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At least 199 records · Page 11Linked to original sources
PubMed2001

Effects of the American College of Rheumatology systemic sclerosis trial guidelines on the nature of systemic sclerosis patients entering a clinical trial.

OBJECTIVES: To compare the systemic sclerosis (SSc) patients entered into the d-penicillamine trial with SSc patients entered into previous controlled SSc trials. It was hypothesized that the d-penicillamine trial patients, who conformed to the American College of Rheumatology (ACR) guidelines for clinical trials in SSc were different from patients entered into previous trials. METHODS: Patients entering a double-blind, randomized trial of low- vs high-dose d-penicillamine were described carefully and completely. Their characteristics were then compared with previously published data on SSc and its treatment. RESULTS: One hundred and thirty-four patients had early [mean duration 9.5 (s.d. 4.2) months], diffuse [skin score 21 (8)] disease. Organ involvement in the patients was as follows: pulmonary 54%, cardiac 20%, joints 38%, muscular 20%. Thirty-three per cent had mild proteinuria and 13% were hypertensive when first seen. Compared with patients in most previous studies, these SSc patients had earlier disease and uniformly had diffuse disease. They had less muscular involvement, less dyspnoea, less abnormal pulmonary function and less cardiac and less renal involvement than patients in earlier studies. CONCLUSIONS: The use of the new ACR guidelines for SSc trials may change the nature of patient populations entering future studies.

Adult↗
PubMed1980

Why does migraine improve during a clinical trial? Further results from a trial of cervical manipulation for migraine.

It is generally accepted that migraine is sensitive to intervention, whether in a treatment situation or in a clinical trial, and a "placebo effect" is often suggested. The influence of a number of non-specific therapeutic ingredients was examined in a recent six-month trial of cervical manipulation for migraine, and results of a 20-month follow-up are reported. During the trial migraine attacks reduced significantly by 28%, and reduced a further 19% up to the follow-up period. The possibility of a trial effect, whereby improvement might stem from circumstances of the trial, was dismissed as an explanation for improvement. There was some evidence to suggest that placebo influences made a slight contribution to improvement, with sex, social class and subjects' optimism about the therapist at the initial treatment being weakly associated with initial improvement. The possibility that improvement levels reflected spontaneous improvement in migraine symptoms is suggested. If this possibility proves valid, clinical trials assessing migraine therapies should be designed so as to consider the natural course of migraine. Degree of improvement at follow-up could be predicted clearly from degree of improvement during the treatment phase and from degree of improvement at the end of the trial. This appears to be important to manipulative therapists who appear to practise without the benefit of valid predictors of response to therapy.

Adolescent↗
PubMed1996

Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and Stroke t-PA Stroke Trial.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop on statistical approaches to analysis of acute stroke trials that have multiple pre-specified outcomes. An objective was to plan for statistical analysis of the NINDS t-PA Stroke Trial, a randomized, double-blind, placebo-controlled trial of recombinant tissue plasminogen activator (rt-PA) for patients with acute ischemic stroke. Treatment success was defined as a "consistent and persuasive difference" in the proportion of patients achieving favorable outcomes on the Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and National Institutes of Health Stroke Scale. The Data and Safety Monitoring Committee for the trial recommended this outcome because the committee did not believe that a positive result for a single outcome would provide sufficient evidence of efficacy. SUMMARY OF COMMENT: Workshop participants accepted the global test as a viable approach to testing the primary trial hypothesis. Clinician participants advocated categorizing outcomes as favorable/unfavorable, outcomes more clinically meaningful than continuous outcomes for evaluating a drug with potentially serious side effects. They agreed that a global test was appropriate for ischemic stroke when no single outcome is accepted. Hypothetical, special-case examples illustrate that highly correlated outcomes diminish the power of the global test. NINDS t-PA Stroke Trial data demonstrate the clinical interpretability of the global test. CONCLUSIONS: Workshop participants concluded that a global statistic should be used to test the trial's primary hypothesis accompanied by secondary tests of individual outcomes. Workshop participants recommended familiarizing the clinical/scientific community with the global approach.

