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Tremendous potential exists for the use of the randomized clinical trial (RCT) in veterinary clinical research. Understanding the fundamentals of RCT design not only benefits clinical researchers, but it can enhance the ability of practitioners to interpret published RCT reports. In this article, the essential components of RCT design and implementation are described using examples from clinical veterinary medicine.
Events of the past decade or so argue that there is little support in the literature for much of the specialty's treatment portfolio. The resulting call for 'evidence-based' treatment (not to mention the obvious intellectual bankruptcy of much of the clinical literature) has prompted many to argue that the randomized clinical trial (RCT) represents the future of orthodontic clinical investigation. The RCT, after all, is medicine's gold standard; what more is there to say? A popular, but ultimately divisive, corollary of this mimicry is the smug tendency to discount all other sources of data. In the face of a need for information, this attitude is also a wasteful conceit: in the end, the RCT can be applied only to a very narrow spectrum of orthodontic questions. Randomization implies equal susceptibility. Any prospective participant would have to be informed of this equality as part of the informed consent process. Unfortunately, it would be nearly impossible to enroll fully-informed subjects into any study whose alternatives are of markedly different morbidity: extraction versus non-extraction or orthodontics versus surgery. Thus, when measured against the most vexing clinical questions, the orthodontic RCT is almost by definition an amusing diversion--expensive, but relatively trivial in scope. Like it or not, it seems reasonable to conclude that most of the specialty's comparative clinical data will have to be generated by way of non-randomized designs in which care is taken to minimize the various known sources of bias. There probably is no other way.
The ability of temperature variants of influenza A2 virus to produce plaques in chick embryo kidney tissue culture was studied at different temperatures. Definite differences in efficiency of plaque formation by cryophilic and thermophilic strains were observed at low and high temperatures. Differentiation of the temperature variants appears to reside in a number of genetic markers, designated rct-40, rct-28, and plaque size (S). Virulence of influenza A2 virus, enhanced after prolonged cultivation at high temperature, is probably related to its greater efficiency of plating at 40 C (rct-40(+)), formation of larger plaques at optimal (36 C) and high (40 C) temperatures, and to loss of ability to form plaques at 28 C (rct-28(-)).
OBJECTIVE: To assess the feasibility of conducting a large randomised controlled trial (RCT) of peer led intervention in schools to reduce the risk of HIV/STD and promote sexual health. METHODS: Four secondary schools in Greater London were randomly assigned to receive peer led intervention (two experimental schools) or to act as control schools. In the experimental schools, trained volunteers aged 16-17 years (year 12) delivered the peer led intervention to 13-14 year old pupils (year 9). In the control schools, year 9 pupils received the usual teacher led sex education. Questionnaire data collected from year 9 pupils at baseline included views on the quality of sex education/intervention received, and knowledge and attitudes about HIV/AIDS and other sexual matters. Focus groups were also conducted with peer educators and year 9 pupils. Data on the process of delivering sex education/intervention and on attitudes to the RCT were collected for each of the schools. Analysis focused on the acceptability of a randomised trial to schools, parents, and pupils. RESULTS: Nearly 500 parents were informed about the research and invited to examine the study questionnaire; only nine raised questions and only one pupil was withdrawn from the study. Questionnaire completion rates were around 90% in all schools. At baseline, the majority of year 9 pupils wanted more information about a wide range of sexual matters. Focus group work indicated considerable enthusiasm for peer led education, among peer educators and year 9 pupils. Class discipline was the most frequently noted problem with the delivery of the peer led intervention. CONCLUSION: Evaluation of a peer led behavioural intervention through an RCT can be acceptable to schools, pupils, and parents and is feasible in practice. In general, pupils who received the peer led intervention responded more positively than those in control schools. A large RCT of the long term (5-7 year) effects of this novel intervention on sexual health outcomes is now under way.
