal laboratory values; life expectancy >4 months. Patients were treated with either antineoplastic therapy or supportive care. All patients received as basic oral treatment polyphenols plus alpha lipoic acid plus carbocysteine plus vitamins A, C and E. Patients were then randomised to one of the following 5 arms: (1) medroxyprogesterone acetate (MPA)/megestrol acetate (MA); (2) pharmaconutritional support containing eicosapentaenoic acid (EPA); (3) l-carnitine; (4) thalidomide; and (5) a combination of all the above agents. Treatment duration was 4 months. Interim analyses were planned after every 100 randomised patients. In September 2008, 280 patients were randomised and 240 were evaluable: M/F 167/113, mean age 62 years (range 30-84), 96% stage IV. A first interim analysis on 125 patients showed a worsening of LBM, REE and fatigue in arm 2 in comparison to the others and therefore it was withdrawn from the study. A second interim analysis after the enrolment of 204 patients showed that arm 1 was clearly significantly less effective than the others for primary efficacy endpoints, therefore it was withdrawn from the study. Statistical analysis in September 2008 showed a significant improvement of LBM (by dual X-ray energy absorptiometry), REE and fatigue in arm 5, a decrease of IL-6 in arms 3 and 5, and a decrease of TNF-α in arms 3 and 4. As for toxicity, 1 patient discontinued MPA because of deep vein thrombosis and 1 patient discontinued L-carnitine because of severe diarrhoea. In conclusion, the interim results seem to suggest that the most effective treatment for cancer patients with CACS/oxidative stress (OS) should be the combination regimen. The study is in progress.     

Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results

OBJECTIVE: In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). METHODS: All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. RESULTS: By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. CONCLUSION: The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.     

Intensive support to improve clinical decision making in cardiovascular care: a randomised controlled trial in general practice

Objective: To evaluate the effects of feedback reports combined with outreach visits from trained non-physicians on the clinical decision making of general practitioners (GPs) in cardiovascular care.

Design: Pragmatic cluster controlled trial with randomisation of practices to support (intervention group) or no special attention (control group); analysis after 2 years.

Setting: 124 general practices in The Netherlands.

Participants: 185 GPs.

Main outcome measures: Compliance rates for 12 evidence-based indicators for the management of patients with hypertension, hypercholesterolaemia, angina pectoris, or heart failure. The evaluation relied on the prospective recording of patient encounters by the participating GPs.

Results: The GPs reported 30 101 clinical decisions at baseline and 22 454 decisions after the intervention. A significant improvement was seen for five of the 12 indicators: assessment of risk factors in patients with hypercholesterolaemia (odds ratio 2.04; 95% CI 1.44 to 2.88) or angina pectoris (3.07; 1.08 to 8.79), provision of information and advice to patients with hypercholesterolaemia (1.58, 1.17 to 2.13) or hypertension (1.55, 1.35 to 1.77), and checking for clinical signs of deterioration in patients with heart failure (4.11, 2.17 to 7.77). Single handed practices, non-training practices, and practices with older GPs gained particular benefit from the intervention.

Conclusions: Intensive support from trained non-physicians can alter certain aspects of the clinical decision making of GPs in cardiovascular care. The effect is small and the strategy needs further development.

     

Patient education methods to support quality of life and functional ability among patients with schizophrenia: a randomised clinical trial

Purpose  

The aim of this study was to estimate the effectiveness of patient education methods on quality of life and functional impairment of patients with schizophrenia.     