Acute Disease↗
PubMed1997

International clinical trials of HIV vaccines: II. phase I trial of an HIV-1 synthetic peptide vaccine evaluating an accelerated immunization schedule in Yunnan, China.

A Phase 1, double-blind, placebo controlled trial was conducted in Longchuan County, China, to evaluate the safety and immunogenicity of a prototype HIV-1 synthetic peptide vaccine in a target population at risk for HIV infection, and to establish the infrastructure for future large-scale HIV vaccine efficacy trials. Subjects were randomly assigned to receive 100 microg or 500 microg of vaccine or alum placebo, and were given three injections at an accelerated 0, 1, and 2 month schedule. The vaccine was well tolerated with no significant local or systemic reactions observed in any subjects. Fifty-five percent (100 microg dose) and 64% (500 microg dose) of subjects who received the vaccine produced binding antibody to the immunogen as determined by ELISA. However, HIV-1 (MN) neutralizing antibody was detected in only 23% (3/13) of subjects with detectable HIV-1 specific binding antibody. It was concluded that this prototype HIV-1 synthetic peptide vaccine was well tolerated, safe and immunogenic, and that a 0, 1, 2 month schedule was not as effective in stimulating HIV-1 specific neutralizing antibodies compared with previous trials utilizing a 0, 1, 6 month schedule. Finally, this trial demonstrated that well-designed HIV vaccine trials can be performed at this clinical trials site in Yunnan, China, and that this site should be considered for conducting larger safety, immunogenicity and efficacy trials of candidate HIV vaccines.

AIDS Vaccines↗
PubMed2003

The assessment of the economic return from controlled clinical trials. A framework applied to clinical trials of colorectal cancer follow-up.

Clinical trials can be considered health interventions as their primary aim is to impact on the health of a population. Given that resources are scarce for both health care and health related research, trials could be designed such that they can be demonstrated to be cost-effective, i.e., the costs of conducting the trial are justified given the forecasted long-term benefits. We demonstrate how a model can be used to predict the cost-effectiveness of undertaking a clinical trial comparing alternative regimens of colorectal cancer follow-up. The model forecasts costs and survival under two scenarios, with and without conducting a clinical trial, with the outcome assessed in terms of years to payback for the clinical trial. The methodology shown can be used both to provide information on appropriate trial design and/or in prioritizing between potential trials.

Journal Article↗
PubMed2004

Attentional modulation of the human somatosensory evoked potential in a trial-by-trial spatial cueing and sustained spatial attention task measured with high density 128 channels EEG.

We investigated the modulation of the somatosensory evoked potential (SEP) elicited by mechanical stimuli in a spatial sustained attention and a spatial trial-by-trial cueing design by means of high density electrode array EEG recordings. Subjects were instructed to detect rare tactile target stimuli at the to-be-attended hand while ignoring stimuli at the other hand. Analysis of the SEP revealed a highly complex pattern of results. The P50 component was significantly increased for attended stimuli in the sustained attention as opposed to the trial-by-trial cueing condition. However, no difference in amplitude was found for attended as opposed to unattended stimuli. High density electrode array recordings revealed a centero-frontal N140 component (N140c), which preceded the parietal N140 (N140p) by about 20 ms. The N140c exhibited an attention effect in particular in the trial-by-trial spatial cueing condition. The N140p was significantly enlarged with attention across both experimental conditions, but a closer inspection demonstrated that this was mainly due to the great attention effect in the trial-by-trial spatial cueing condition. The late positive component (190-380 ms after stimulus onset) exhibited a significant attention effect in both experimental conditions. The present experiment provides evidence that the attentional modulation of the SEP is different when tactile as opposed to electrical stimuli were used and when only somatosensory stimuli are presented with no further sensory stimulation in other modalities. Furthermore, transient as opposed to sustained spatial attention affected various components of the SEP in a different way.

