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Results for “Clinical Trials Data Monitoring Committees”

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PubMed1995

Design of the multicenter study of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia is a randomized double-blind placebo-controlled trial to test whether hydroxyurea can reduce the rate of painful crises in adult patients who have at least three painful crises per year. The sample size of 299 patients yields at least 90% power to detect a 50% or greater reduction in crisis rate. Dosage starts at 15 mg/kg/day and is titrated to the patient's maximum tolerated dose up to 35 mg/kg/day. Placebo dosage is titrated in similar fashion to maintain blinding. Attempts are made to ascertain medical contacts for at least 2 years after study entry. The Core Laboratory, Treatment Distribution Center, and Data Coordinating Center collaborate to provide standardized monitoring for toxicity and dose adjustments. The Core Laboratory also reduces the possibility of inadvertent unmasking of treatment assignment during review of hematologic data in clinical centers. An independent Crisis Review Committee classifies clinical events to assure that outcome evaluations are standardized and unbiased by knowledge of treatment assignments. The Data and Safety Monitoring Board assures scientific integrity of the study, as well as the safety and ethical treatment of study patients. We expect the study to determine whether or not treatment with hydroxyurea can offer significant clinical benefit to patients with the most common hereditary disorder among African-Americans in the United States.

Adult↗

PubMedDate not supplied

The prostate, lung, colon, and ovarian (PLCO) cancer screening trial: Status and promise.

The Prostate, Lung, Cancer, and Ovarian Cancer Screening Trial is a randomized, multicenter, study evaluating whether screening for prostate, lung, colon, and ovarian cancer will reduce cancer-specific mortality. More than 155,000 participants have been identified and will be monitored through 2015. A biorepository of screened individuals and control participants has been created. Together, the data derived from the intervention and control arms and material in the biorepository provide a valuable resource to allow identification and testing of novel biomarkers for human disease.

Aged↗

PubMed1997

Rationale, design, and organization of the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF). The International Steering Committee.

Metoprolol is a cardioselective beta blocker that has been shown to improve left ventricular function and symptoms of congestive heart failure (CHF) and also to decrease the number of hospitalizations due to CHF. However, the effects of metoprolol on mortality in patients with CHF have yet to be determined. Accordingly, the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) has been designed to investigate the effect of once-daily dosing of metoprolol succinate controlled release/extended release (CR/XL) when added to standard therapy in patients with CHF. A total of 3,200 patients will be recruited for this international, double-blind, randomized, placebo-controlled survival study. The 2 primary objectives of MERIT-HF are to determine the effect of metoprolol CR/XL on (1) total mortality and (2) the combined endpoint of all-cause mortality and all-cause hospitalizations (time to first event). Eligible patients are 40-80 years old, with a reduced left ventricular ejection fraction (< or =0.40) and symptoms of CHF (New York Heart Association functional classes II-IV). After a 2-week placebo run-in period, an optimal allocation procedure will be used to randomize patients in a 1:1 ratio to metoprolol CR/XL or matching placebo. After an initial titration phase starting with 12.5 mg or 25 mg once daily (depending on functional class), the target dose will be 200 mg in all patients who tolerate this dose. The mean follow-up is estimated to be 2.4 years. The study data will be analyzed on an intention-to-treat basis. An Independent Safety Committee will monitor the safety aspects of the trial, and an Independent Endpoint Committee will classify all endpoints.

Adrenergic beta-Antagonists↗

PubMed2004

Implementing the UK Medical Research Council (MRC) RT01 trial (ISRCTN 47772397): methods and practicalities of a randomised controlled trial of conformal radiotherapy in men with localised prostate cancer.