Effectiveness of health-related quality-of-life measurement in clinical practice: a prospective,randomized controlled trial in patients with chronic liver disease and their physicians

Background This study assessed the effectiveness of computerized measurement and feedback of health-related quality of life (HRQoL) in daily clinical practice in patients with chronic liver disease. Methods One hundred and sixty-two patients (61% men; mean age 47.5 years) regularly completed computerized HRQoL questionnaires before each consultation for the duration of 1 year. Six physicians were randomly assigned to the experimental group and received an instant online graphical output of data. Five other physicians were randomly assigned to the control group and conducted their consultations as usual. Differences between groups on generic- and disease-specific HRQoL, patient management, and patient satisfaction with the consultation were assessed, as were physicians’ experiences with HRQoL data and effects on their consultations. Results No direct effect of the experimental condition on patients’ HRQoL was found. However, an interaction effect of the experimental condition and age was found: older patients in the experimental group had significantly better disease-specific HRQoL (F = 4.16; P = 0.04) and generic mental HRQoL (F = 4.62; P = 0.03) than patients in the control group. Also, male patients in the experimental group had better generic mental HRQoL than patients in the control group (F = 6.10; P = 0.02). Physicians in the experimental group altered their treatment policy significantly more often than did physicians in the control group (z = −3.73, P = 0.00), and their experiences with the availability of HRQoL information were generally positive. The scores on patient satisfaction with the consultation did not differ significantly between the experimental and control groups (z = −1.20, P = 0.23). Conclusions Computerized measurement and feedback of HRQoL in a daily clinical practice of an outpatient department of hepatology did not improve HRQoL for the entire group of chronic liver patients but, rather, improved disease-specific HRQoL of older patients with chronic liver disease and mental HRQoL of older patients and male patients with chronic liver disease. It also had an effect on patient management.     

Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis

In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis.     

A multicentre randomised clinical trial to evaluate the benefit of testing for thrombophilia following a first venous thromboembolism: the NOSTRADAMUS study

It is unknown whether testing patients for thrombophilia after a first episode of venous thromboembolism (VTE) and prolonging anticoagulant treatment in those with thrombophilia is justified. The NOSTRADAMUS trial, a multicentre randomised controlled trial, is being conducted to assess whether this strategy is beneficial in terms of clinical outcomes, quality of life and costs. Patients with a first VTE will be randomly assigned to one of two groups. The first group will be tested for thrombophilia and subsequently receive the test results; those in the second group will be tested but the results will not be disclosed. A total of 1336 patients will be included. Additional anticoagulant treatment for a predefined period will be initiated in patients found to have thrombophilia, while others will receive a standard predefined duration oftreatment. Primary outcomes are the risk of recurrent VTE, clinically important bleeding and the composite outcome of both. Other outcomes include overall quality of life and costs associated with outcome measures 18 months after the initial episode of VTE.     

Oral dietary supplements in pre- and postoperative surgical patients: a prospective and randomized clinical trial

It has been suggested that the routine provision of oral dietary supplements (ODS) in postoperative surgical patients is of benefit in terms of morbidity and length of hospital stay. The aim of this study was to evaluate the effects of both pre- and postoperative ODS in patients undergoing an elective laparotomy. Patients requiring elective major gastrointestinal surgery were prospectively randomized into one of four groups: Group I received ODS in addition to normal diet both pre- and postoperatively, Group II were given ODS in the preoperative period only, Group III received ODS only in the postoperative period, and Group IV did not receive any supplements. Assessments of nutritional status, voluntary food intake, weight loss, serum albumin, morbidity and mortality, anxiety and depression, and postoperative activity levels were performed, and comparisons made between the groups. One hundred patients were included in the study. The mean daily energy intake from preoperative ODS was 507 +/- 140 kcal, significantly more than the 252 +/- 195 kcal in the postoperative period (P < 0.001). The postoperative voluntary food intake in patients receiving ODS was not significantly different from that in patients receiving normal diet alone (1090 versus 1268 kcal, 46.2 versus 49.1 g protein, P > 0. 05). All groups demonstrated an overall weight loss, with no significant differences between the groups, and there was no demonstrable effect on clinical outcome. At 6 mo postoperatively there were no differences between the study groups in terms of levels of activity. These results suggest that the routine use of perioperative ODS in well-nourished patients undergoing major gastrointestinal surgery confers no clinical or functional benefit.     