Adult↗
PubMed2003

Lack of midazolam-induced anxiolysis in the plus-maze Trial 2 is dependent on the length of Trial 1.

The influence of the first exposure length upon the effect of midazolam (MDZ) administration prior to the second exposure in the elevated plus-maze (EPM) was investigated. Drug-free rats were assigned to freely explore the EPM for 1, 2 or 5 min (Trial 1). Twenty-four hours later, each group was subdivided in two further groups, which were retested in the EPM for 5 min, 30 min after either saline or MDZ (1.5 mg kg(-1)) administration (Trial 2). The data showed that during Trial 2, the percentage of entries (%Open arm entries) and time spent in the open arms (%Open arm time) were decreased if rats were pre-exposed to the EPM for 2- or 5-min Trial 1, while the group submitted to 1-min Trial 1 length displayed decreased %Open arm time only. The anxiolytic effect of MDZ prior to Trial 2 was present in the group submitted to 1-min, impaired in the group submitted to 2-min and absent in the group submitted to 5-min Trial 1 length. Data are analyzed taking into account the emotional learning which underlies the exploratory behavior during the EPM Trial 2.

Animals↗
PubMed1994

Trial spacing and trial distribution effects in Pavlovian conditioning: contributions of a comparator mechanism.

A potential basis for trial spacing and trial distribution effects was investigated in rats. In Experiment 1, a conditioned stimulus (e.g., CS A) was trained with either massed (e.g., A---->A---->A) or spaced (e.g., A-->A-->A) trials. When trials were massed, brief exposure to the training context (a condition typical of massed training) impaired responding, whereas more extensive exposure to the context during or after training reduced this apparent massed trials deficit. In Experiment 2, different CSs were trained in either a massed (e.g., A-->A-->A--> B-->B-->B-->C-->C-->C) or a distributed (e.g., A-->B-->C-->A-->B-->C, etc.) manner. Trials massed in this sense resulted in impaired responding to the CS, and this impairment was attenuated by posttraining extinction of the context cues. Thus, trial distribution and apparent trial spacing effects are at least in part reversible deficits in performance rather than failures of learning.

Animals↗
PubMed2005

Trial-to-trial variability and its effect on time-varying dependency between two neurons.

The joint peristimulus time histogram (JPSTH) and cross-correlogram provide a visual representation of correlated activity for a pair of neurons, and the way this activity may increase or decrease over time. In a companion paper we showed how a Bootstrap evaluation of the peaks in the smoothed diagonals of the JPSTH may be used to establish the likely validity of apparent time-varying correlation. As noted in earlier studies by Brody and Ben-Shaul et al., trial-to-trial variation can confound correlation and synchrony effects. In this paper we elaborate on that observation, and present a method of estimating the time-dependent trial-to-trial variation in spike trains that may exceed the natural variation displayed by Poisson and non-Poisson point processes. The statistical problem is somewhat subtle because relatively few spikes per trial are available for estimating a firing-rate function that fluctuates over time. The method developed here decomposes the spike-train variability into a stimulus-related component and a trial-specific component, allowing many degrees of freedom to characterize the former while assuming a small number suffices to characterize the latter. The Bootstrap significance test of the companion paper is then modified to accommodate these general excitability effects. This methodology allows an investigator to assess whether excitability effects are constant or time-varying, and whether they are shared by two neurons. In data from two V1 neurons we find that highly statistically significant evidence of dependency disappears after adjustment for time-varying trial-to-trial variation.

Action Potentials↗
PubMed1998

Phosphorylation of mitogen-activated protein kinase by one-trial and multi-trial classical conditioning.