The effects of long-term constant infusion of moderate doses (2-32 ng/h) of salmon calcitonin (sCT) on plasma Ca (and its radionuclide 45Ca), Pi, Mg, and on endogenous rat CT (rCT) metabolism were investigated in the rat. Daily variations were included. 1) The plasma concentrations of Ca and Pi fell and that of Mg increased transiently during infusion, with the duration of responses (1-3 days) depending on the sCT dose. Rats infused with 8 ng/h sCT remained sensitive to CT after 7 and 14 days, as indicated by the effects of minipump removal and of a bolus injection of exogenous sCT on plasma mineral concentrations. 2) In contrast to control rats, the well-established daily variations in plasma Ca and Pi levels were no longer observed after 7 and 14 days of sCT infusion (8 ng/h), but normal variations persisted for plasma Mg, circulating rCT, rCT mRNA, and rCT thyroid content. 3) Statistical analysis of plasma mineral data, collected at five sequential times during days 7 and 14, showed that the means were not significantly different and that the daily variations were essentially identical on days 7 and 14 in control rats. In contrast, the variability of measurements for plasma Ca and Pi, but not for Mg, increased significantly between days 7 and 14 in infused rats, and the mean differences were significantly lower in infused rats on day 7 than in control rats. These results are consistent with a transitory loss of the daily variations for Ca and Pi (day 7) and the later (day 14) spontaneous recovery of some variations in these parameters, although the individuals remain unsynchronized.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Preoperative radio-chemotherapy (RCT) may play an important role in decreasing local recurrence and possibly improving survival for patients with advanced rectal carcinoma. PATIENTS AND METHODS: Between 1995 and 1998 we treated 30 patients (pts) (median age 61.5 years) with advanced low rectal cancer. Radiotherapy was administered using a 10-MV linear accelerator delivering a total dose of 45 Gy to the pelvis over 5 weeks. 5-FU (500 mg/m2/d i.v.) was given concomitantly on days 1-3 and 29-31. Surgery was performed 2-4 weeks after RCT and included abdomino-perineal resection (APR) in 15 pts, anterior resection in 11 pts, transanal resection in 1 pt, and explorative laparotomy in 1 pt; 2 pts refused surgery. RESULTS: There were no serious toxicities associated with RCT. Mild to moderate transient radiation dermatitis was noted in 3 pts, and grade II diarrhea in 4 pts. Postoperative pathologic staging was as follows: no tumor found (CR): 4 pts, MAC B1 (T2N0M0): 5 pts, MAC B2 (T3N0M0): 17 pts, B3 (vaginal involvement): 1 pt, MAC C2 (T3N1M0): 2 pts, and MAC D: 1 pt. Necrosis and/or fibrosis was noted as a prominent histopathologic feature. CONCLUSION: Preoperative RCT in this series of 30 pts with advanced rectal cancer was well tolerated and associated with a high response rate (13% CR, 17% PR, 57% NC). 5-year overall survival was 70%, and 8-year survival was 58%.
BACKGROUND: Overexpression of human apolipoprotein (apo) A-II in transgenic mice induces high-density lipoprotein (HDL) deficiency, and increased atherosclerosis susceptibility only when fed an atherogenic diet. This may, in part, be caused by impairment in reverse cholesterol transport (RCT). METHODS AND RESULTS: [3H]cholesterol-labeled macrophages were injected intraperitoneally into mice maintained on a chow diet or an atherogenic diet. Plasma [3H]cholesterol did not differ from human apoA-II transgenic and control mice at 24 or 48 hours after the label injection. On the chow diet, human apoA-II transgenic mice presented increased [3H]cholesterol in liver (1.3-fold) and feces (6-fold) compared with control mice (P<0.05). The magnitude of macrophage-specific RCT did not differ between transgenic and control mice fed the atherogenic diet. CONCLUSIONS: Human apoA-II maintains effective RCT from macrophages to feces in vivo despite an HDL deficiency. These findings suggest that the increased atherosclerotic lesions observed in apoA-II transgenic mice fed an atherogenic diet are not caused by impairment in macrophage-specific RCT.
The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.
PURPOSE: To assess ocular and systemic safety and pharmacodynamic effects of the oral PKC beta selective inhibitor ruboxistaurin (RBX; LY333531) mesylate in patients with diabetes. METHODS: This was a double-masked, placebo-controlled, parallel, randomized, single-center clinical study evaluating the effect of oral administration of RBX (8 mg twice a day, 16 mg per day, or 16 mg twice a day) or placebo for 28 days in patients with no or very mild diabetic retinopathy on mean retinal circulation time (RCT), retinal blood flow (RBF), treatment-emergent adverse events, and other safety parameters. RESULTS: Twenty-nine persons aged 18 to 65 years with type 1 or 2 diabetes were evaluated. The only treatment-emergent adverse event with a statistically significant difference among treatment groups was abdominal pain, which was more common in placebo-treated subjects (P = 0.049). Statistically significant effects of RBX were observed on several hematologic and laboratory parameters, but values were within the normal reference range and none of the changes was deemed clinically meaningful. In patients receiving 16 mg RBX twice daily, the diabetes-induced increase in RCT was ameliorated, with a baseline-to-endpoint difference of -0.84 seconds (P = 0.046) relative to placebo. Increasing RBX dose was linearly associated with greater effect on RCT (P = 0.03). Similar results were observed with RBF. CONCLUSIONS: RBX was well tolerated at doses up to 16 mg twice daily for 28 days in patients with diabetes. It ameliorated diabetes-induced RCT abnormalities. No serious safety problems were identified in this patient population. Compared with prior published data, these findings represent the first direct human evidence of both bioavailability of RBX to retinal vessels and amelioration of diabetes-induced retinal hemodynamic abnormalities by an oral PKC beta inhibitor.
