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PubMedDate not supplied

The Consolidated Standards of Reporting Trials (CONSORT): Guidelines for reporting randomized trials.

BACKGROUND: The rules for reporting the results of randomized controlled trials (RCTs) in published manuscripts have been elusive, and many nurse scientists have learned to write research reports by trial and error. APPROACH: New comprehensive guidelines for reporting RCTs are now available to authors, editors, and readers, a development that is likely to improve the quality of published reports. The Consolidated Standards of Reporting Trials (CONSORT) guidelines consist of two parts, a 22-item checklist and a flowchart template, that track the flow of all participants through the RCT. Currently, some journals, including Nursing Research, have adopted CONSORT and suggest or require its use in submitted manuscripts, but other journals do not. RESULTS: The CONSORT has potential to be useful beyond writing manuscripts. Because CONSORT is a comprehensive guide to essential elements of an RCT report, it also provides a useful guide for designing RCTs and writing funding proposals that include all the essential elements of a trial. It also could be a useful synopsis of important concepts when teaching research design to doctoral students. DISCUSSION: Reports of RCTs that use CONSORT are easier to read, interpret, and evaluate for relevancy to clinical practice. In addition, excellent reports of research increase the visibility of nursing research beyond our discipline. The CONSORT adds value to nursing research because researchers and readers alike will benefit if it is used more often.

Nursing Research↗
PubMed2006

A cost-effectiveness analysis of the intrapartum fetal pulse oximetry multicentre randomised controlled trial (the FOREMOST trial).

OBJECTIVE: To report an economic analysis of the Australian intrapartum fetal pulse oximetry (FPO) multicentre randomised controlled trial (the FOREMOST trial), which examined whether adding FPO to conventional cardiotocographic (CTG) monitoring (intervention group) was cost-effective in reducing operative delivery rates for non-reassuring fetal status compared with the use of CTG alone (control group). DESIGN: Cost-effectiveness analysis of the FOREMOST trial. SETTING: Four Australian maternity hospitals, each with more than 4000 births/year. POPULATION: Women in labour at > or =36 weeks of gestation, with a non-reassuring CTG. METHODS: Costs were for treatment-related expenses, incorporating diagnosis-related grouping costs and direct costs (including fetal monitoring). Incremental cost-effectiveness ratio (ICER) and cost-effectiveness plane were calculated, and sensitivity analysis was conducted. The primary outcome was that of the clinical trial: operative delivery for non-reassuring fetal status avoided in the intervention group relative to that in the control group. MAIN OUTCOME MEASURES: The ICER. RESULTS: The ICER demonstrated a saving of $A813 for each operative birth for non-reassuring fetal status averted by the addition of FPO to CTG monitoring compared with the use of CTG monitoring alone. CONCLUSION: The addition of FPO to CTG monitoring represented a less costly and more effective use of resources to reduce operative delivery rates for non-reassuring fetal status than the use of conventional CTG monitoring alone.

Adult↗
PubMed1991

Clinical trials in Alzheimer's disease. A report from the Medical Research Council Alzheimer's Disease Clinical Trials Committee.

Recent advances in Alzheimer's disease imply a need for adequate clinical trials of new treatments which require careful design. The disorder is progressive and shows clinical heterogeneity. While large-scale trials of elderly subjects are appropriate in relation to assessment of drugs or other treatments designed to prevent progression of the disorder, the outcome measurements in such biological treatment trials require careful planning. Studies of individual patients are relevant for answering certain specific questions. Relatively short cross-over trial designs may be appropriate to some pharmacological studies. The choice of neuropsychological instruments for measuring change is critically important, particularly in excluding test/retest artefact and in avoiding floor and ceiling effects. Test scales designed for assessment of specific neuropsychological deficits, or forming part of standard IQ assessments are unlikely to prove robust. Tests can be selected and developed for individual patients, but generalisation of the results of such experiments to the disease as a whole is not inevitable. There is a need to develop psychological instruments for measuring change that are robust and relevant to the clinical problem of progressive dementia.

Aged↗
PubMed2000

The future of clinical trials in chronic renal disease: outcome of an NIH/FDA/Physician Specialist Conference. Evaluation of Clinical Trial Endpoints in Chronic Renal Disease Study Group.