The pathway supporting the conditioned stimulus (CS) is one site of plasticity that has been studied extensively in conditioned Hermissenda. Several signal transduction pathways have been implicated in classical conditioning of this preparation, although the major emphasis has been on protein kinase C. Here we provide evidence for the activation and phosphorylation of a mitogen-activated protein kinase (MAPK) pathway by one-trial and multi-trial conditioning. A one-trial in vitro conditioning procedure consisting of light (CS) paired with the application of 5-HT results in the increased incorporation of 32PO4 into proteins detected with two-dimensional gel electrophoresis. Two of the phosphoproteins have molecular weights of 44 and 42 kDa, consistent with extracellular signal-regulated protein kinases (ERK1 and ERK2). Phosphorylation of the 44 and 42 kDa proteins by one-trial conditioning was inhibited by pretreatment with PD098059, A MEK1 (ERK-Activating kinase) inhibitor. Assays of ERK activity with brain myelin basic protein as a substrate revealed greater ERK activity for the group that received one-trial conditioning compared with an unpaired control group. Western blot analysis of phosphorylated ERK using antibodies recognizing the dually phosphorylated forms of ERK1 and ERK2 showed an increase in phosphorylation after one-trial conditioning compared with unpaired controls. The increased phosphorylation of ERK after one-trial conditioning was blocked by pretreatment with PD098059. Hermissenda that received 10 or 15 conditioning trials showed significant behavioral suppression compared with pseudo-random controls. After conditioning and behavioral testing, the conditioned animals showed significantly greater phosphorylation of ERK compared with the pseudo-random controls. These results show that the ERK-MAPK signaling pathway is activated in Pavlovian conditioning of Hermissenda.

Animals↗
PubMed2004

Clinical trials with moving targets: a commentary on a non-inferiority trial in testicular cancer.

Clinical trials in cancer often have several measures of outcome, such as recurrence, survival, and toxic effects of treatment, and it is rare that the same treatment will be better for all outcomes. Benefits and risks therefore need to be balanced against one another. Quantification of this trade-off is a particular issue in so-called equivalence and non-inferiority trials in which a very small loss in survival (affecting few patients) is frequently deemed acceptable for a very large gain in toxic effects (affecting many). For various reasons, views about this trade-off can change during a trial's progress. From our experience of a recent chemotherapy trial for advanced testicular cancer, we discuss the issues that investigators, statisticians, and data monitoring and ethics committees face when the factors that affect the trade-off change substantially during the course of a clinical trial. We show the value of structured questionnaires--completed by clinicians who participate in the trial--that elicit individual decision-making change-points (or ranges of equivalence) with respect to the primary outcome measure, and discuss their use in the design and monitoring of equivalence and non-inferiority trials.

Clinical Trials as Topic↗
PubMed2002

General practitioners' use of magnetic resonance imaging: an open randomized trial comparing telephone and written requests and an open randomized controlled trial of different methods of local guideline dissemination.

AIM: To determine the impact and cost-effectiveness of telephone versus written access to magnetic resonance imaging (MRI), and of different strategies for disseminating locally produced guidelines, upon requests by general practitioners (GPs) for knee and lumbar spine investigation. MATERIAL AND METHODS: Two sequential pragmatic open cluster-randomized trials were conducted within 39 general practices. The outcome measure in each trial was concordance of request with local guidelines. Trial 1: practices requested MRI by telephone or in writing. Trial 2: all practices received guidelines, plus either: a practice-based seminar, practice-specific audit feedback, both seminar and feedback, or neither. RESULTS: A total of 414 requests were assessed in the two trials. Trial 1: telephone access cost pound4.86 more per request but rates of concordant requests were equivalent (65%/64%: telephone/written). Trial 2: compared to the control group, costs per practice were pound1911 higher in seminar group, pound1543 higher in feedback group and pound3578 higher for those receiving both. Concordance was greater following the intervention (74% vs 65%; P < 0.05), but there was no difference between the four study groups. CONCLUSIONS: Method of access did not affect concordance. Written access was more cost-effective. Seminars and feedback were no more effective in modifying practice than guidelines alone, which was thus the most cost-effective option.

Chi-Square Distribution↗
PubMed2006

Factors that influence the applicability of sham needle in acupuncture trials: two randomized, single-blind, crossover trials with acupuncture-experienced subjects.

