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PubMed2006

Rationale and design of The Delphi Trial--I(RCT)2: international randomized clinical trial of rheumatoid craniocervical treatment, an intervention-prognostic trial comparing 'early' surgery with conservative treatment [ISRCTN65076841].

BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease, which affects 1% of the population. Hands and feet are most commonly involved followed by the cervical spine. The spinal column consists of vertebrae stabilized by an intricate network of ligaments. Especially in the upper cervical spine, rheumatoid arthritis can cause degeneration of these ligaments, causing laxity, instability and subluxation of the vertebral bodies. Subsequent compression of the spinal cord and medulla oblongata can cause severe neurological deficits and even sudden death. Once neurological deficits occur, progression is inevitable although the rapidity of progression is highly variable. The first signs and symptoms are pain at the back of the head caused by compression of the major occipital nerve, followed by loss of strength of arms and legs. The severity of the subluxation can be observed with radiological investigations (MRI, CT) with a high sensitivity. The authors have sent a Delphi Questionnaire about the current treatment strategies of craniocervical involvement by rheumatoid arthritis to an international forum of expert rheumatologists and surgeons. The timing of surgery in patients with radiographic instability without evidence of neurological deficit is an area of considerable controversy. If signs and symptoms of myelopathy are present there is little chance of recovery to normal levels after surgery. DESIGN: In this international multicenter randomized clinical trial, early surgical atlantoaxial fixation in patients with rheumatoid arthritis and radiological abnormalities without neurological deficits will be compared with prolonged conservative treatment. The main research question is whether early surgery can prevent radiological and neurological progression. A cost-effectivity analysis will be performed. 250 patients are needed to answer the research question. DISCUSSION: Early surgery could prevent serious neurological deficits, but may have peri-operative morbidity and loss of rotation of the head and neck. The objective of this study is to identify the best timing of surgery for patients at risk for the development of neurological signs and symptoms.

Adolescent↗
PubMed2004

Lessons for cluster randomized trials in the twenty-first century: a systematic review of trials in primary care.

BACKGROUND: Evidence suggests that cluster randomized trials are often poorly designed and analysed. There is little recent research on the methodologic quality of cluster randomized trials and none focuses on primary health care where these trials are increasingly common. METHODS: We conducted a systematic review of recent cluster randomized trials in primary health care, searching the Cochrane Controlled Trials Register. We also searched for unpublished trials in conference proceedings, and the UK National Research Register. We assess methodologic quality using a checklist, articulate problems facing investigators conducting these trials, and examine the extent to which carrying out a cluster randomized trial (as opposed to an individually randomized trial) in primary care may reduce power. RESULTS: We found 367 trial reports. Many trials were reported more than once. We characterize 152 independent cluster randomized trials in primary health care published between 1997 and 2000, and briefly describe 47 trials unpublished at December 2000. The quality of design and analysis was variable. Of published trials reporting sample size calculations 20% accounted for clustering in these calculations, 59% of published trials accounted for clustering in analyses. Unpublished trials were more recent and of higher quality. Reporting quality was better in journals reporting more cluster randomized trials. Many trial investigators reported problems with adherence to protocol, recruitment and type of intervention. CONCLUSIONS: Methodologic quality of cluster randomized trials in primary health care is variable and reporting needs improvement. The use of cluster randomization should be indicated in the title or abstract so these kinds of trials are easier to identify. Communicating appropriate methodology to health care researchers continues to be a challenge. Cluster randomized trials should always be piloted and information from pilots and unsuccessful trials shared more widely.

Cluster Analysis↗
PubMed2001

Does an HIV clinical trial information booklet improve patient knowledge and understanding of HIV clinical trials?

