Randomized Clinical Trial Design Research Articles

Helping Families of Patients With Cancer

To discuss the impact of cancer on families of patients with cancer. National reports on caregiving and research articles related to cancer and families. Family caregivers are the bedrock of chronic care in the United States. They provide an enormous amount of unpaid care that is often invisible. Cancer can affect the emotional, social, physical, and spiritual well-being of family members. Family intervention research can have a positive effect on patient and family caregiver outcomes. More intervention research with families is needed that is theoretically based, uses randomized clinical trial designs, and uses instruments that are sensitive to intervention effects. Although family intervention research is limited, descriptive and exploratory research has identified protective factors and risk factors that need to be addressed in clinical practice.

PENTOSAN POLYSULFATE SODIUM THERAPY FOR MEN WITH CHRONIC PELVIC PAIN SYNDROME: A MULTICENTER, RANDOMIZED, PLACEBO CONTROLLED STUDY

We evaluated the efficacy and tolerability of pentosan polysulfate sodium (PPS) for the treatment of men with chronic pelvic pain syndrome (CPPS), National Institutes of Health (NIH) category III. In a 16-week double-blind study 100 men with a clinical diagnosis of CPPS were randomized to receive 300 mg PPS or placebo 3 times daily. Clinical Global Improvement (CGI) was the primary outcome measure. Additional outcome measures were the NIH-Chronic Prostatitis Symptom Index (CPSI), Subjective Global Assessment and Symptom Severity Index assessment tools. Significantly more patients receiving PPS experienced moderate to marked improvement based on CGI assessment (18 or 37% vs 8 or 18%, p = 0.04). However, mean CGI scores were not significantly different between the PPS group (1.0) and placebo groups (1.0 vs 0.6, p = 0.107). All NIH-CPSI domains suggested a positive effect for PPS and for total NIH-CPSI the difference approached statistical significance (-5.9 or 22% vs -3.2 or 12%, p = 0.068). The PPS group showed significantly greater improvement in NIH-CPSI quality of life domain scores than the placebo group (-2.0 or 22% vs -1.0 or 12%, p = 0.031). Of patients receiving PPS 67% and 80% of those receiving placebo completed the 16-week study. Diarrhea, nausea and headache were the most common adverse events. Pentosan polysulfate (900 mg daily) was more likely than placebo to provide relief for CPPS symptoms.

On the efficiency of targeted clinical trials

The development of genomics-based technologies is demonstrating that many common diseases are heterogeneous collections of molecularly distinct entities. Molecularly targeted therapeutics is often effective only for some subsets patients with a conventionally defined disease. We consider the problem of design of phase III randomized clinical trials for the evaluation of a molecularly targeted treatment when there is an assay predictive of which patients will be more responsive to the experimental treatment than to the control regimen. We compare the conventional randomized clinical trial design to a design based on randomizing only patients predicted to preferentially benefit from the new treatment. Trial designs are compared based on the required number of randomized patients and the expected number of patients screened for randomization eligibility. Relative efficiency depends upon the distribution of treatment effect across patient subsets, prevalence of the subset of patients who respond preferentially to the experimental treatment, and assay performance.

Rethinking research on psychosocial interventions in biopsychosocial oncology: an essay written in honor of the scholarly contributions of Bernard H. Fox.

In his best known contribution to the field of psychooncology, the late Dr Bernard H. Fox applied his breadth of scholarship in biopsychosocial cancer epidemiology to address the question of whether and to what extent stress and other psychosocial factors may contribute to cancer risk. Less well known but equally important to the field is his incisive critique of the 1989 study by Spiegel et al. on survival time of patients with metastatic breast cancer following a psychosocial intervention. This essay represents an attempt to take Fox's line of thought to the next logical level of rethinking research on psychosocial interventions in biopsychosocial oncology. Following an analysis of the inadequacy of randomized clinical trials (RCT) to evaluate the causal effects of psychosocial interventions on cancer outcomes and distinguish these from mere prediction, an integrated RCT design is suggested to take into account the psychogenicity of a given intervention, potential mediating mechanisms, and individual differences that could help illuminate hypothesized causal processes linking an experimental intervention and cancer outcomes.