OBJECTIVES: In recent years the retractable type of sham needle has been anticipated to be a possible solution for masking patients in acupuncture research. However, this needle has been intended mainly for acupuncture-naïve subjects. The authors' goal in this study was to assess the validity of the retractable type of sham needle. METHODS: The authors conducted two randomized, single-blind, crossover trials with acupuncture-experienced subjects. Different acupuncture points were used in each trial (a LI-4 trial and a BL-23 trial). The subjects received two sessions of different stimulations in each trial. A Park Sham Needle was used in one session, a genuine acupuncture needle in the other. RESULTS: In the LI-4 trial, all of the 21 subjects (100%) felt penetration with the genuine needle, but only 7 of the 20 subjects (35%) felt a similar sensation with the sham needle (P=0.0002). Fifteen of the 21 subjects (71%) felt a dull sensation with the genuine needle, but only 4 of the 20 subjects (20%) felt a similar sensation with the sham needle (P=0.01). In the BL-23 trial, 14 of the 20 subjects (70%) felt penetration with the genuine needle and 10 of the 20 subjects (50%) felt "penetration" with the sham needle (P=0.39). Eight of the 20 subjects (40%) felt a dull sensation with the genuine needle and 2 of the 20 subjects (10%) did with the sham needle (P=0.109). CONCLUSIONS: Potential factors that influence the applicability of "placebo" needling include not only inter-tester variability but also the patient's knowledge and experience of acupuncture, acupuncture point selection, the visual impact of needling, and so on.

Acupuncture Therapy↗
PubMed2005

Guidelines for trials of behavioral treatments for recurrent headache, first edition: American Headache Society Behavioral Clinical Trials Workgroup.

Guidelines for design of clinical trials evaluating behavioral headache treatments were developed to facilitate production of quality research evaluating behavioral therapies for management of primary headache disorders. These guidelines were produced by a Workgroup of headache researchers under auspices of the American Headache Society. The guidelines are complementary to and modeled after guidelines for pharmacological trials published by the International Headache Society, but they address methodologic considerations unique to behavioral and other nonpharmacological treatments. Explicit guidelines for evaluating behavioral headache therapies are needed as the optimal methodology for behavioral (and other nonpharmacologic) trials necessarily differs from the preferred methodology for drug trials. In addition, trials comparing and integrating drug and behavioral therapies present methodological challenges not addressed by guidelines for pharmacologic research. These guidelines address patient selection, trial design for behavioral treatments and for comparisons across multiple treatment modalities (eg, behavioral vs pharmacologic), evaluation of results, and research ethics. Although developed specifically for behavioral therapies, the guidelines may apply to the design of clinical trials evaluating many forms of nonpharmacologic therapies for headache.

Behavior Therapy↗
PubMed1999

A trial to study the effect on breast cancer mortality of annual mammographic screening in women starting at age 40. Trial Steering Group.

OBJECTIVE: Although there is clear evidence from randomised trials of the effectiveness of mammographic screening in women over 50 in reducing mortality from breast cancer, the benefit of screening in younger women remains less certain. This paper describes a randomised controlled trial in progress to study the effect on breast cancer mortality of annual mammographic screening of women starting at age 40-41. SETTING: Screening centres of the NHS Breast Screening Programme. METHODS: In 1991 a national multicentre randomised controlled trial was set up by the United Kingdom Coordinating Committee on Cancer Research (UKCCCR). This trial (the "age" trial) aims at recruiting 195,000 women aged 40-41 such that 65,000 form a study group and the remaining 130,000 a control group. Women in the study group are invited for annual screening by mammography, and become eligible for the National Health Service Breast Screening Programme (NHSBSP) after age 50. Those in the control group are not offered any additional services, but will also join the national programme after age 50. All malignant breast histology in trial women is recorded. ANALYSIS: The principal method of evaluation will be the comparison of cumulative breast cancer mortality rates in the study and control groups; interim analyses of prognostic factors of breast cancers will also be possible. Additional NHS screening costs incurred owing to lowering the age of screening will be assessed as part of an economic evaluation. The amount of unscheduled screening occurring in the control group of the trial will also be assessed.