The objective of this review was to assess outcomes in trauma patients undergoing early tracheostomy (ET). Abstract databases for the Eastern and American Associations for the Surgery of Trauma and Medline were searched to find trauma patient studies comparing ET and late tracheostomy (LT) or ET and no ET. Fixed-effects meta-analyses were performed on the randomized controlled trial (RCT) studies. Of five retrospective and four RCT studies, none demonstrated survival benefit or harm with ET (P > 0.05). In five RCT studies of ET and no ET, ET pneumonia rates were similar to the no ET group (relative risk 1.00 [95% confidence intervals 0.88-1.15], P = 0.97). In five RCT studies of ET and no ET, ET ventilator/intensive care unit (ICU) days were similar to the no ET group (P = 0.27). In the two severe brain injury studies, ET ventilator/ICU days were lower than the no ET group (P = 0.06). In the three nonbrain injury studies, ET ventilator/ICU days were similar to the no ET group (P = 0.79). Five studies described similar laryngotracheal pathology rates with ET and no ET or LT (P > 0.05). In conclusion, ET has no influence on mortality, pneumonia, or laryngotracheal pathology rates in trauma patients. Patients with severe brain injury may be more rapidly liberated from mechanical ventilation with ET. However, additional research is needed.
Most health care initiatives are evaluated using observational study designs in lieu of randomized controlled trials (RCT) due primarily to resource limitations. However, although observational studies are less expensive to implement and evaluate, they are also more problematic in determining causality than the RCT. This trade off is most apparent in the initial planning stage of program development. An RCT is generally preferred though the cost of implementing a pilot program using the RCT might outstrip the potential benefit if the desired results are not obtained. This article describes a simple quasi-experimental model called the regression point displacement (RPD) design, which compares the prepost results of a single or multiple treatment groups to that of a control population. This design has shown great potential in evaluating health care pilot programs or demonstration projects-especially those that are community based-due to its relative ease of implementation and low cost of analysis.
In a retrospective review, the telemedical management of 65 outpatients from a randomized controlled trial (RCT) of telemedicine for non-urgent referrals to a consultant neurologist was compared with the management of 76 patients seen face to face in the same trial, with that of 150 outpatients seen in the neurology clinics of district general hospitals and with that of 102 neurological outpatients seen by general physicians. Outcome measures were the numbers of investigations and of patient reviews. The telemedicine group did not differ significantly from the 150 patients seen face to face by neurologists in hospital clinics in terms of either the number of investigations or the number of reviews they received. Patients from the RCT seen face to face had significantly fewer investigations but a similar number of reviews to the other 150 patients seen face to face by neurologists (the disparity in the number of investigations may explain the negative result for telemedicine in that RCT). Patients with neurological symptoms assessed by general physicians had significantly more investigations and were reviewed significantly more often than all the other groups. Patients from the RCT seen by telemedicine were not managed significantly differently from those seen face to face by neurologists in hospital clinics but had significantly fewer investigations and follow-ups than those patients managed by general physicians. The results suggest that management of new neurological outpatients by neurologists using telemedicine is similar to that by neurologists using a face-to-face consultation, and is more efficient than management by general physicians.