For people with chronic renal insufficiency, the therapeutic goal is to prevent progression to end-stage renal disease, a serious condition that can only be treated with dialysis and kidney transplantation. Although restriction of dietary protein slows the progression of renal disease somewhat, the principal treatment to slow chronic renal disease is appropriate reduction of blood pressure. Antihypertensive agents, particularly those that produce sustained, long-term reductions in proteinuria, such as angiotensin-converting enzyme inhibitors, not only decrease blood pressure but also preserve renal function. Clinical trials to evaluate these and other drug therapies in renal disease progression have used both "hard end points" (e.g., dialysis, transplantation, death) and intermediate end points of renal disease progression (e.g., doubling of serum creatinine concentration, reductions in proteinuria). Trials that have used hard end points typically recruited patients with advanced renal disease to demonstrate a difference in therapies within a period of 2 to 5 years. However, proteinuria reduction, along with a decrease in the time to doubling of serum creatinine in very early diabetic renal disease, could demonstrate an altered natural history of renal disease. Although hard end points are indicators of a drug's efficacy in reducing cardiovascular events or preserving renal function, they do not assess the impact of a treatment on altering the natural history of early renal disease. For clinical trials of people with all but the most advanced renal disease, use of intermediate end points of renal disease progression is the only practical option for assessment of treatment efficacy and effectiveness. Given the available data on proteinuria reduction and doubling of serum creatinine from clinical trials, these end points, taken together, appear to provide an acceptable means of assessing a treatment's impact on slowing renal disease progression.

Antihypertensive Agents↗
PubMed2006

Clinical trial design issues: at least 10 things you should look for in clinical trials.

Randomized controlled trials remain the gold standard study design and yield the highest level of scientific credence. However, recognition of the limitations of the randomized controlled trial is important. This review highlights 10 potentially problematic areas one should carefully assess when performing or reading an article reporting the results of a randomized controlled trial, problematic areas that can affect the outcome of the trial and therefore mislead the reader. These areas include ethical issues, eligibility criteria, masking (blinding), randomization, analytic methods, the selection of subjects for the interventional and comparison groups, selection of end points, and the interpretation of the results. Each of these is discussed, and examples of published articles are used to highlight the main points.

Ethics, Research↗
PubMedDate not supplied

Confounders in rehabilitation trials of task-oriented training: lessons from the designs of the EXCITE and SCILT multicenter trials.

Two multicenter randomized clinical trials (MRCT), the Extremity Constraint Induced Therapy Evaluation (EXCITE) to improve upper extremity function after stroke and the Spinal Cord Injury Locomotor Trial (SCILT) to enable functional walking after incomplete spinal cord injury, demonstrate that complex, task-oriented physical therapies can be studied using a scientific methodology during inpatient or outpatient rehabilitation. In the past, a new therapy's benefit may have been overestimated by comparing it to no treatment or to a conventional treatment at a low intensity of practice. Sample sizes were often too small and may have failed to detect the efficacy of a new intervention. In addition, whereas statistical significance in outcomes has been critical to understanding whether one treatment is better than another, the clinical significance of outcomes must also impact the interpretation of the results of a trial. MRCT designs will continue to improve through attention to the limitations of preclinical animal models that offer a conceptual basis for the treatment, [corrected] from enrichment strategies at every phase of trial development, [corrected] from more vigorous dose-response studies using adaptive methods, [corrected] by capturing interim measures of behavior and functional neurophysiologic adaptations during the treatment phase, [corrected] by aiming for a clinically meaningful control intervention, [corrected] and by including ratio or interval outcome measures when feasible that capture a target of the intervention in relation to gains in daily functioning and quality of life.

Humans↗
PubMed2007

Protocol for the smoking, nicotine and pregnancy (SNAP) trial: double-blind, placebo-randomised, controlled trial of nicotine replacement therapy in pregnancy.

BACKGROUND: Smoking in pregnancy remains a public health challenge. Nicotine replacement therapy (NRT) is effective for smoking cessation in non-pregnant people, but because women metabolise nicotine and cotinine much faster in pregnancy, it is unclear whether this will be effective for smoking cessation in pregnancy. The NHS Health Technology Assessment Programme (HTA)-funded smoking, nicotine and pregnancy (SNAP) trial will investigate whether or not nicotine replacement therapy (NRT) is effective, cost-effective and safe when used for smoking cessation by pregnant women. METHODS/DESIGN: Over two years, in 5 trial centres, 1050 pregnant women who are between 12 and 24 weeks pregnant will be randomised as they attend hospital for ante-natal ultrasound scans. Women will receive either nicotine or placebo transdermal patches with behavioural support. The primary outcome measure is biochemically-validated, self-reported, prolonged and total abstinence from smoking between a quit date (defined before randomisation and set within two weeks of this) and delivery. At six months after childbirth self-reported maternal smoking status will be ascertained and two years after childbirth, self-reported maternal smoking status and the behaviour, cognitive development and respiratory symptoms of children born in the trial will be compared in both groups. DISCUSSION: This trial is designed to ascertain whether or not standard doses of NRT (as transdermal patches) are effective and safe when used for smoking cessation during pregnancy.