OBJECTIVES: To evaluate the impact of an information booklet on HIV clinical trials, Clinical Trials in HIV and AIDS: Information For People Who Are Thinking About Joining a Trial, in addition to the standard trial information (SI) on patients' knowledge; understanding and attitudes about clinical trials; and to investigate patients' motivations and reasons for enrolling or not enrolling in a clinical trial. METHODS: Fifty HIV-1 positive patients who attended the HIV clinic at a west London hospital were randomized to receive either SI alone (n = 27) or SI and a 16 page information booklet explaining the principles and procedures of HIV clinical trials (n = 23). A self-administered questionnaire was used at baseline to assess past experience and attitudes to clinical trials (10 questions), knowledge and understanding of HIV treatments (8 questions) and clinical trials (11 questions). At 2-6 months after randomization, a second interviewer-administered questionnaire addressed the patient's assessment of the usefulness and comprehensiveness of the information provided by the SI and information booklet, whether or not the patient had enrolled in a clinical trial and reasons for enrolling/not enrolling, knowledge of specific aspects of the trial protocol the patient was eligible to join (13 questions) and general knowledge of clinical trial procedures (repeat of 11 baseline questions). Changes in the attitudes and scores on knowledge and understanding of clinical trials were compared for the two groups. RESULTS: In both groups, patient knowledge of clinical trial procedures improved significantly over the study period. The median score increased from 30 at baseline to 35/44 at follow-up (SI only) vs. 24-31/44 (SI plus booklet), but this did not differ significantly between the two groups. However, knowledge of the specific trial protocol was poor [median score 13/25, interquartile range (IQR) 8-14], and there was no difference in the scores for the two groups. The prime motivations for joining a clinical trial were to benefit personal health and to gain access to new treatments. Potential side-effects were the main concern of prospective trial participants. CONCLUSIONS: This small trial shows that, while the patients' general knowledge and understanding of clinical trials improved over time, this was not improved by the information booklet and recollection of the details of the relevant trial protocol remained poor.

Adult↗
PubMed2005

Informed patient consent to participation in cluster randomized trials: an empirical exploration of trials in primary care.

Cluster randomized trials are increasingly common. Obtaining informed patient consent to participation in these trials raises practical challenges and ethical issues. The aims of this paper were to 1) develop a typology of interventions employed in cluster randomized trials in primary care; 2) assess whether the likelihood of seeking individual consent to participation varies by intervension type; 3) assess whether this likelihood has increased over time; 4) assess evidence for under reporting of consent procedures; 5) articulate reasons for not obtaining consent; and 6) make recommendations for future trial investigators. We collected data on trial interventions and consent procedures from reports of 152 recently published trials, and 47 unpublished trials. We develop a typology of interventions based on reasons for adopting a clustered design. We examine proportions seeking individual consent to participation among trials involving different types of intervention, in different periods, and among published and unpublished trials. Two-thirds of the trials had multifaceted interventions. Trials involving different types of intervention had different propensities to seek consent, largely because of practical obstacles to obtaining consent. Obtaining consent can compromise internal validity. More recent trials are no more likely to obtain consent than past trials. There was no evidence of under-reporting of consent procedures in publications. In conclusion, future trial investigators should consider both practical reasons and scientific arguments for not obtaining individual patient consent for all interventions in their trials. Where feasible, they should allow patients to opt out of the trial. Lay individuals should represent trial participants as part of the process of cluster consent to participation, and lay individuals could also be involved in considering ethical issues during trial planning. A more public debate may clarify the general acceptability of not obtaining consent in certain situations.

Biomedical Research↗
PubMed2006

Amphetamine and pentylenetetrazole given post-trial 1 enhance one-trial tolerance to the anxiolytic effect of diazepam in the elevated plus-maze in mice.

There are several hypotheses to explain the lack of an anxiolytic effect on animals with previous maze experience (one-trial tolerance). Some of these hypotheses are related to learning and memory, so the reduction of trial 1 duration to 1 min or amnesic drug administration before trial 1 prevents the lack of an anxiolytic effect in trial 2. Amphetamine and pentylenetetrazole have been shown to enhance memory consolidation when administered immediately after training. Thus, the aim of the present study was to evaluate the effect of amphetamine (1.0-3.0 mg/kg) or pentylenetetrazole (30.0 mg/kg), at putative memory-enhancing doses, on the effect of diazepam (2.5 mg/kg) in the elevated plus-maze trial 2 on mice exposed to a 1-min long trial 1. Mice were submitted to 1-min trial 1 in the elevated plus-maze immediately followed by drug treatment (saline, amphetamine, or pentylenetetrazole) and to elevated plus-maze trial 2 after 48 h. Animals were treated with vehicle or diazepam 30 min before trial 2. The results showed that post-trial 1 saline and 1.0 mg/kg amphetamine did not induce one-trial tolerance. On the other hand, 2.0 and 3.0 mg/kg amphetamine and 30 mg/kg pentylenetetrazole induced a lack of anxiolytic effect of diazepam on trial 2 even with 1-min trial 1 length. Furthermore, these data were not due to novelty exposure in trial 1 or to amphetamine treatment so that mice exposed to an activity chamber instead of the plus-maze (trial 1) and then immediately submitted to amphetamine treatment (2.0 mg/kg) did not show one-trial tolerance 48 h after trial 1. Taken as a whole, these data support the hypothesis that memory is involved in the lack of an anxiolytic effect in the elevated plus-maze trial 2.