BACKGROUND: Early interventions proved to be able to improve prognosis in acute stroke patients. Prompt identification of symptoms, organised timely and efficient transportation towards appropriate facilities, become essential part of effective treatment. The implementation of an evidence based pre-hospital stroke care pathway may be a method for achieving the organizational standards required to grant appropriate care. We performed a systematic search for studies evaluating the effect of pre-hospital and emergency interventions for suspected stroke patients and we found that there seems to be only a few studies on the emergency field and none about implementation of clinical pathways. We will test the hypothesis that the adoption of emergency clinical pathway improves early diagnosis and referral in suspected stroke patients. We designed a cluster randomised controlled trial (C-RCT), the most powerful study design to assess the impact of complex interventions. The study was registered in the Current Controlled Trials Register: ISRCTN41456865--implementation of pre-hospital emergency pathway for stroke--a cluster randomised trial. METHODS/DESIGN: Two-arm cluster-randomised trial (C-RCT). 16 emergency services and 14 emergency rooms were randomised either to arm 1 (comprising a training module and administration of the guideline), or to arm 2 (no intervention, current practice). Arm 1 participants (152 physicians, 280 nurses, 50 drivers) attended an interactive two sessions course with continuous medical education CME credits on the contents of the clinical pathway. We estimated that around 750 patients will be met by the services in the 6 months of observation. This duration allows recruiting a sample of patients sufficient to observe a 30% improvement in the proportion of appropriate diagnoses. Data collection will be performed using current information systems. Process outcomes will be measured at the cluster level six months after the intervention. We will assess the guideline recommendations for emergency and pre-hospital stroke management relative to: 1) promptness of interventions for hyperacute ischaemic stroke; 2) promptness of interventions for hyperacute haemorrhagic stroke 3) appropriate diagnosis. Outcomes will be expressed as proportions of patients with a positive CT for ischaemic stroke and symptoms onset < or = 6 hour admitted to the stroke unit. DISCUSSION: The fields in which this trial will play are usually neglected by randomised controlled trial (RCT). We have chosen the cluster-randomised controlled trial (C-RCT) to address the issues of contamination, adherence to real practice, and community dimension of the intervention, with a complex definition of clusters and an extensive use of routine data to collect the outcomes.
BACKGROUND: The evidence base for improving reproductive health continues to grow. However, concerns remain that the translation of this evidence into appropriate policies is partial and slow. Little is known about the factors affecting the use of evidence by policy makers and clinicians, particularly in developing countries. The objective of this study was to examine the factors that might affect the translation of randomised controlled trial (RCT) findings into policies and practice in developing countries. METHODS: The recent publication of an important RCT on the use of magnesium sulphate to treat pre-eclampsia provided an opportunity to explore how research findings might be translated into policy. A range of research methods, including a survey, group interview and observations with RCT collaborators and a survey of WHO drug information officers, regulatory officials and obstetricians in 12 countries, were undertaken to identify barriers and facilitators to knowledge translation. RESULTS: It proved difficult to obtain reliable data regarding the availability and use of commonly used drugs in many countries. The perceived barriers to implementing RCT findings regarding the use of magnesium sulphate for pre-eclampsia include drug licensing and availability; inadequate and poorly implemented clinical guidelines; and lack of political support for policy change. However, there were significant regional and national differences in the importance of specific barriers. CONCLUSION: The policy changes needed to ensure widespread availability and use of magnesium sulphate are variable and complex. Difficulties in obtaining information on availability and use are combined with the wide range of barriers across settings, including a lack of support from policy makers. This makes it difficult to envisage any single intervention strategy that might be used to promote the uptake of research findings on magnesium sulphate into policy across the study settings. The publication of important trials may therefore not have the impacts on health care that researchers hope for.
BACKGROUND: Standardization of quality of life (QOL) assessment and reporting in clinical trials is an imperative issue. While English-speaking countries have led this movement in standardization, there persists to be a limited amount of information from non-English-speaking including Japan. In this study, we bibliographically analyze the reporting of randomized controlled trials (RCT) conducted in Japan that used a QOL instrument. METHODS: A PubMed search of reports published between 1970-2003 followed by an examination of QOL reporting and its frequency of use in RCTs published from Japan. RESULTS: Percentages of QOL reporting in RCTs have increased between 1970-2003 both worldwide (0% for 1970-1974 to 4.4% for 2000-2003) and in Japan (0% to 1.8% for the identical periods). We found and evaluated 46 RCT reports published from Japan (32 in English, 14 in Japanese). The most commonly studied clinical condition was cancer (26, 56.5%) and the most common intervention was drug therapy (29, 63.0%). QOL was used as the primary endpoint in 10 studies (21.7%). Authors used established QOL instruments in 12 studies (26.1%), developed original instruments in 8 studies (17.5%) and assessed the symptoms or performance status in 10 studies (21.7%). Authors conceptually defined QOL in only 6 studies (13.0%). Neither response rate nor number of respondents for questionnaire surveys was specified in 16 studies (34.8%); furthermore, 11 studies (23.9%) did not describe respondents' attributes. CONCLUSIONS: Findings on relative frequency suggested that Japanese authors of RCT reports have less interest in QOL instruments than other international researchers in Western Europe and North America. Examination of RCT reports published from Japan revealed that there were several points to be improved in reporting QOL instruments. This study highlights the need to define QOL measures specific to clinical specialty and to examine methodology for assessing and reporting QOL.