Adolescent↗
PubMed2004

A randomized trial of recruitment methods for older African American men in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

BACKGROUND: Incidence rates for many types of cancer are higher among African American men than in the general population, yet African American men are less likely to participate in cancer screening trials. This paper describes the outcomes of a randomized trial (the AAMEN Project) designed to recruit African American men aged 55-74 years to a prostate, lung and colorectal cancer screening trial. METHODS: The recruitment interventions address four types of barriers to clinical trial participation: sociocultural barriers, economic barriers, individual barriers and barriers inherent in study design. Subjects were randomized to a control group or one of three increasingly intensive intervention arms, which used different combinations of mail, phone and in person church-based recruitment. RESULTS: Of the 39,432 African American men residing in the geographically defined study population (southeastern Michigan and northern Ohio), 17,770 men (45%) could be contacted, and 12,400 (31% of 39,432) were found to be eligible to participate. No statistically significant differences in age, education or income level were found among participants in the four study arms. A significantly greater enrollment yield (3.9%) was seen in the most intensive, church-based intervention arm, compared to the enrollment yields in the other two intervention arms (2.5 and 2.8%) or the control group (2.9%) (P < 0.01). CONCLUSIONS: The intervention that involved the highest rate of face-to-face contact with the study participants produced the highest enrollment yield, but several strategies that were thought could improve yield had no effect. These findings, which are consistent with current literature on population-based recruitment, should facilitate the development of future recruitment efforts involving older African American men.

Black or African American↗
PubMed2005

Microbiologic surrogate end points in clinical trials of infectious diseases: example of acute otitis media trials.

Clinical outcomes that measure how patients feel, function, or survive are the most important and relevant outcomes of therapy in clinical trials and in clinical practice. Surrogate end points, which do not directly measure clinical benefit to the patient, may function as substitutes for clinical end points in clinical trials. Such surrogates are attractive as they may allow measurement of outcomes earlier in time or with a smaller sample size than with clinical outcomes. Microbiologic biomarkers, such as culture results at a specific time after start of therapy, or pharmacodynamic analyses of the effect of drugs on organisms often are proposed as surrogate end points in clinical trials of therapies for infectious diseases. However, evaluation of biomarkers as surrogate end points poses distinct challenges, and only a few biomarkers have been useful replacements for clinical end points. Evaluation of biomarkers as potential surrogate end points first requires an understanding of the differences among measurements of the cause of a disease, risk factors for outcome, and measurements of treatment effects. We will discuss the definitions of clinical and surrogate end points and the reasons why surrogate end points may not predict the true clinical benefit of therapies. We will use the example of the biomarker of microbiologic outcomes from tympanocenteses performed during therapy as the sole measure of clinical effectiveness in clinical trials of acute otitis media to illustrate the challenges in evaluating biomarkers as surrogate end points.

Acute Disease↗
PubMed2000

Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: practical issues and specific cases.

Placebo controls are commonly used in clinical trials of investigational treatments because they have important advantages. In recent years, some have criticized the use of placebo-controlled trials when effective alternative therapy exists, regardless of the expected effect of the therapy. In part 1 of this paper, ethical arguments are addressed and the interpretive problems inherent in the use of active-control equivalence trials to establish efficacy of a new treatment are clarified. However, uncertainties may complicate decisions about appropriate use of placebo controls in some situations. Part 2 discusses more fully the ethical considerations for using placebo controls in particular medical settings. The value and relevance of placebo-controlled trials of new agents in situations in which proven effective therapy is available are also explored.

Controlled Clinical Trials as Topic↗
PubMed2001

Placebo-controlled clinical trials in multiple sclerosis: ethical considerations. National Multiple Sclerosis Society (USA) Task Force on Placebo-Controlled Clinical Trials in MS.

