Crossover designs for clinical trials

I discuss three-period crossover designs for an efficient comparison of two test treatments with special application to clinical trials which often have many practical limitations. In this paper I specify a subset of three-period crossover designs so that the investigators are not left with the problematic two-period two-sequence design, should the trials be terminated after the second period. I show that there is a dramatic reduction in variability for estimating the direct and residual treatment effects in three-period designs compared to two-period designs. I also show that the universally optimal design with ABB and BAA sequences is unsuitable when a complex form of residual effects is suspected, such as the second-order residual effects or treatment by period interactions. The design with ABB, BAA, AAB, and BBA sequences is relatively robust to these uncertain model assumptions. I also discuss missing data problems and conclude that, even with a large proportion of missing values, the three-period design is far more efficient than the two-period design.     

A 25-week placebo-controlled study of eptastigmine in patients with Alzheimer disease

Studies of Pneumocystis carinii have been limited by our inability to propagate it in continuous culture. In this context, studies of P. carinii antigens have provided significant insight into the biology of this organism. The mannose-rich surface major surface glycoprotein of P. carinii termed glycoprotein A (gpA) is the best studied of these P. carinii antigens. Significant genetic and immunologic diversity exists between the gpA molecules expressed by P. carinii derived from different mammalian sources. The molecular and biochemical nature of gpA and other P. carinii antigens including p55 are reviewed. In addition, available information concerning the role of P. carinii gpA and other antigens in host-organism interactions are also discussed.     

Community consultation in socially sensitive research: Lessons from clinical trials of treatments for AIDS.

Contends that few studies have more starkly posed the dilemmas in socially sensitive research than the recent and ongoing clinical trials of medications (such as azidothymidine [AZT]) to treat acquired immune deficiency syndrome (AIDS). One response to such dilemmas is to include potential participants or surrogates for them in decision making. Although the investigator and relevant regulatory bodies are not absolved of responsibility by community consultation, such a procedure may help to create a partnership between the investigator and participants, consistent with ethical duties of respect for persons, beneficence, and fidelity. Community consultation also may dampen participants' anxiety and increase perceived justice of decisions about the research. Such a procedure has the potential to mitigate ethical problems in research involving a wide variety of socially sensitive topics and in randomized clinical trials of treatments for conditions other than AIDS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

New and emerging drug treatments for hypertension

BACKGROUND: Existing antihypertensive therapies are effective in lowering blood pressure, however, they are associated with adverse effects that may contribute to medication non-compliance. Furthermore, morbidity and mortality benefits have not been established with commonly used agents such as ACE inhibitors and calcium channel blockers. OBJECTIVE: Newer antihypertensive therapies offer similar efficacy with fewer adverse effects and may be of benefit in a number of concomitant disease states. DISCUSSION: This article examines the promise of the newer therapies: angiotensin II antagonists, T-type calcium channel blockers, dual metalloprotease inhibitors and endothelin receptor antagonists.     

Psychological factors in end-stage renal disease: An emerging context for behavioral medicine research.

End-stage renal disease (ESRD) is a chronic, life-threatening condition afflicting over 300,000 Americans. Patient nonadherence and psychological distress are highly prevalent among ESRD patients, and both have been found to contribute to greater morbidity and earlier mortality in this population. A range of factors have been examined as potential determinants of adherence and adjustment. Evidence suggests that adherence and adjustment are maximized when a patient's preferred style of coping is consistent with the contextual features or demands of the renal intervention the patient is undergoing. Challenges for future clinical research include refining methodologies for the assessment of depression and adherence, more clearly evaluating the efficacy of psychological interventions, and clarifying the role that depression and social support play in influencing patient mortality. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