Amphetamine↗
PubMed2001

Closeout of four phase II Vanguard trials and patient rollover into a large international phase III HIV clinical endpoint trial.

Large phase III clinical trials typically require many years of planning and preparation. During this time, proposed study methods and overall trial feasibility can be assessed in smaller pilot studies. However, the patients enrolled in these pilot studies are not routinely included in the larger study. In preparation for a multinational randomized clinical end point trial of interleukin-2 in HIV-infected patients, four phase II "Vanguard" studies were initiated. These Vanguard trials served to increase safety and surrogate marker data in diverse patient cohorts, increase clinical experience with the study medication, and identify the optimal dose of medication for the phase III trial. These trials also served to assess patient recruitment potential and to develop international clinical trial coordination experience. The Vanguard trials were designed to allow continued follow-up of their patients as participants of the phase III trial once the feasibility of the phase III trial was confirmed. The purpose of this paper is to describe the steps taken in the closeout of these four phase II trials while reconsenting these patients to the phase III trial. Specifically, the reconsent process, the data collection transition plan, and the steps taken to minimize bias due to differential reconsent according to the assigned treatment arm in the phase II trial are described. The procedures employed are relevant to the reconsent of patients for long-term follow-up at the completion of clinical trials. Control Clin Trials 2001;22:42-48

Adult↗
PubMed2001

Are randomized clinical trials good for us (in the short term)? Evidence for a "trial effect".

OBJECTIVE: To assess whether there is evidence that randomized controlled trials are systematically beneficial, or harmful, for patients. In other words, is there a "trial effect"? If so, to examine whether the evidence sheds light on the likely sources of the difference in outcomes. METHODS: Systematic review of the literature. RESULTS: We set out in some detail potential sources of a "trial effect" and potential biases. We found only 14 research articles (covering more than 21 trials) with relevant primary data. We extracted, with difficulty, quantitative data-sets from the articles, and classified these according to likely source of any apparent trial effect. The categories used were: differences in prognosis; superior treatment in the trial; and "protocol/Hawthorne effect" (benefit from improved routine care within a trial). ANALYSIS: The evidence available is limited in breadth (coming largely from cancer trials) and quality, as well as quantity. There is weak evidence to suggest that clinical trials have a positive effect on the outcome of participants. This does not appear to depend strongly on the trial demonstrating that an experimental treatment is superior. However, benefit to participants is less evident where scope for a "protocol/Hawthorne effect" was apparently limited (because there was no effective routine treatment or because the comparison group also received protocol care). A form of bias, arising if clinicians who tend to recruit to trials also tend to be better clinicians, could also explain these results. CONCLUSION: While the evidence is not conclusive, it is more likely that clinical trials have a positive rather than a negative effect on the outcome of patients. In the limited data available, the effect seems to be larger in trials where an effective treatment already exists and is included in the trial protocol. RECOMMENDATION: That carefully researched treatment protocols, and monitoring of outcomes, be used for all patients, not just those in trials.

Bias↗
PubMed2006

Who is blinded in randomized clinical trials? A study of 200 trials and a survey of authors.