A systematic review of Swedish research in orthodontics during the past decade

The aims of this systematic review were to identify the study designs and topics of Swedish orthodontic articles, to elucidate their international position, and to verify in which scientific journals the articles had been published in the past decade. A search of the Medline database for papers published between 1992 and 2002 was made using the Medical Search Heading terms ‘orthodontics’, ‘malocclusion’, ‘cephalometry’, and ‘facial bones and growth’. Two independent reviewers selected the articles of Swedish origin and categorized each article according to research design and principal topic. Overall, 15,571 articles in orthodontic research were found, and the Swedish contribution was 1.9% with the majority of these (71.5%) being submitted by universities. Most of the Swedish articles (84.5%) had been published in 10 journals and many high‐quality studies with orthodontic interest were published in non‐orthodontic journals with higher impact factor scores than the orthodontic journals. Every second study was prospective, and of these, 15 (5.2% of all Swedish articles) were randomized clinical trials (RCTs). It was found that nearly every third study, prospective as well as retrospective, was uncontrolled. The main classification was treatment studies (51.9%), followed by development (18.6%) and diagnostic information (10.7%) studies. Thus, the majority of the articles evaluated therapeutic interventions; however, although the RCT is the preferred study design in evaluation studies, few used this method. In an era focused on evidence‐based medicine, studies with an RCT design will be the future challenge for research in the field of orthodontics.

Maximizing Benefits and Minimizing Risks in Health Services Research Near the End of Life

This article explores the ethical issues specific to Health Services Research (HSR) in palliative care, with particular attention to similarities and differences between HSR and institutional quality improvement (QI) initiatives. We focus on the challenges of determining what level of protection is warranted by investigations of health services and programs of care, in contrast to the traditional randomized clinical trial design, and how best to assure subject protection. A decision algorithm regarding the requirements for full IRB review and informed consent is proposed as a mechanism to assure that the level of protection is commensurate with the level of risk.

Selective exclusion of treatment arms in multi-arm randomized clinical trials.

In this paper we discuss a design for multi-arm randomized clinical trials (RCTs) in which clinicians and their patients can selectively exclude one of the randomized treatment arms. This approach has the advantage that it should expedite protocol development, and allow easier and faster recruitment of patients into the trial. However, to preserve the randomized nature of treatment comparisons, not all recruited patients can be included in all treatment comparisons. This dictates that treatment arms are compared in a pairwise fashion, and that the numbers of patients included in different treatment comparisons may not be equal. The total trial size of a multi-arm RCT that allowed selective exclusion of arms would be greater than the size of an equivalent standard multi-arm RCT. However, the duration of time taken to recruit the study would be reduced. The implications for the design, monitoring and analysis of such RCTs are discussed.

Advances in understanding protection from cerebral ischemia

Cerebral ischemia and protection is a large field, so for the purposes of this review, which focuses on results published in the last 9 months, we have chosen to discuss a few aspects of ischemia in which our understanding has advanced significantly in this period of time. Recent progress in the clinical use of hypothermia for neurological protection as well as laboratory progress on the role of stress proteins, estrogen and a few other potential adjuncts will be discussed. Two papers have now been published documenting improved neurological outcome in patients treated with hypothermia following cardiac arrest, both using randomized clinical trial designs. These reports and several laboratory studies identifying mechanisms of hypothermic brain protection are reviewed. In understanding the mechanisms underlying protection by estrogens, new results on both direct vascular effects and a demonstration that estrogens can reduce apoptosis are presented. The third area to be described is current progress in identifying mechanisms of stress protein protection from ischemia, in which new mechanisms have been identified with the demonstration of inhibition of several points in the cell death cascade. The remaining areas considered touch on the effects of approaches that reduce inflammation by blocking adhesion molecules, those that reduce free radical production and those that improve blood rheology. An important common theme in brain protection is reduction of cell death by blocking apoptosis or programmed cell death. While the use of hypothermia should now enter clinical practice, many areas of brain injury require further studies both to define injury mechanisms and to translate these understandings into clinically useful treatments to reduce ischemic brain injury.

Design of a multicenter randomized clinical trial for chronic prostatitis/chronic pelvic pain syndrome