Ixekizumab treatment and the impact on SF-36: results from three pivotal phase III randomised controlled trials in patients with moderate-to-severe plaque psoriasis

Quality of Life Research - To assess improvements in health-related quality of life (HRQoL) with ixekizumab treatment in patients with moderate-to-severe psoriasis. Adults with plaque psoriasis...     

Interpretation of Renal Quality of Life Profile scores in routine clinical practice: an aid to treatment decision-making

Purpose

High Renal Quality of Life Profile (RQLP) scores are associated with impaired health-related quality of life; however, the clinical meaning of the scores is difficult for clinicians and healthcare planners to interpret. The aim of this study was to determine clinical significance of RQLP scores which could be used to aid clinical decision-making.

Methods

The anchor-based technique (a method for categorizing numeric scores to ease interpretation) was used to develop a categorization system for the RQLP scores using a global question (GQ). The GQ scores (i.e. no effect to extremely large effect) were mapped against the RQLP scores, and intraclass correlation coefficient (ICC) was used to test their agreement. The RQLP and the GQ were administered to 260 adult patients (males = 165 and females = 95) with chronic renal failure (CRF).

Results

The mean RQLP score was 67.2, median = 61, SD = 41.5, and range 0–172. The mean GQ score was 1.74, median = 2, SD = 1.27, and range 0–4. The mean, mode, and median of the GQ scores for each RQLP score were used to devise several sets of categories of RQLP score, and the ICC test of agreement was calculated. The proposed set of RQLP score banding for adoption includes: 0–20 = no effect on patient’s life (GQ = 0, n = 35); 21–51 = small effect on patient’s life (GQ = 1, n = 66); 52–93 = moderate effect on patient’s life (GQ = 2, n = 87); 94–134 = very large effect on patient’s life (GQ = 3, n = 54); and 135–172 = extremely large effect on patient’s life (GQ = 4, n = 18). The ICC coefficient for the proposed banding system was 0.80.

Conclusion

The proposed categorization of the RQLP will aid the clinical interpretation of change in RQLP score informing treatment decision-making in routine practice.

     

A controlled time-series trial of clinical reminders: using computerized firm systems to make quality improvement research a routine part of mainstream practice

OBJECTIVE: To explore the feasibility of conducting unobtrusive interventional research in community practice settings by integrating firm-system techniques with time-series analysis of relational-repository data. STUDY SETTING: A satellite teaching clinic divided into two similar, but geographically separated, primary care group practices called firms. One firm was selected by chance to receive the study intervention. Forty-two providers and 2,655 patients participated. STUDY DESIGN: A nonrandomized controlled trial of computer-generated preventive reminders. Net effects were determined by quantitatively combining population-level data from parallel experimental and control interrupted time series extending over two-month baseline and intervention periods. DATA COLLECTION: Mean rates at which mammography, colorectal cancer screening, and cholesterol testing were performed on patients due to receive each maneuver at clinic visits were the trial's outcome measures. PRINCIPAL FINDINGS: Mammography performance increased on the experimental firm by 154 percent (0.24 versus 0.61, p = .03). No effect on fecal occult blood testing was observed. Cholesterol ordering decreased on both the experimental (0.18 versus 0.1 1, p = .02) and control firms (0.13 versus 0.07, p = .03) coincident with national guidelines retreating from recommending screening for young adults. A traditional uncontrolled interrupted time-series design would have incorrectly attributed the experimental-firm decrease to the introduction of reminders. The combined analysis properly indicated that no net prompting effect had occurred, as the difference between firms in cholesterol testing remained stochastically stable over time (0.05 versus 0.04, p = .75). A logistic-regression analysis applied to individual-level data produced equivalent findings. The trial incurred no supplementary data collection costs. CONCLUSIONS: The apparent validity and practicability of our reminder implementation study should encourage others to develop computerized firm systems capable of conducting controlled time-series trials.     