BACKGROUND: Insufficient blinding of persons involved in randomized clinical trials is associated with bias. The appraisal of the risk of bias is difficult without adequate information in trial reports. PURPOSE: We wanted to study how blinding is reported in clinical trials and how lack of reporting relate to lack of blinding. METHODS: A cohort study of 200 blinded randomized clinical trials published in 2001 randomly sampled from the Cochrane Central Register of Controlled Trials, and a questionnaire survey of the trial authors. RESULTS: One-hundred and fifty-six (78%) articles described trials as 'double blind'. In three (2%) of such articles the blinding status of patients, health care providers and data collectors was explicitly described. Eighty-eight (56%) articles did not describe the blinding status of any trial person, and 41 articles (26%) reported no blinding relevant information at all beyond the trial being 'double blind'. One-hundred and thirty (65%) surveyed authors responded. Patients were blinded in 101 (97%) 'double blind' trials, and health care providers in 93 (89%). Twenty (19%) 'double blind' trials had not blinded either patients, health care providers or data collectors. Survey responders provided 15 different operational meanings of the term 'double blind', and typically felt that their preferred definition was the most widely used. LIMITATIONS: The proportions in the author survey may be too optimistic due to reporting bias. It is not known how the increased use of the CONSORT guidelines may have affected reporting in years after 2001. CONCLUSIONS: The blinding status of key trial persons was incompletely reported in most randomized clinical trials. Unreported blinding may be frequent, but one of five 'double blind' trials did not blind either patients, treatment providers or data collectors. Authors, referees, and journal editors could improve the completeness of reporting of blinding, eg, by adhering to the CONSORT statement. It is inappropriate to presume blinding of key trial persons based only on the ambiguous term 'double blind'.

Double-Blind Method↗
PubMed2001

Hypertension in the Very Elderly Trial (HYVET): protocol for the main trial.

A number of trials and meta-analyses have demonstrated clear benefits of blood pressure (BP) reduction in patients aged <80 years with regard to the reduction in stroke and cardiovascular events. However, a variety of studies have suggested that the positive relationship between BP and cardiovascular mortality is weakened or indeed reversed in the very elderly. Most intervention trials to date have either excluded or not recruited sufficient patients aged > or =80 years to determine whether there is a significant benefit from treatment in this age group. A meta-analysis of intervention trials that recruited patients aged > or =80 years has suggested a benefit in terms of stroke reduction but has also raised the possibility of an increase in total mortality. The benefit to risk ratio therefore needs to be clearly established before recommendations can be made for treating very elderly patients with hypertension. The Hypertension in the Very Elderly Trial (HYVET) pilot recruited 1283 patients aged > or =80 years and showed the feasibility of performing such a trial in this age group. It was a Prospective Randomised Open Blinded End-Points (PROBE) design but the main trial has additional pharmaceutical sponsorship to run a double-blind trial. Therefore, the main trial is a randomised, double-blind, placebo-controlled trial designed to assess the benefits of treating very elderly patients with hypertension. It compares placebo with a low dose diuretic (indapamide sustained release 1.5mg daily) and additional ACE inhibitor (perindopril) therapy if required. As in the pilot trial, the primary end-point is stroke events (fatal and non-fatal) and the trial is designed to determine whether or not a 35% difference occurs between placebo and active treatment. The main objective will be achieved with 90% power at the 1% level of significance. Secondary outcome measures will include total mortality, cardiovascular mortality, cardiac mortality, stroke mortality and skeletal fracture. 2100 patients aged > or =80 years are to be recruited and followed up for an average of 5 years. Entry BP criteria after 2 months of a single-blind placebo run-in period are a sustained sitting systolic BP (SBP) of 160 to 199mm Hg and a diastolic BP of 90 to 109mm Hg. The standing SBP must be >140mm Hg. The trial will be carried out in accordance with the principles of Good Clinical Practice. We describe in detail the protocol for the main trial and discuss the reasons for the changes from the pilot, the use of the drug regimen, and the BP criteria to be used in the trial.

Age Factors↗
PubMed2006

What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies.

BACKGROUND: A commonly reported problem with the conduct of multicentre randomised controlled trials (RCTs) is that recruitment is often slower or more difficult than expected, with many trials failing to reach their planned sample size within the timescale and funding originally envisaged. The aim of this study was to explore factors that may have been associated with good and poor recruitment in a cohort of multicentre trials funded by two public bodies: the UK Medical Research Council (MRC) and the Health Technology Assessment (HTA) Programme. METHODS: The cohort of trials was identified from the administrative databases held by the two funding bodies. 114 trials that recruited participants between 1994 and 2002 met the inclusion criteria. The full scientific applications and subsequent trial reports submitted by the trial teams to the funders provided the principal data sources. Associations between trial characteristics and recruitment success were tested using the Chi-squared test, or Fisher's exact test where appropriate. RESULTS: Less than a third (31%) of the trials achieved their original recruitment target and half (53%) were awarded an extension. The proportion achieving targets did not appear to improve over time. The overall start to recruitment was delayed in 47 (41%) trials and early recruitment problems were identified in 77 (63%) trials. The inter-relationship between trial features and recruitment success was complex. A variety of strategies were employed to try to increase recruitment, but their success could not be assessed. CONCLUSION: Recruitment problems are complex and challenging. Many of the trials in the cohort experienced recruitment difficulties. Trials often required extended recruitment periods (sometimes supported by additional funds). While this is of continuing concern, success in addressing the trial question may be more important than recruitment alone.