Objectives. To describe the study design and rationale for the first placebo-controlled, randomized clinical trial to be conducted by the Chronic Prostatitis Collaborative Research Network sponsored by the National Institutes of Health. Methods. The clinical trial will use a 2 by 2 factorial design to evaluate four treatments: placebo, tamsulosin hydrochloride alone, ciprofloxacin alone, and tamsulosin hydrochloride and ciprofloxacin combined. The primary objectives are to compare the efficacy and safety endpoints in patients with chronic prostatitis/chronic pelvic pain syndrome. The study population consists of men with symptoms of discomfort or pain in the pelvic region for at least a 3-month period. One hundred eighty-four participants will be treated for 6 weeks and followed up for an additional 6 weeks. The primary endpoint is the change in the overall National Institutes of Health Chronic Prostatitis Symptom Index from baseline to 6 weeks. Secondary endpoints include a patient-reported global assessment of response and white blood cell counts and cultures in urine, expressed prostatic secretions, and semen. The evaluation of changes from 6 to 12 weeks will be used to assess the durability of the response. Results. This trial was opened to enrollment in July 2001. The study is expected to require 14 months of accrual and follow-up. Conclusions. The issues considered in the design of this clinical trial may provide guidelines for future clinical trials in chronic prostatitis/chronic pelvic pain syndrome.

Evaluating informatics applications—clinical decision support systems literature review

This paper reviews clinical decision support systems (CDSS) literature, with a focus on evaluation. The literature indicates a general consensus that clinical decision support systems are thought to have the potential to improve care. Evidence is more equivocal for guidelines and for systems to aid physicians with diagnosis. There also is general consensus that a variety of systems are little used despite demonstrated or potential benefits. In the evaluation literature, the main emphasis is on how clinical performance changes. Most studies use an experimental or randomized controlled clinical trials design (RCT) to assess system performance or to focus on changes in clinical performance that could affect patient care. Few studies involve field tests of a CDSS and almost none use a naturalistic design in routine clinical settings with real patients. In addition, there is little theoretical discussion, although papers are permeated by a rationalist perspective that excludes contextual issues related to how and why systems are used. The studies mostly concern physicians rather than other clinicians. Further, CDSS evaluation studies appear to be insulated from evaluations of other informatics applications. Consequently, there is a lack of information useful for understanding why CDSSs may or may not be effective, resulting in making less informed decisions about these technologies and, by extension, other medical informatics applications.

An Evidence-Based Medicine Approach to the Treatment of Endometriosis-Associated Chronic Pelvic Pain: Placebo-Controlled Studies

Objective Use an evidence-based medicine (EBM) approach to evaluate the evidence regarding efficacy of treatment of endometriosis-associated chronic pelvic pain (CPP) in placebo-controlled randomized clinical trials (RCT) Design Review of six randomized, controlled trials (Canadian Task Force classification I). Setting University of Rochester School of Medicine and Dentistry. Patients Three hundred eighty-one women with endometriosis enrolled in placebo-controlled randomized clinical trials. Intervention A MEDLINE search of published medical articles from January 1976, to January 1998. Measurements and Main Results Six placebo-controlled randomized clinical trials were found that addressed the treatment of pelvic pain associated with endometriosis and met validity criteria; one was a study of surgical treatment, two of medical therapies, and three of combined surgical and medical treatments. They clearly show that laparoscopic surgery and medical treatment with medroxyprogesterone acetate, danazol, or nafarelin are more effective than placebo. Evidence for efficacy of leuprolide acetate is weaker. At 6 months, absolute decreases in pain scores are quite similar with surgical or medical treatment. Medical therapy after surgical treatment significantly reduced pain, but six months after it was stopped there was no difference between women treated and not treated postoperatively. Conclusions Although either surgical or medical treatment of endometriosis in women with CPP is clearly indicated, pain relief of 6 or more months' duration can be expected in only 40 to 70% of women with endometriosis-associated CPP.

The Diagnostic Process and Indication for Physiotherapy: A Prerequisite for Treatment and Outcome Evaluation

The need for the profession of physiotherapy to illustrate its value to the external world is becoming more obvious each year. Those who pay for physiotherapy services would like to limit the number of sessions and the length of the treatment episode of physiotherapy care. It is therefore incumbent on the profession to design a conceptual framework for the physiotherapy process that can be used to study the efficacy, effectiveness and efficiency of physiotherapy by employing appropriate clinical research techniques. The result of this research can contribute to the development of treatment guidelines to produce optimal patient outcomes.The purpose'of this paper is twofold: (1) to provide insight into the similarities and differences between medical and physiotherapy diagnoses; and (2) to provide a basis by which the physiotherapist's diagnosis helps to determine the indication for physiotherapy, the strategy of physiotherapeutic care, and the outcome prognosis.A systematic multilevel system approach to the process of physiotherapy practice is a prerequisite for the improvement of the quality of patient care, and the design of meaningful randomized clinical trials.

