Recommendations for clinical trial evaluation of acute stroke therapies.
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The development of therapies for acute ischemic stroke has achieved a few notable successes and, unfortunately, many unsuccessful efforts. Many valuable lessons for the future assessment of new acute stroke therapies can be gleaned from the positive and negative prior trials. Phase I and II trials must be carefully designed and implemented to derive relevant, valuable information needed to proceed to phase III trials with promising interventions. The phase III trial should evaluate drug efficacy in an appropriately targeted stroke population evaluated by a meaningful and reliable outcome measure. Combinations of various types of stroke therapies will likely be increasingly assessed in future trials that are designed and implemented by cooperative efforts between the pharmaceutical industry, government agencies, academic advisors and clinical investigators. The chances for future success in demonstrating efficacy with acute stroke therapies will be enhanced by carefully conceived, scientifically based clinical trials. The recommendations contained in this document may help to focus attention on how to achieve the goal of developing an expanding number of a effective and safe acute stroke therapies. (+info)
A simple stratification factor prognostic for survival in advanced cancer: the good/bad/uncertain index.
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PURPOSE: This article summarizes the third step of a research program to identify variables that supplement the predictive power of the the Eastern Cooperative Oncology Group (ECOG) performance status (PS) for survival. The objective was to produce a simple, practical, stratification factor for phase III oncology clinical trials involving patients with advanced malignant disease. PATIENTS AND METHODS: A questionnaire was administered to 729 patients with metastatic colorectal or lung cancers. Patients provided a Karnofsky index and appetite rating while physicians provided a survival estimate and the ECOG-PS. Scores for each item were categorized as having a positive, neutral, or negative indication for survival. A patient was classified as having a relatively good prognosis if three or more of the four items showed a positive indication, a bad prognosis if three or more items were negative, and an uncertain prognosis otherwise (Good/Bad/Uncertain [GBU] index). RESULTS: The GBU index improved on the prognostic power of a Cox model quartile index and PS alone and increased the accuracy of survival classification estimates by 5% to 10% more than ECOG-PS alone. For patients with PS of 0 or 1, significant survival patterns exist between GBU groups (P=.002 and.0001, respectively). CONCLUSION: The GBU index may be recommended as a supplementary stratification factor for certain future phase III trials in metastatic lung or colorectal cancer where patient heterogeneity is a particular concern. The GBU represents a relatively modest increase to the cost and patient burden of a clinical trial given the additional control that is achieved over the potentially confounding concomitant to the treatment variable. (+info)
Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); methodology for coverage of phase II and phase III clinical trials sponsored by the National Institutes of Health. Office of the Secretary; DoD. Final rule.
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This final rule allows the Department of Defense to waive normal requirements so that covered beneficiaries can participate in Phase II and Phase III clinical trials sponsored or approved by the National Institutes of Health National Cancer Institute (NIH NCI). This waiver authority is expected to promote beneficiary access to promising new treatments and contribute to the development of such treatments. (+info)
Cyclooxygenase 2-implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives.
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Cyclooxygenase (COX), the key enzyme for synthesis of prostaglandins, exists in two isoforms (COX-1 and COX-2). COX-1 is constitutively expressed in the gastrointestinal tract in large quantities and has been suggested to maintain mucosal integrity through continuous generation of prostaglandins. COX-2 is induced predominantly during inflammation. On this premise selective COX-2 inhibitors not affecting COX-1 in the gastrointestinal tract mucosa have been developed as gastrointestinal sparing anti-inflammatory drugs. They appear to be well tolerated by experimental animals and humans following acute and chronic (three or more months) administration. However, there is increasing evidence that COX-2 has a greater physiological role than merely mediating pain and inflammation. Thus gastric and intestinal lesions do not develop when COX-1 is inhibited but only when the activity of both COX-1 and COX-2 is suppressed. Selective COX-2 inhibitors delay the healing of experimental gastric ulcers to the same extent as non-COX-2 specific non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, when given chronically to experimental animals, they can activate experimental colitis and cause intestinal perforation. The direct involvement of COX-2 in ulcer healing has been supported by observations that expression of COX-2 mRNA and protein is upregulated at the ulcer margin in a temporal and spatial relation to enhanced epithelial cell proliferation and increased expression of growth factors. Moreover, there is increasing evidence that upregulation of COX-2 mRNA and protein occurs during exposure of the gastric mucosa to noxious agents or to ischaemia-reperfusion. These observations support the concept that COX-2 represents (in addition to COX-1) a further line of defence for the gastrointestinal mucosa necessary for maintenance of mucosal integrity and ulcer healing. (+info)
Update on intravenous tissue plasminogen activator for acute stroke: from clinical trials to clinical practice.
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Tissue plasminogen activator (tPA) injected intravenously within 3 hours of symptom onset has emerged as a treatment option for acute ischemic stroke. Although controversial and not universally accepted, its use in carefully selected patients is supported by evidence from randomized controlled trials and by mounting community experience. In this paper we review the literature published in the past 5 years regarding the safety, clinical trial efficacy and real-world effectiveness of intravenous tPA for stroke. First we review data from the phase III clinical trials on which approval for tPA is based. Then we summarize a growing literature of postmarketing phase IV studies and discuss the limitations and challenges that lie ahead. Our aim is to provide clinicians with an overview of this evolving therapy. (+info)
Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.
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BACKGROUND: In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs. METHODS AND RESULTS: CV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonselective NSAIDs used in the development program (diclofenac, ibuprofen, and nabumetone). The major outcome measure was the combined end point used by the Antiplatelet Trialists' Collaboration, which includes CV, hemorrhagic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal strokes. More than 28 000 patients, representing >14 000 patient-years at risk, were analyzed. The relative risk for an end point was 0.84 (95% CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55) when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69) when comparing rofecoxib with naproxen. CONCLUSIONS: This analysis provides no evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs that were studied. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent. (+info)
Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria.
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The synergistic antifolate combination of chlorproguanil with dapsone (CPG-DDS; LAPDAP) is being developed by a public-private partnership as a low-cost treatment for uncomplicated falciparum malaria. LAPDAP is rapidly eliminated from the body, giving it low selection pressure for drug resistance. Clinical cases with sulphadoxine-pyrimethamine (SP)-resistant infections acquired in Africa have been predicted to be responsive to LAPDAP, and clinical evidence is available to support this. A regulatory dossier is being prepared for simultaneous submission to the UK Medicines Control Agency and African licencing authorities. The team working on LAPDAP has also started to develop the triple combination of chlorproguanil-dapsone-artesunate (CDA) as a low-cost combination therapy for uncomplicated falciparum malaria. Although LAPDAP does not have regulatory approval (and development of CDA is at an early stage), the development team is keen to communicate with public health scientists to try to anticipate the policy and implementation hurdles that lie ahead. This short paper outlines the current stages that LAPDAP and CDA have reached, and sketches the anticipated public health issues. (+info)
Bridging phase 2 and phase 3 pneumococcal immunologic data for future combination vaccines.
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Pneumococcal conjugate vaccines (PncCs) will be introduced into childhood vaccination programs now that the first PncC has been licensed for use. The next generation of PncCs and possible combination vaccines containing PncC will most probably be approved on the basis of phase 2 immunogenicity and safety data. PncCs are combination vaccines that include, at present, 7-11 components. Immune response to different components may vary. Furthermore, there seem to be population-based differences in immune response. Whether these differences are due to the other vaccines that are given simultaneously or due to the genetic background remains to be seen. Immune response can be evaluated by determining both the quantity and the quality of antibodies after vaccination. However, data are still missing on the minimal protective immune response and serologic correlates or surrogates of protection. (+info)