Journal Article↗
PubMed2004

Clinical trials in sub-Saharan Africa and established standards of care: a systematic review of HIV, tuberculosis, and malaria trials.

CONTEXT: The minimum standard of care required for participants in clinical trials conducted in resource-poor settings is a matter of controversy; international documents offer contradictory guidance. OBJECTIVE: To determine whether recently published trials conducted in sub-Saharan Africa met standards of care consistent with best current clinical standards for human immunodeficiency virus (HIV) treatment, tuberculosis treatment, and malaria prevention. DATA SOURCES: Trials published during or after January 1998 that were indexed at the time of the MEDLINE and Cochrane Controlled Trials Register Search (November 20, 2003). STUDY SELECTION: All randomized clinical trials that were conducted in sub-Saharan Africa in 3 clinical domains: HIV disease, tuberculosis treatment, and malaria prophylaxis. DATA EXTRACTION: To establish criteria for best current standards of care, evidence from the literature and published guidelines accepted for well-resourced settings were analyzed; the actual care offered in the trial was then compared with these standards. DATA SYNTHESIS: A total of 128 eligible articles described data from 73 different randomized clinical trials. Only 12 trials (16%) provided care that met guidelines to both intervention and control patients. Only 1 of the 34 trials that enrolled patients with HIV disease provided antiretroviral treatment that conformed to guidelines. Conversely, all tuberculosis treatment trials (n = 13, including 3 for HIV-infected patients) provided tuberculosis therapy that conformed to guidelines. Twenty-one (72%) of 29 malaria prophylaxis trials tested interventions that met guidelines, but only 3 (10%) used any active prophylactic intervention in the control group. Of the 59 trials (81%) that reported on the process of ethical review, all were reviewed by a host African institution and 64% were additionally reviewed by an institution in a developed country. CONCLUSIONS: Rates of adherence to established clinical guidelines of care in randomized clinical trials of HIV treatment, tuberculosis treatment, and malaria prophylaxis varied considerably between disease categories. In determining clinical standards for trials in sub-Saharan Africa, researchers and ethics committees appear to take the local level of care into account.

Africa South of the Sahara↗
PubMedDate not supplied

Breast cancer patients' attitudes toward clinical trials in the radiation oncology clinic versus those searching for trial information on the Internet.

Web-based clinical trials matching systems including breast cancer patients are expanding rapidly. However, limited data exist regarding the demographics and attitudes of breast cancer patients using the Internet to search for clinical trials information. Biases in patient populations could be introduced by recruiting patients to trials through the Internet. This study was designed to compare breast cancer patients in the radiation oncology clinic to those using the Internet to search for clinical trials information. A piloted questionnaire assessing demographics and attitudes regarding clinical trials was offered through the radiation oncology clinic at the University of Pennsylvania and on the OncoLink website (http://www.oncolink.org). The questionnaire consisted of 18 questions and was answered by a total of 157 patients with breast cancer. Breast cancer patients using the Web were more likely to be interested in clinical trials testing new drugs or therapies (71 [53%] versus 4 [17%], p = 0.002). More clinic patients indicated they would need a greater than 50% chance of benefiting from a trial (12 [52%] versus 33 [25%], p = 0.01) and a less than 10% potential for serious toxicity from a trial (15 [65%] versus 51 [38%], p = 0.02) for consideration of enrollment. African Americans were more likely than other races to have never used the Internet to search for cancer-related information (4 [40%] versus 18 [12%], p = 0.01), more likely to indicate that they need a greater than 50% chance of benefit to enroll in clinical trials (8 [80%] versus 37 [25%], p = 0.001), and less likely to be interested in clinical trials testing new drugs or therapies (1 [10%] versus 73 [50%], p = 0.01). Breast cancer patients have different attitudes regarding clinical trials based on race, Internet usage, and previous trial enrollment. Biases may be introduced with recruitment for clinical trials through the Internet. Radiation oncologists must consider these issues when offering clinical trials information through the Internet.