The value of the randomized clinical trial in the field of physiotherapy

meta-analysis and systematic reviews. In this paper the focus will be on the randomized clinical trial. The design and its main features will be presented. Thereafter some frequent methodological problems, which have to be dealt with when conducting randomized clinical trials in the field of physiotherapy, will be discussed. Finally, as an example, a design of a new randomized clinical trial on the efficacy of interventions for neck pain will be presented.

Clinician preferences and the estimation of causal treatment differences

Clinician treatment preferences affect the ability to perform randomized clinical trials and the ability to analyze observational data for treatment effects. In clinical trials, clinician preferences that are based on a subjective analysis of the patient can make it difficult to define eligibility criteria for which clinicians would agree to randomize all patients who satisfy the criteria. In addition, since each clinician typically has some preference for the choice of treatment for a given patient, there are concerns about how strong that preference needs to be before it is inappropriate for him to randomize the choice of treatment. In observational studies, the fact that clinician preferences affect the choice of treatment is a major source of selection bias when estimating treatment effects. In this paper we review alternative designs that have been proposed in the literature for randomized clinical trials that utilize clinician preferences differently than the standard randomized trial design. We also examine the effects of clinician preferences on the ability to estimate causal treatment differences from observational data, and propose an alternative method of analysis for observational data that uses clinician preferences explicitly. We report on our experience to date in using our alternative randomized clinical trial design and our new method of observational analysis to compare two treatments at the orthodontic clinics at the University of California San Francisco and the University of the Pacific, San Francisco.

An evidence-based approach to earlier initiation of dialysis

The objective was to review evidence addressing the optimal time to initiate dialysis treatment. The database was derived from an evidence-based review of the medical literature and from the Canada-United States peritoneal dialysis study. The publications were divided into (1) those addressing the clinical impact of early versus late referral to a dialysis program; (2) those evaluating the association between residual renal function at initiation of dialysis and the concurrent nutritional status; (3) those evaluating the association between residual renal function at initiation of dialysis and subsequent clinical outcomes, including patient survival. There were five studies evaluating early versus late referral, three cohort design and two case-control design. Late referrals had worse outcomes than early referrals. The former had more serious comorbidity and many had been noncompliant with follow-up. The latter were more likely to have hereditary renal disease. Renal function was slightly worse at initiation among those referred late. Three studies addressed the association between renal function at initiation of dialysis and concurrent nutritional status. Two showed decreased protein intake with diminished glomerular filtration rate (GFR). Poor nutritional status is associated with decreased patient survival among both incident and prevalent dialysis patients. The third study reported excellent patient survival among patients with late initiation of dialysis. These patients had received a supplemented low-protein diet and were not malnourished at initiation of dialysis. Three groups have studied the association between GFR at initiation of dialysis and clinical outcomes. Decreased GFR at initiation of dialysis is associated with a increased probability of hospitalization and death. None of these studies has used the rigorous randomized clinical trial design, and they are therefore subject to bias. Referral time bias, comorbidity, patient compliance, and starting time bias are potential confounders. A randomized clinical trial is required to resolve this important issue. However, there is sufficient evidence to justify initiation of dialysis at a Ccr of 9 to 14 mL/min if there is any clinical or laboratory evidence of malnutrition.

Current status of the multicenter randomized clinical trial on fetal oxygen saturation monitoring in the United States

Current clinical methods of intrapartum fetal assessment are sensitive but poorly specific in detecting fetal compromise during labor. These limitations have substantially contributed to the escalating cesarean section rate which occurred in the US during the last several decades. Experimental and clinical research efforts directed towards application of the oxygen saturation monitor (pulse oximeter) to intrapartum fetal assessment have produced encouraging results. If this new method of fetal assessment is to enter the clinical arena, safety and efficacy issues must first be properly evaluated via randomized clinical trials. The purpose of this report is to describe the design of a multicenter randomized clinical trial of intrapartum fetal oxygen saturation monitoring recently begun in the US. Specific aspects of the trial, including purpose, study design, sample size estimates, control and test groups, inclusion and exclusion criteria, fetal heart rate classification, definition of normal fetal arterial oxygen saturation (Spo2), clinical management protocol, and assessment of maternal–fetal outcomes will be addressed.© 1997 Elsevier Science Ireland Ltd.