肠内营养对术后病人营养支持疗效的前瞻、随机、对照临床研究

目的 :观察肠内营养 (EN)、肠外营养 (PN)支持对维持或改善手术创伤后病人营养状态及肠粘膜屏障功能的影响。　方法 :选择腹部手术后需行营养支持的 6 0例成年病人随机进入EN组及PN组。两组营养支持均等热量、等氮量。分别于营养支持前、中、后检测营养状态指标及肠道粘膜通透性。营养支持期间每天测定氮平衡 ,并计算累计氮平衡。　结果 :①EN组体重、白蛋白、转铁蛋白高于PN组 ,但无显著差异。EN组前白蛋白、纤维连接蛋白在术后第 7、12天显著高于PN组 ;②EN组累计氮平衡为正氮平衡 ,而PN组为负氮平衡 ,二者之间差异非常显著 ;③研究期间EN组肠道通透性显著低于PN组。　结论 :与PN支持相比 ,EN可有效地改善术后病人的营养状态 ,促进肠粘膜屏障功能的恢复。     

Value of basic and intensive management of patients with heart failure; results of a randomised controlled clinical trial

OBJECTIVE: To determine the efficacy of 2 nurse-directed programmes of different intensity for the counselling and follow-up of patients hospitalised for heart failure, compared with standard care by a cardiologist. DESIGN: Multicentre randomised clinical trial (www.trialregister.nl: NCT 98675639). METHOD: A total of 1023 patients were randomized after hospitalisation for heart failure to 1 of 3 treatment strategies: standard care provided by a cardiologist, follow-up care from a cardiologist with basic counselling and support by a nurse specialising in heart failure, or follow-up care from a cardiologist with intensive counselling and support by a nurse specialising in heart failure. Primary end points were the time to rehospitalisation due to heart failure or death and the number of days lost to rehospitalisation or death during the 18-month study period. Data were analysed on an intent-to-treat basis. RESULTS: Mean patient age was 71 years, 38% were women, 50% had mild heart failure and 50% had severe heart failure. During the study, 411 patients (40%) were rehospitalised due to heart failure or died from any cause: 42% in the control group, and 41% and 38% in the basic and intensive support groups, respectively (differences not significant). The time to rehospitalisation or death was similar in the 3 groups: hazard ratios for the basic and intensive support groups versus the control group were 0.96 (95% CI: 0.76-1.21; p = 0.73) and 0.93 (95% CI: 0.73-1.17; p = 0.53), respectively. The number of days lost to rehospitalisation or death was 39,960 in the control group; this number was 15% less in the intervention groups, but the difference was not significant. However, there was a trend toward lower mortality in the intervention groups. In all 3 groups, more visits occurred than planned, which may have had a considerable effect on care, notably in the control group. CONCLUSION: The results of this study indicated that the provision of additional counselling and support by a nurse specialising in heart failure as an adjuvant to intensive follow-up care provided by a cardiologist does not always lead to a reduction in rehospitalisation frequency.     

Dietary treatment of rheumatoid cachexia with beta-hydroxy-beta-methylbutyrate, glutamine and arginine: a randomised controlled trial