Breast Neoplasms↗
PubMed2004

The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.

BACKGROUND: In randomized trials there may be no overriding reason whether or not to have a placebo control. PURPOSE: We assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention. METHODS: We undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design. RESULTS: From 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85). CONCLUSIONS: We conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.

Aged↗
PubMed2004

Can clinical trials requiring frequent participant contact be conducted over the Internet? Results from an online randomized controlled trial evaluating a topical ointment for herpes labialis.

BACKGROUND: The Internet has tremendous appeal for conducting randomized clinical trials and may be especially applicable to trials requiring frequent participant contact. Trials of cold sore remedies, for example, often require daily clinic visits during outbreaks, imposing substantial burden on participants. An Internet-based randomized clinical trial design may reduce this burden, permitting frequent symptom reports with considerably less effort. OBJECTIVE: To evaluate the feasibility of a Web-based randomized clinical trial requiring frequent participant interaction, using a 6-month, double-blind, randomized, placebo-controlled pilot trial of a topical ointment containing dioctyl sodium sulfosuccinate (DSS) (Zilex; Meditech Pharmaceuticals, Inc, Scottsdale, Arizona, USA) intended for treatment of recurrent herpes labialis. A secondary objective was to obtain preliminary data on effectiveness outcomes, to assist in planning a fully-powered trial of DSS. METHODS: Adults with physician-confirmed herpes labialis were recruited to apply to the trial. Eligible applicants were randomized to DSS or placebo, mailed to them upon enrolment with instructions to apply topically every 2 hours for the duration of every cold sore outbreak. Participants were instructed to complete online questionnaires at 2-week intervals and, at the initiation of a cold sore, daily "outbreak questionnaires" until outbreak termination. Feasibility outcome measures included trial participant characteristics, frequency of cold sores, participant retention and adherence (to study medication), and data completeness. Treatment effectiveness outcome measures included outbreak duration, days to crust formation, and pain. RESULTS: Of the 292 individuals applying, 182 screened eligible; 32 participants with confirmed herpes labialis enrolled in the trial. 16 were randomized into the verum group and 16 into the placebo group. 29 (91%) participants completed the trial. During the trial, 34 outbreaks were reported among 23 (72%) participants, resulting in a cold sore incidence rate of 19.8 per 100 person-months of observation. Online data were available for 32 outbreaks; the absence of a resolution date made it impossible to accurately calculate the duration of 12 (38%) outbreaks. Although the DSS treatment group had a shorter mean outbreak duration (6.6 vs 7.7 days, P =.2) and fewer mean days to crust formation (3.5 vs 4.9, P =.1), these differences did not reach statistical significance. The DSS group has statistically significant lower mean pain scores (3.1 vs 7.6, P =.04), but participants in this group also consumed more acetaminophen tablets than the placebo group (1.1 versus 0.5, P=.55). Adherence to medication was similar in both groups: 7 (50%) of the verum group reported using the cream as directed compared to 6 (46.2%) in the placebo group; (P =.8). CONCLUSIONS: We efficiently recruited participants and achieved high overall retention rates. However, participant adherence to the daily outbreak visit schedules was low and only 7 (50%) participants used the cream as directed. These limitations could be addressed in future Internet-based studies by using Personal Digital Assistants (PDAs), using reminder devices, and providing incentives. By enhancing participant adherence, clinical trials requiring frequent participant contact may be feasible over the Internet.

Administration, Topical↗
PubMed2002

Trial-to-trial variability of cortical evoked responses: implications for the analysis of functional connectivity.

