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.

     

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.     

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.     

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.     

Diagnostic yield of patient-activated loop recorders for detecting heart rhythm abnormalities in general practice: a randomised clinical trial

BACKGROUND: Because palpitations and light headedness often occur paroxysmally these complaints are difficult to diagnose. The hazards for a GP are too many diagnostic interventions for worried well and too few diagnostics for potentially life threatening complaints. OBJECTIVES: Patient-activated memo event recorders have proved to be successful in diagnosing episodes of cardiac arrythmias in secondary care. We tested the diagnostic yield of these devices in general practice. METHODS: A randomized clinical trial in general practice. Consecutive patients with complaints of palpitations or light-headedness were randomized to either usual care or usual care plus event-recorder. The main outcome was the difference in explained episodes. Secondary outcomes were the differences in the number and character of cardiac diagnoses and the feasibility of the event-recorder. RESULTS: There were fewer patients without a diagnosis in the intervention group (17% vs 38%; RR = 0.5, 95% CI 0.3 to 0.7) and more patients with a cardiac diagnosis (67% vs. 27%: RR 2.5, CI 1.8 to 3,5). More relevant cardiac arrhythmias were detected (22% vs 7%) with event recording than with usual care (RR 3.2, 95% CI 1.5 to 6.8). CONCLUSION: Patient-activated loop recorders are feasible and effective diagnostic tools in patients with palpitations or light-headedness in primary care. More research into patient characteristics and selection criteria is needed to fine-tune the use of these devices in primary care.     

Flexible selection of a single treatment incorporating short‐term endpoint information in a phase II/III clinical trial

Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short‐term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short‐term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.     

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.     

Adjusting for treatment selection in phase II/III clinical trials with time to event data

Phase II/III clinical trials are efficient two-stage designs that test multiple experimental treatments. In stage 1, patients are allocated to the control and all experimental treatments, with the data collected from them used to select experimental treatments to continue to stage 2. Patients recruited in stage 2 are allocated to the selected treatments and the control. Combined data of stage 1 and stage 2 are used for a confirmatory phase III analysis. Appropriate analysis needs to adjust for selection bias of the stage 1 data. Point estimators exist for normally distributed outcome data. Extending these estimators to time to event data is not straightforward because treatment selection is based on correlated treatment effects and stage 1 patients who do not get events in stage 1 are followed-up in stage 2. We have derived an approximately uniformly minimum variance conditional unbiased estimator (UMVCUE) and compared its biases and mean squared errors to existing bias adjusted estimators. In simulations, one existing bias adjusted estimator has similar properties as the practically unbiased UMVCUE while the others can have noticeable biases but they are less variable than the UMVCUE. For confirmatory phase II/III clinical trials where unbiased estimators are desired, we recommend the UMVCUE or the existing estimator with which it has similar properties.     

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.

     

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.     

Effects of two different glibenclamide dose-strengths in the fixed combination with metformin in patients with poorly controlled T2DM: a double blind, prospective, randomised, cross-over clinical trial

A double-blind, prospective, randomised, cross-over clinical trial was performed comparing a glibenclamide (G) 5.0 mg/metformin (M) 400 mg combination with a G 2.5 mg/M 400 mg formulation to evaluate whether a higher dose of glibenclamide was able to improve glycaemia in poorly controlled Type 2 diabetic patients. One hundred and ninety-eight patients with poorly controlled Type 2 diabetes mellitus were randomised to receive one of the two trial drugs for a first 3-month period, and were then assigned to the alternative combination for further 3 months. The starting dose (2 tablets/day, 30 min before breakfast and dinner) was to be up-titrated to 3 tablets/day when required. A standard dietary regimen was kept constant for the total trial duration. Fasting plasma glucose, HbA1c, C-peptide, insulin and lactate levels, haematology and blood chemistry were measured at the start/end of each cycle. Patients' self-assessment of the glycaemic profile (at fasting and 2 hr after the main meals) was performed weekly. Patients were constantly monitored for adverse events and episodes of hypoglycaemia, and all events were recorded. Decrease of mean fasting glucose levels measured in the first cycle was more pronounced in the group treated with G 5.0 mg/M 400 (p<0.01) compared to baseline, although the difference was not significant--no changes were observed in the second 3-month period. Results of patients' self-assessment of the glycaemic profile in the overall 6-month period show that the two trial drugs produced similar effects on fasting glucose, but the decrease of post-prandial glycaemic levels was markedly higher with G 5 mg/M 400 mg than with G 2.5 mg/M 400 mg at both main meals. A similar significant decrease (p<0.01) of HbA1c was observed in both sequence groups at the end of the first 3-month treatment period, and mean levels remained unchanged at 6 months. Drug-related adverse events were observed in 2 patients during treatment with G 2.5 mg/M 400 mg and in 5 with G 5 mg/M 400 mg, while 14 and 22 episodes of hypoglycaemia occurred with the two trial drugs, respectively (p=NS between treatments). Metformin-induced increases of lactate levels were similar in the two sequence groups. No differences between groups were found either in the number of up-titrated patients or in all the other laboratory parameters. In conclusion, the new combination containing 5-mg glibenclamide produced a greater improvement in post-prandial glycaemic control compared with the standard fixed doses, and resulted equally safe and well tolerated.     

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.