Available evidence suggests that both hydrostatic and osmotic forces are important in the development of acute respiratory distress syndrome (ARDS) or, more broadly, acute lung injury (ALI). More than 80% of ARDS patients in a large-scale randomized controlled trial (RCT) exhibited, at least intermittently, pulmonary artery wedge pressures (PAWP) above 18 mmHg. Retrospective analyses have shown that PAWP elevation is associated with increased mortality. Reduction in serum total protein (STP) has been shown, in a recent retrospective analysis of data from a sepsis patient population with a high frequency of ARDS, to be highly predictive of positive fluid balance, weight gain, development of ARDS, prolonged mechanical ventilation, and mortality. These findings suggest that therapy with diuretics and colloids might be of benefit in the prevention or treatment of ALI. A prospective RCT was designed and conducted to evaluate combination therapy with furosemide and albumin over a 5-day period in 37 ALI patients. Both mean serum albumin and mean STP increased promptly and substantially in furosemide + albumin recipients. The furosemide + albumin group also achieved a mean weight loss of 10 kg by the end of the treatment phase, and their weight loss exceeded that of placebo patients throughout. Hemodynamics improved in the treatment group during the 5-day protocol. Oxygenation, as assessed by the ratio between the fraction of inspired oxygen and the partial pressure of oxygen in arterial blood (PaO2/FiO2), was significantly higher within 24 h after commencement of treatment in the furosemide + albumin than the placebo group. No clinically important adverse effects of furosemide + albumin therapy were encountered. These results provide evidence that combined therapy with furosemide and albumin is effective in augmenting serum albumin and STP levels, promoting weight loss, and improving oxygenation and longer-term hemodynamic stability. Although mortality did not differ between groups, the RCT showed a trend toward reduced duration of mechanical ventilation and length of stay in the intensive care unit in patients receiving furosemide + albumin. The findings of the RCT further highlight the importance of both hydrostatic and osmotic forces in hypoxemic respiratory failure, a subject that requires further investigation.
Medullary thyroid carcinoma (MTC) cells synthesize large amounts of calcitonin (CT), which serves clinically as a useful tumor marker. To examine the possibility of CT serving as a target in immunotherapy for MTC, we raised and characterized more than 40 monoclonal antibodies (mAbs) against rat CT (rCT). The affinity constants for the mAbs were between 2.8 x 10(9) and 1.8 x 10(11) M(-1). Some mAbs react preferentially with solid phase rat CT, but not with liquid phase 125I-labeled rCT. Thirty-nine mAbs cross-react with human CT. We evaluated the antitumor effect of the mAbs in vitro by analysis of [3H]thymidine incorporation into the rat MTC cell line CRL-1607. Some antibodies show an antiproliferative effect, but most are inactive. One mAb (2E5G5, IgG2b), which preferentially reacts with solid phase rCT, but not with liquid phase 125I-labeled rCT, exerts an antiproliferative activity on CRL-1607. At 6.25 x 10(-7) M, 2E5G5 killed all of the tumor cells independently of complement in a cytotoxicity assay. We explored the cytotoxic mechanisms by assays for cell cycle arrest and DNA fragmentation. The antitumor effect was manifested by apoptosis and cell cycle arrest. Hence, a secreted peptide may serve as a target in tumor immunotherapy. Therapeutically antibodies may exert antitumor activity by a variety of mechanisms. The antitumor effect of this mAb in a rat animal tumor model is being tested.
We found eight randomized controlled trials (RCTs) of miscellaneous interventions that were designed to facilitate the process of weaning from mechanical ventilation. The two RCTs of high-fat/low-carbohydrate enteral nutrition found favorable physiologic effects on CO2 production and respiratory quotient, rendering this type of nutrition potentially useful in patients with impaired ventilatory reserve; however, no conclusions can be made about the outcomes of the duration of ventilation and weaning success. The two RCTs of postextubation use of noninvasive ventilation are conflicting, showing potential short-term physiologic benefit in one study, but no benefit in terms of reintubation rates or other morbidity. These RCTs are less promising than other applications of noninvasive ventilation such as those in patients with COPD exacerbations. One RCT showed no improvement in success of weaning with exogenous growth hormone administration. In the setting of very frequent baseline blood gas analyses, one RCT of oximetry and capnography was associated with significantly fewer blood gas analyses. Biofeedback to enhance safe and rapid weaning showed a dramatically lower duration of ventilation in one RCT that did not report the weaning methods used. One RCT of preextubation acupuncture showed lower rates of laryngospasm in the acupuncture group. Overall, these studies were underpowered for clinically important outcomes. Multidisciplinary, patient-centered, holistic, and non-pulmonary approaches to weaning may provide additional safe, effective adjunctive methods of hastening liberation from mechanical ventilation.