The availability of partially effective therapies for some forms of multiple sclerosis (MS) raises practical and ethical issues for future placebo-controlled clinical trials. An international Task Force of clinicians, statisticians, ethicists and regulators was convened to discuss these issues and develop consensus. The Task Force concluded that placebo-controlled clinical trials in forms of MS for which partially effective therapies exist were ethical, so long as study subjects were fully apprised of the availability of such therapies and were encouraged to pursue them outside of a clinical trial. Patients who decline to utilize available treatments, after proper education and counseling, or those that fail all therapies can be considered to have no treatment alternatives and thus may participate in a placebo-controlled trial.

Ethics, Medical↗
PubMed2002

[Multicenter clinical trial of angiotensin receptor blocker in patients with chronic heart failure: review of recent clinical trial].

Angiotensin receptor blocker(ARB) is expected to be a substitute of ACE inhibitor for ACE inhibitor(ACEi) incompetent patient or an additive drug for the treatment of severe heart failure. Two large mega-trials(ELITE II & Val-HEFT) have been reported so far and one large trial(CHARM) is ongoing. In ELITE II study, there was no additional beneficial effects of ARB compared to ACEi(captopril). On the other hand, additive ARB may be beneficial for most of patients with heart failure, according to the Val-Heft trial. However, some adverse effects of ARB by the combinatory use with ACEi and beta-blocker should be taken into careful consideration. Ongoing CHARM trial may answer if ARB is ultimately useful for the treatment of heart failure.

Aged↗
PubMed2003

[The Ditrame (ANRS 049) clinical trial aimed at reducing the mother-child transmission of HIV in Abidjan. Participants' understanding of the trial principles].

OBJECTIVE: The HIV vaccine attempts in developing countries have underlined many ethical questions on the informed consent of the participants. These problems have already been encountered in the context of studies on the prevention of mother-child transmission (MCT) of HIV in Africa. This study is aimed at describing the level of understanding and interpretations that these women have of the clinical trial, randomisation and placebo, as well as their motivations for participating in the study. METHODS: This was a qualitative study conducted in 1997 by a sociologist in the form of in-depth, structured interviews among 57 women participating in a clinical trial on the prevention of MCT of HIV. The interview included a section on the representation of MCT then questions on the eventual sharing of information concerning the HIV-infection status, the motivations for participating in the study and the understanding of the randomIsation and the placebo. RESULTS: Nearly half of the women had not shared the result of their blood test with anyone. Their isolation enhanced the difficulties in getting information on the study. The notion of a probability of transmission was not easy to explain in terms adapted to the level of education of the women. The randomisation was understood as a number pulled out of a hat during a lucky draw. The women did not really understand the pictures used to describe the placebo. They claimed that they wanted to participate in the study essentially to protect their child and to have access to treatment. CONCLUSION: The correct information of patients participating in clinical trials requires repeated interventions throughout the research period. When there is no social protection, the notion of freedom of choice itself, including the idea of informed consent, is relative and the pragmatic choices made by the women clearly show this. These elements must be taken into consideration in the projects of vaccination trials.

AIDS Vaccines↗
PubMed1983

Efficacy of and errors in randomized multicenter trials. A review of 230 clinical trials.

An attempt was made to study the efficacy in and one of the errors of randomized multicenter clinical trials. Efficacy was defined for the present purpose as a statistically significant clinical difference between at least 2 of the treatment arms studied. The error studied was defined here as non-excluded protocol deviations found during a systematic record review. The nature (multicenter randomized trial or un-controlled pilot study) of 8 so-called "breakthrough" studies which seemed particularly important for future cancer treatment was also established. The number of yearly randomized trials seems to have increased by a factor of 10 between 1969 and 1981, as judged by the abstracts published by the American Society of Clinical Oncology. 23% yielded statistically significant results, which is 18% over the 5% expected chance significances. Of 174 papers and abstracts published by one group, only 18 were reviewable original studies. The corresponding figures for another group was 6 of 22. This explains why only 8 scientifically new statistical significances were found in one series of 76 original articles. The mean dose of cytostatics actually given to 192 breast cancer patients varied, as judged by a record review, between 71 and 93% of the protocol doses. These figures agree with the 15-30% of nonexcluded protocol deviations found previously. Of the 8 "breakthrough" studies, 7 were single center pilot studies without randomized controls, and only 1 was a randomized multicenter study. It is suggested that more relevant questions can be asked in multicenter randomized clinical trials if they are based on promising single center pilot results, and that record reviews should be performed so that protocol deviations can regularly be reported.