Adult↗
PubMed2004

The Society for Clinical Trials supports United States legislation mandating trials registration. Position paper.

The official position of the Society for Clinical Trials is to support legislation in the United States and internationally that mandates registration of all controlled clinicals trials at or before enrollment of the first participant. The major trial sponsor would be responsible for ensuring contribution of trial information. The mechanism for registering trials would be through research ethics review boards, and registration would be required for ethics approval and before trial initiation. Standardized data and a unique identification number would be available for each registered trial.

Controlled Clinical Trials as Topic↗
PubMed1992

The effect of adjuvant tamoxifen: the latest results from the Cancer Research Campaign Adjuvant Breast Trial. Cancer Research Campaign Breast Cancer Trials Group.

The CRC Adjuvant Breast Trial, launched in 1980 to repeat both the Nolvadex Adjuvant Trial Organisation tamoxifen trial and the Scandinavian trial of perioperative cyclophosphamide trial, randomised 2230 stage I or II early breast cancer patients in a 2 x 2 factorial design to investigate the benefits of a short course of perioperative cyclophosphamide or tamoxifen daily for 2 years. At a median follow-up of 7.8 years, no significant benefit is noted for perioperative cyclophosphamide, however the main effect analysis for adjuvant tamoxifen demonstrates a significant improvement in disease-free survival which increases with time over the follow-up period. These results are in keeping with the World Overview of Trials of Adjuvant Tamoxifen. However, this study is unique, having a large number of node negative patients and over 500 premenopausal women in a comparison of tamoxifen and control. The relative risk reductions for the node negative patients for disease-free survival are greater than for node positive patients. This might suggest that the absolute benefit for adjuvant tamoxifen is similar in both groups of patients, bearing in mind the increase risk of relapse with node positive patients. No trend for interaction emerges according to age or menopausal status suggesting an identical benefit for pre and postmenopausal women. Similar relative risk reductions are seen when the data are stratified according to tumour size, suggesting a similar positive benefit may be seen for all patients irrespective of tumour size. Of particular interest is the incidence of contralateral breast cancer, the initial overall effect which emerged at the third year of follow-up ceases to be apparent. However subgroup analysis according to menopausal status suggests a trend for interaction with a reduction in the risk of contralateral breast cancer in the postmenopausal women and a marginal increase in the risk of contralateral breast cancer in premenopausal women. Plausible mechanisms exist to explain this difference in outcome and these data need to be confirmed or refuted by other large trials of adjuvant tamoxifen especially at this time when the chemoprophylaxis of breast cancer in high risk premenopausal women by tamoxifen is being considered.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

The early termination of clinical trials: causes, consequences, and control. With special reference to trials in the field of arrhythmias and sudden death. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology.

The early termination of clinical trials, for either benefit or harm, often generates undue enthusiasm or alarm. The enhanced publicity attending early termination of a trial promotes inappropriate interpretations because of the inherent difficulty of a prompt and comprehensive data review. Furthermore, the process of monitoring the accumulating outcome data for early evidence of treatment benefit or harm is fraught with many statistical and methodological difficulties. This report from a Task Force convened by the Working Group on Arrhythmias of the European Society of Cardiology incorporates first, a series of trials terminated appropriately or inappropriately for benefit or harm and used as examples to illustrate the importance of suitable trial design and of proper stopping rules; second, a description of the committee structure of a clinical trial; third, an analysis of the general design issues; fourth, a review of the main issues in interim analysis with special reference to main strategies for reducing the rate of false-positive claims that could result from early trial termination; and finally, a series of specific recommendations concerning the design, structure, analysis, interpretation, and presentation of a clinical trial.

Anti-Arrhythmia Agents↗