ROLE OF META-ANALYSES IN DESIGN AND MONITORING OF RANDOMIZED CLINICAL TRIALS: SUMMARY OF FIRST DAY OF THE WORKSHOP

Statistics in MedicineVolume 15, Issue 12 p. 1313-1315 Research Article ROLE OF META-ANALYSES IN DESIGN AND MONITORING OF RANDOMIZED CLINICAL TRIALS: SUMMARY OF FIRST DAY OF THE WORKSHOP NANCY L. GELLER, NANCY L. GELLER ng@helix.nih.gov NHLBISearch for more papers by this author NANCY L. GELLER, NANCY L. GELLER ng@helix.nih.gov NHLBISearch for more papers by this author First published: 30 June 1996 https://doi.org/10.1002/(SICI)1097-0258(19960630)15:12<1313::AID-SIM313>3.0.CO;2-RCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume15, Issue1230 June 1996Pages 1313-1315 RelatedInformation

ROLE OF META‐ANALYSES IN DESIGN AND MONITORING OF RANDOMIZED CLINICAL TRIALS: SUMMARY OF FIRST DAY OF THE WORKSHOP

Statistics in MedicineVolume 15, Issue 12 p. 1313-1315 Research Article ROLE OF META-ANALYSES IN DESIGN AND MONITORING OF RANDOMIZED CLINICAL TRIALS: SUMMARY OF FIRST DAY OF THE WORKSHOP NANCY L. GELLER, NANCY L. GELLER ng@helix.nih.gov NHLBISearch for more papers by this author NANCY L. GELLER, NANCY L. GELLER ng@helix.nih.gov NHLBISearch for more papers by this author First published: 30 June 1996 https://doi.org/10.1002/(SICI)1097-0258(19960630)15:12<1313::AID-SIM313>3.0.CO;2-RCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume15, Issue1230 June 1996Pages 1313-1315 RelatedInformation

Population pharmacodynamics: strategies for concentration-and effect-controlled clinical trials.

To explore and evaluate various strategies for drug concentration-and effect-controlled clinical trials, respectively, in the context of studies of population pharmacodynamics (concentration-effect relationships). The relative utility of drug concentration- and pharmacologic effect-controlled, randomized clinical trials with two or three concentration-effect measurements for each subject has been explored by computer simulation. The basis for these simulations was a sigmoid-Emax (maximum effect) pharmacodynamic model with Emax = 100%, EC50 (drug concentrations required to produce an effective intensity of 50%) = 10 concentration units, gamma = 2, and no hysteresis. Emax and gamma were held constant whereas EC50 was assumed to be log-normally distributed with a 26% coefficient of variation of the natural lognormalized data. A smaller random variability and variability due to measurement error also were incorporated in the simulations. To explore the implications of variable and unknown Emax and gamma values, the suitability of linear and log-linear interpolation procedures for two-point concentration-effect data in different regions of the sigmoid-Emax curve was compared. Pharmacologic effect-controlled clinical trials with 300 hypothetical subjects and targeted effect intensities of 25% and 75% yielded very good estimates of drug concentrations required to produce effect intensities of 35%, 50%, and 65%, whereas concentration-controlled trials yielded much poorer estimates. Moreover, the concentration-controlled trials, despite optimum choice of targeted concentrations, yielded a large number of data points with poor information content (effect intensities of < 15% or > 85%). Determinations based on targeted effect intensities of 25% and 75% yielded better estimates of individual EC50 values than those targeted for 25% and 50% or 50% and 75% effect intensity. Results were not significantly improved by adding a third measurement (targeted to 50% effect) to the 25% and 75% effect design. Estimations of drug concentrations required to produce an effect intensity of 50%, based on log-linear interpolation of exact concentration-effect data at 25% and 75%, yielded exact results independent of gamma value (0.5-8.0) whereas linear interpolation produced large overestimates at gamma = 0.5 or 1.0 but satisfactory estimates at gamma > or = 2.0. Similar calculations for an effect intensity of 15% based on exact concentration-effect data at 5% and 25% yielded reasonably good estimates by both methods of interpolation over a wide range of gamma values. A review of the clinical literature showed that gamma values are usually 2 or higher. Population pharmacodynamic studies of reversibly acting drugs without pharmacodynamic hysteresis or time dependency (e.g., tolerance) can be successfully conducted using a pharmacologic effect-controlled randomized clinical trial design with only two properly selected target effect intensities per subject.

Clinical trial design: veterinary perspectives.

Tremendous potential exists for the use of the randomized clinical trial (RCT) in veterinary clinical research. Understanding the fundamentals of RCT design not only benefits clinical researchers, but it can enhance the ability of practitioners to interpret published RCT reports. In this article, the essential components of RCT design and implementation are described using examples from clinical veterinary medicine.