BACKGROUND & AIMS: Rheumatoid arthritis (RA) is complicated by cytokine-driven alterations in protein and energy metabolism and consequent muscle wasting (cachexia). The aim of this randomised controlled trial was to investigate the efficacy of a mixture of beta-hydroxy-beta-methylbutyrate, glutamine and arginine (HMB/GLN/ARG) as nutritional treatment for rheumatoid cachexia. METHODS: Forty RA patients supplemented their diet with either HMB/GLN/ARG or a nitrogen (7.19 g/day) and calorie (180 kcal/day) balanced mixture of alanine, glutamic acid, glycine, and serine (placebo) for 12 weeks. Body composition and other outcomes were assessed at baseline and follow-up, and analysed by mixed ANOVA. RESULTS: Dietary supplementation with HMB/GLN/ARG was not superior to placebo in the treatment of rheumatoid cachexia (groupxtime interactions P>0.05 for all outcomes). Both amino acid mixtures significantly increased (main effect of time) fat-free mass (727+/-1186 g, P<0.01), total body protein (719+/-1703 g, P=0.02), arms (112+/-183 g, P<0.01) and legs (283+/-534 g, P<0.01) lean mass, and some measures of physical function. No significant adverse event occurred during the study, but patients in the HMB/GLN/ARG group reported fewer gastrointestinal complaints compared to placebo. CONCLUSIONS: Dietary supplementation with HMB/GLN/ARG is better tolerated but not more effective in reversing cachexia in RA patients compared to the mixture of other non-essential amino acids used as placebo. Further controlled studies are necessary to confirm the beneficial anabolic and functional effects of increased nitrogen intake in this population.     

Do clinical trials improve quality of care? A comparison of clinical processes and outcomes in patients in a clinical trial and similar patients outside a trial where both groups are managed according to a strict protocol

Background: The conventional view that participants in randomised controlled trials sacrifice themselves for the good of future patients is challenged by increasing evidence to suggest that individual patients benefit from participation in trials.

Objective: To test the hypothesis that trial participants receive higher quality care and, as a consequence, have better outcomes than patients receiving guideline driven routine care.

Methods: Retrospective comparative study of 408 women with pre-eclampsia all managed according to a strict protocol. Trial participants were 86 women who participated in a multicentre randomised controlled trial of magnesium sulphate for the treatment of pre-eclampsia (Magpie Trial); 322 non-participants formed the control group. Indicators of the process of care and clinical outcomes were compared between the two groups.

Results: Trial participants were significantly more likely to have received daily blood tests (odds ratio (OR) 6.82, 95% CI 1.62 to 28.72) and had their respiration rate measured hourly (OR 3.42, 95% CI 1.69 to 6.92) than control patients. There were no significant differences in other markers of clinical process and no significant difference in clinical outcomes.

Conclusion: This study shows minor differences in process markers and no difference in clinical outcomes between patients in a clinical trial and patients receiving protocol driven care. The benefits of improved clinical care that have previously been associated with being in a trial may be explained by the use of clear clinical protocols. In routine practice, patients may be well advised to insist on treatment as part of a protocol.

     

Breast screening: a randomised controlled trial in UK general practice of three interventions designed to increase uptake.

STUDY OBJECTIVES: To determine the relative effectiveness of three interventions designed to increase the uptake of breast screening. DESIGN: Randomised controlled trial of a nurse visit with health education (group A), nurse visit without health education (group B), and GP letter (group C). SETTING: The area of south east London served by the Butterfly Walk Breast Screening Unit in Camberwell. PARTICIPANTS: Women aged between 50 and 64 years who were registered with 27 GPs in the Lambeth, Southwark and Lewisham family health services authority and who had not attended for first round screening. MAIN RESULTS: Altogether 799 women were randomly allocated to the three groups. In general, delivering the nurse based interventions proved difficult. In group A, 11.4% (95% CI 7.9, 14.9%) of women subsequently attended for screening compared with 7.8% (95% CI 5.1, 11.4%) in group B and 13.1% (95% CI 7.9, 18.4%) in group C. The differences between the groups (95% CIs) were not statistically significant: A versus C, -1.7% (-8.0, +4.6%); B versus C, -5.3% (-11.3, +0.7%); A versus B, +3.6% (-1.0, +8.2%). CONCLUSIONS: A personal letter from the GP seems to be at least as effective at increasing the uptake of breast screening in non-attenders as a nurse making a home visit to discuss the issue of breast screening, and is not noticeably less effective than a visit at which a health education intervention is delivered. It is possible that the GP letter is considerably more effective than either of the two interview-based interventions. With regard to implementing strategies which will increase breast screening uptake and are cost effective, further trials of similar minimal interventions in primary care are required.