Antineoplastic Agents↗
PubMed1994

The interferon-beta 1b clinical trial and its implications for other trials.

This trial was monitored by both clinical and magnetic resonance imaging (MRI) methods. Clinical effect was a 30% reduction in relapse rate in the group treated with a high dose. The MRI activity rate was reduced by a median of 70% in both treatment groups. The burden of disease measure showed a clear-cut dose effect in the 2-year analysis. Future trials must be monitored by MRI. In addition, placebo controls will continue to be necessary in most trials, especially if long-term effects are to be measured.

Brain↗
PubMed2004

Mature results of a phase III randomized trial of bacillus Calmette-Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I-III melanoma (E1673): a trial of the Eastern Oncology Group.

BACKGROUND: The local and systemic effects of bacillus Calmette-Guerin (BCG) have been known for decades. To investigate the adjuvant effect of BCG on resected American Joint Committee on Cancer (AJCC) Stage I-III melanoma, the Eastern Cooperative Oncology Group conducted a large trial to study the use of BCG alone or a combination of BCG and dacarbazine between 1974 and 1978. METHODS: A total of 734 patients were randomized to 4 clinical groups consolidated into 2 cohorts. Cohort I compared BCG with observation and Cohort II compared BCG with a combination of BCG and dacarbazine. The primary end points were survival time and time to disease progression. RESULTS: Within Cohort I, no statistically significant difference in disease-free survival (DFS) (P = 0.84) or overall survival (OS) (5-year survival 67% vs. 62%; P = 0.40) was observed between BCG treatment and observation. Within Cohort II, the addition of dacarbazine to BCG did not improve DFS (P = 0.74) or OS (P = 0.81) compared with BCG alone. Toxicity was mild to moderate in both cohorts. Although toxicity with this agent is mild, the use of BCG is associated with the development of punctate abscesses in greater than two-thirds of patients treated. CONCLUSIONS: In what to our knowledge is the largest ever trial to test the role of BCG as adjuvant therapy for melanoma, no benefit for BCG was observed for patients with AJCC Stage I-III disease. The mature results of the current trial projected to 30 years confirmed the negative results of previous smaller studies utilizing this agent.

Adjuvants, Immunologic↗
PubMedDate not supplied

Stopping a clinical trial early: frequentist and Bayesian approaches applied to a CALGB trial in non-small-cell lung cancer.

In May 1984, the Cancer and Leukemia Group B (CALGB) opened a phase III clinical trial for patients with stage III non-small-cell lung cancer (NSCLC). The experimental design entailed randomization of 240 patients equally to one of two treatments: radiotherapy alone or chemotherapy followed by radiotherapy. The original design was a fixed sample size design with the intent to analyse the results after 190 deaths. Shortly after the trial began, it was decided to apply group sequential concepts by using a truncated O'Brien-Fleming stopping rule, implemented via a Lan-DeMets alpha-spending function. A study monitoring committee was established to review the analyses as they were produced. The study was stopped at the fifth interim analysis in May 1987 after 155 eligible patients had been entered. This paper reviews the statistical and other considerations leading to this decision and presents later follow-up information on these patients. Some Bayesian alternatives to the standard frequentist approaches are also explored and it is demonstrated how these alternatives provide a natural way to address many of the issues raised in monitoring clinical trials.

Bayes Theorem↗
PubMed1980

Adjuvant endocrine therapy of breast cancer--a controlled clinical trial of oestrogen and anti-oestrogen: preliminary results of the Copenhagen breast cancer trials.

In an attempt to clarify the value of adjuvant endocrine therapy as an alternative to other treatment modalities, we have started two controlled, prospective, double-blind trials, the Copenhagen Breast Cancer Trials. In these studies postmenopausal women are randomised after primary local treatment to treatment with DES, tamoxifen, or placebo. Premenopausal women are similarly randomised to receive treatment with tamoxifen or placebo. Entry to the trials was closed in March 1978, when 343 patients had entered the studies. The preliminary results indicate that postmenopausal patients with ER+ tumours benefit from adjuvant treatment with tamoxifen. Adjuvant treatment with DES seems to be effective in ER- postmenopausal patients. In postmenopausal patients the ER+ tumors have a lower rate of recurrence. At present these preliminary results do not permit definite conclusions.

Adult↗