OBJECTIVES: The time series of single trial cortical evoked potentials typically have a random appearance, and their trial-to-trial variability is commonly explained by a model in which random ongoing background noise activity is linearly combined with a stereotyped evoked response. In this paper, we demonstrate that more realistic models, incorporating amplitude and latency variability of the evoked response itself, can explain statistical properties of cortical potentials that have often been attributed to stimulus-related changes in functional connectivity or other intrinsic neural parameters. METHODS: Implications of trial-to-trial evoked potential variability for variance, power spectrum, and interdependence measures like cross-correlation and spectral coherence, are first derived analytically. These implications are then illustrated using model simulations and verified experimentally by the analysis of intracortical local field potentials recorded from monkeys performing a visual pattern discrimination task. To further investigate the effects of trial-to-trial variability on the aforementioned statistical measures, a Bayesian inference technique is used to separate single-trial evoked responses from the ongoing background activity. RESULTS: We show that, when the average event-related potential (AERP) is subtracted from single-trial local field potential time series, a stimulus phase-locked component remains in the residual time series, in stark contrast to the assumption of the common model that no such phase-locked component should exist. Two main consequences of this observation are demonstrated for statistical measures that are computed on the residual time series. First, even though the AERP has been subtracted, the power spectral density, computed as a function of time with a short sliding window, can nonetheless show signs of modulation by the AERP waveform. Second, if the residual time series of two channels co-vary, then their cross-correlation and spectral coherence time functions can also be modulated according to the shape of the AERP waveform. Bayesian estimation of single-trial evoked responses provides further proof that these time-dependent statistical changes are due to remnants of the evoked phase-locked component in the residual time series. CONCLUSIONS: Because trial-to-trial variability of the evoked response is commonly ignored as a contributing factor in evoked potential studies, stimulus-related modulations of power spectral density, cross-correlation, and spectral coherence measures is often attributed to dynamic changes of the connectivity within and among neural populations. This work demonstrates that trial-to-trial variability of the evoked response must be considered as a possible explanation of such modulation.

Animals↗
PubMedDate not supplied

Enhancing cancer clinical trial management: recommendations from a qualitative study of trial participants' experiences.

Using a qualitative approach, a total of 55 adult patients with advanced cancer were interviewed to examine their perceptions of participating in early phase anti-cancer drug trials. Patients' views and experiences were explored, primarily through the use of in-depth interviews, with additional information accessed through two widely-used quality of life questionnaires, at the beginning of, during and after trial participation. The picture of trial participation established from this work suggests that it is a dynamic process, that has a different meaning and impact according to the stage of trial involvement the patient is experiencing. The findings identify how patients perceived the offer of the trial, dealt with the trial treatment, and came to terms with trial conclusion. The insight and understanding that this work provides in terms of the impact of trial involvement over time as well as details of patients' information, decision-making and support needs has significant implications for cancer clinical trial management. The recommendations put forward in this paper focus on acknowledging the contribution trial participants make to cancer research, enhancing the process of preparing patients for trial participation, recognizing the need for continuing care, the incorporation of patients and potential patients' views into the clinical trials system, and educating the public about clinical trials.

Adaptation, Psychological↗
PubMed1992

The Lipid Research Clinics Coronary Primary Prevention Trial. Results of 6 years of post-trial follow-up. The Lipid Research Clinics Investigators.

BACKGROUND: Participants in the Lipid Research Clinics Coronary Primary Prevention Trial, a randomized, cholesterol-lowering trial comparing cholestyramine (N = 1907) vs placebo (N = 1899) treatment in 35- and 59-year-old asymptomatic hypercholesterolemic men, conducted between 1973 and 1983, were followed up annually from 1985 until 1989. Post-trial treatment was not provided. METHODS: Eleven predefined hypotheses pertaining to possible benefits and adverse effects of in-trial cholestyramine treatment were tested by standard statistical comparisons of the two original Coronary Primary Prevention Trial treatment groups (cholestyramine and placebo). RESULTS: Similar increasing proportions of cholestyramine and placebo used cholesterol-lowering drugs post-trial. After 13.4 years of in-trial plus post-trial follow-up, there were 13 (143 vs 156) fewer deaths in the cholestyramine group than in the placebo group. Although not statistically significant, the mortality hazard ratio (0.89) was similar to that in other cholesterol-lowering trials. This trend, a result of reduced coronary heart disease mortality, occurred despite a post-trial narrowing of the in-trial cholestyramine-placebo difference in coronary heart disease incidence from 32 (155 vs 187) to 16 (268 vs 284). The cholestyramine and placebo groups had similar 13.4-year mortality rates from cancer, other medical causes, and trauma and similar cancer incidence rates. However, 13.4-year incidences of benign colorectal tumors (50 vs 34), cancer of the buccal cavity and pharynx (eight vs two), gallbladder disease (68 vs 53), and gallbladder surgery (58 vs 40) were nonsignificantly increased in the cholestyramine group. CONCLUSION: Overall, 6 years of post-Coronary Primary Prevention Trial follow-up have not provided conclusive evidence of benefit or long-term toxicity of cholestyramine treatment beyond that evident at the cessation of the trial.

Cause of Death↗