EMS evaluation: criteria for standards and research designs

Transepithelial potential difference (p.d.) was measured in the proximal tubule of Necturus kidney in vivo, by means of microelectrodes filled either with a 3M KClion or with a Ringer's solution for amphibians. The average transepithelial p.d., measured with KCl-tips, was: -1.4 +/- 2.4 mV (early convolutions), -0.1 +/- 2.0 mV (middle convolutions) and +0.1 +/- 2.4 mV (straight segment). The corresponding values obtained with Ringer's-filled microelectrodes were -2.3 +/- 1.8 mV, -1.3 +/- 1.1 mV and +0.1 +/- 1.2 mV, respectively. Tip localization into the lumen was ascertained by luminal injection of either oil (KCl electrode measurements) or artificial solutions which produced a measurable shift of transepithelial p.d. (determinations obtained with Ringer's-tips). Transepithelial p.d. in split-drops (mean reabsorptive half time 27.1 +/- 2.5 min) was -1.8 +/- 1.1 mV. The magnitude of transepithelial p.d. is discussed with respect to an equivalent electrical circuit; it is shown that high transepithelial p.d.'s are inconsistent with the known values of relative conductances of cell membranes in series and shunt pathway, respectively.     

Clinical trials and tribulations: implementation processes in schizophrenia research outcome

This article focuses on an area in clinical drug trials for new antipsychotic medications for the treatment of schizophrenia which has not received sufficient attention in the literature: the day-to-day implementation tasks performed by research staff which have potential effects on study results. Implementation tasks are viewed as dynamic processes involving interactions among research and nonresearch staff, patients, families, and pharmaceutical company staff. Research-related demands and possible sources of stress for all participants in the process, such as recruiting and maintaining patients in studies, are discussed. Suggestions are offered for increasing the ease of participation. Further investigation is called for in several areas including variability in the effectiveness of research teams and in the rarely discussed interactions between site staff and pharmaceutical company personnel, as they may affect research outcomes. It is posited that increased knowledge about implementation processes in schizophrenia drug development is needed to more fully understand study results and to enhance patients' and their families' willingness to participate.     

Modification of smoking behavior: Good designs ineffective treatments.

Cigarette smoking provides opportunities to investigate behavior change processes in a meaningful, naturalistic context that still permits adequate measurement and controls. Although several recent behavior modification studies, exemplified by the A. R. Marston and R. M. McFall (see PA, Vol. 46:Issue 2) paper, are well designed, the treatments employed remain ineffective. It is suggested that treatment ineffectiveness may be due to insufficient pilot (clinical) work and premature freezing of techniques into group programs. It is also argued that process studies of smoking modification must await demonstration of an outcome effect or, at the least, process variables must be shown to effect outcome. The problems involved in verifying smoking rates and whether Ss are performing the "homework" assignments frequently given by behaviorists are also discussed. (25 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of psychotherapeutic treatments for PTSD: a meta-analysis of controlled clinical trials

This meta-analysis synthesized the results from controlled, clinical trials of psychotherapeutic treatments for posttraumatic stress disorder (PTSD). Psychotherapeutic modalities included behavioral, cognitive, and psychodynamic treatments, in group and individual settings. Participants in the studies included combat veterans from the Vietnam and Lebanon Wars, crime-related victims, and severe bereavement sufferers. The impact of psychotherapy on PTSD and psychiatric symptomatology was significant, d = .52, r = .25, when measured immediately after treatments were administered. Similarly, there was no decay in the effect of treatment at follow-up, d = .64, r = .31. Moreover, for target symptomes of PTSD and general psychological symptomes (intrusion, avoidance, hyperarousal, anxiety, and depression), effect sizes were significant, ranging from r's of .2-.49. Results suggest substantial promise for improving psychological health and decreasing related symptoms for those suffering from PTSD.     

Single-case research designs: A neglected alternative.

Comments on the article by L. Wilkinson & the Task Force on Statistical Inference (see record 1999-03403-008) which was meant to initiate discussion in the field about changes in current practices of data analysis and reporting. The report was concerned with the use of statistical methods only and is not meant as an assessment of research methods in general. The present article criticizes Wilkinson's article, noting that it lacks any recognition that single-case research design might be an alternative to current practices. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Research-informed benchmarks for psychological treatments: Efficacy studies, effectiveness studies, and beyond.

To examine whether the results of effectiveness studies match those obtained for efficacy studies on the same treatments, we conducted a focused review of the published treatment effectiveness literature. A literature search yielded 35 effectiveness studies for adult disorders (N = 21) and child and adolescent disorders (N = 14). A comparison of data from these studies with benchmarks from recent reviews of efficacy trials revealed treatment completion rates comparable with those found in the efficacy benchmarks. The improvement rates were comparable in effectiveness studies with those reported in randomized clinical trials of treatment efficacy. Despite methodological limitations in many effectiveness studies, these initial data provide encouraging support for the transportability to clinical settings of treatments with established efficacy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The semantics of addiction: moving beyond expert models to lay understandings

Disseminated intravascular coagulation (DIC) syndromes can be defined as the formation of fibrin deposits within the microcirculation, occurring in definite clinical situations. Their biological counterpart is a consumption coagulopathy. The clinical profiles of DIC have been well known for decades, are multiform and range from latency to overwhelming haemorrhagic diatheses, including also characteristic but rare situations, such as purpura fulminans, acral cyanosis and pictures resembling thrombotic thrombocytopenic purpura or haemolytic-uraemic syndrome. Biological tests of DIC show a consumption coagulopathy, displayed on the standard haemostasis sheet; along with signs of paracoagulation and/or of secondary fibrinolysis (FDP). New tests have recently been introduced: D-dimers are specific and sensible; Antithrombin-III, protein C and alpha 2-antiplasmin also can sometimes be useful. The knowledge of the pathophysiology of DIC has made advances with passing years. Fibrin deposits may be non-occlusive, and indeed they are swiftly removed by a secondary fibrinolysis. Except in very rare situations, such as those leading to a cortical renal necrosis, and perhaps in some ARDS, there is little evidence relating DIC to organ failure syndromes. Moreover, there is no clear relationship between the severity of the consumption coagulopathy and the prognosis. For instance, the mortality is much lower in abruptio placentae, where the coagulopathy is very severe, than in septic shock, where it is usually moderate. In septic shock, the disorders of haemostasis were related initially to a platelet activation, then to an activation of the contact system (releasing kinins and triggering complement cascade), and nowadays to the activation of the extrinsic coagulation system. The treatment of DIC is mainly the treatment of its cause. Indications for heparin therapy should be strictly limited to a few exceptional circumstances. When haemorrhagic diathesis threatens, FPC and/or platelet transfusion may be indicated. Aprotinin can be useful in rare cases of overwhelming secondary fibrinolysis. Trials with antithrombin-III or C1-esterase inhibitors are in progress.     

Clinicopathologic study of probable Alzheimer disease: assessment of criteria for excluding cerebrovascular disease

The National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association criteria for probable Alzheimer disease (AD) require exclusion of non-AD dementia-producing conditions but do not specify how the non-AD conditions are to be identified. We addressed this issue for the case of cerebrovascular disease (CVD) by defining exclusion rules based on commonly described clinical features: (a) history of strokelike episodes; (b) history of stepwise cognitive decline; (c) focal deficits on neurological examination; and (d) evidence of significant CVD on neuroimaging. We applied these rules retrospectively to clinical records for 92 cognitively impaired patients who otherwise met criteria for probable AD and whose brains were subsequently available for postmortem examination. We used Fisher's exact test to assess the effectiveness of the exclusion rules in predicting the presence of CVD on autopsy. Prediction was better than chance when all four clinical features were used together (p = 0.0008) and when the stepwise decline or neuroimaging criteria were used alone (p = 0.03 and p = 0.05, respectively). Overall, the CVD exclusion rules were deficient because of low accuracy (50.0%) and low sensitivity (52.6%). These results support provisional use of the CVD criteria chosen for this study but suggest that modifications are needed for acceptable diagnostic accuracy and sensitivity to be achieved.     

New treatments for peptic ulcer disease

The aim of this presentation is to study the advantages and disadvantages of perioperative prophylaxis with the antibiotic Mefoxin against the classical postoperative antibiotic prophylaxis with penicillin and gentamicine, as well as to analyse the place of this antibiotic in modern treatment of different forms of pelvic inflammatory disease. The authors conclude that the qualities of Mefoxin (high resistant wide spectrum antibiotic, covering aerobes and anaerobes), make it an ideal antibiotic for perioperative prophylaxis in gynaecologic and oncologic surgery; the clinical effectiveness of Mefoxin in the treatment of inflammatory diseases of the female pelvis precludes the need for a combined parenteral antibiotic therapy.