BACKGROUND AND PURPOSE: Radiotherapy is the most frequently used treatment for men with localised prostate cancer. Conformal radiotherapy (CFRT) is a relatively new development. MRC RT01 was set-up to explore optimum CFRT dose. PATIENTS AND METHODS: RT01 was an international multi-centre randomised controlled trial for men with T1b-T3a, N0, M0 prostate cancer that evolved from a single-centre pilot trial of similar design. All men received at least 3 months of pre-radiotherapy hormone treatment, before randomisation to standard (64 Gy) or high dose (74 Gy) radical CFRT. Accrual was completed in December 2001 with 843 men randomised from 25 centres in less than 4 years. RT01 has been a catalyst for implementing CFRT across UK. In addition to the Trial Management Group, independent Data Monitoring and Ethics Committee and independent Trial Steering Committee, a Quality of Life and Health Economics (QL/HE) group, a radiotherapy Quality Assurance (QA) Group and a Radiography Trial Implementation Group were set up. The QL/HE group ensured implementation, compliance, analysis and interpretation of the QL and HE data in the trial. The inauguration of QA and Radiography groups facilitated inter-centre collaboration. The QA Group ensured procedures were in place before and during trial participation, and monitored quality and consistency with systems including a physics questionnaire, a clinical examples exercise, a standard operating procedure document, designing and building a phantom, and convening a complications modelling subgroup. The Radiography group agreed and implemented technique improvements. RESULTS: More centres participated than initially predicted, enabling recruitment better than scheduled. The trial expedited the implementation of CFRT in many UK radiotherapy centres. Additionally, the QA and Radiography groups helped ensure smooth initiation and established consistency in planning, dosimetry and delivery of prostate CFRT services at participating UK centres. Considerable data has been collected; a series of papers will be produced, although mature clinical trial results are not anticipated until 2006-2008.

Humans↗

PubMed1990

[Current practice of drug trials in healthy volunteers].

It is impossible to extrapolate for men the animal's data. Pre-therapeutical studies are a necessity to state precisely in man ADME for a new drug and to confirm pharmacological properties seen in animals. Very often, the only healthy volunteers are useful for Phase 1 studies: The selection of volunteers keeps physical and metabolic status, and psychological motivation. True but restricted information is necessary for "free and informed consent". Rights and duties must be clearly defined in written convention. Financial advantages are in agreement of trouble but not of hazard in the study. The safety is the main point in human studies. That means a safe methodology and a protocol approved by independent ethical committee. The monitoring of these studies must be precisely conducted with many clinical and laboratory examinations. Healthy volunteers studies are required by French Ministry of Health, rejected by medical law, condemned by civil law but covered by legal insurances. In French mind is illicit that is not specifically permitted by law. We need special legislation as we refuse medical and ethical responsibility.

Adult↗

PubMed1999

Long-term oral platelet glycoprotein IIb/IIIa receptor antagonism with sibrafiban after acute coronary syndromes: study design of the sibrafiban versus aspirin to yield maximum protection from ischemic heart events post-acute coronary syndromes (SYMPHONY) trial. Symphony Steering Committee.

BACKGROUND: Despite progress, atherosclerotic vascular disease remains a major cause of morbidity and mortality. Intravenous therapy with platelet glycoprotein (GP) IIb/IIIa receptor antagonists improves outcome in patients with acute coronary syndromes (ACS). Whether potent long-term antiplatelet therapy with oral GP IIb/IIIa antagonists will further improve outcome at a dose that is tolerable in long-term treatment is unknown. TRIAL DESIGN: SYMPHONY (Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary syndromes) was a randomized, double-blind, aspirin-controlled trial with 2 concentration regimens of sibrafiban, an oral peptidomimetic GP IIb/IIIa antagonist, for long-term treatment instead of aspirin in patients after an ACS. Patients were eligible for SYMPHONY if they presented within 7 days of an ACS (>/=20 minutes of ischemic symptoms), had been clinically stable for at least 12 hours, and met one of the following inclusion criteria: ST-segment depression or elevation of at least 0.5 mm or new left bundle branch block with the ACS or elevated creatinine kinase MB more than the upper limit of normal and >3% of total creatine kinase or, if creatine kinase MB was not measured, an elevated level of troponin T or I. Approximately 9000 patients post ACS were randomized 1:1:1 to treatment with either aspirin (80 mg every 12 hours) or high-dose or low-dose sibrafiban every 12 hours. Assignment of tablet strength (3, 4.5, or 6 mg) within the sibrafiban arms was based on body weight and renal function to achieve a target steady-state plasma concentration. The duration of study drug therapy was 90 days. Patients who had intracoronary stenting during the course of the study initially received a blinded stent medication assignment for 2 to 4 weeks based on their initial randomization as follows: aspirin/ticlopidine 250 mg twice daily, low-dose sibrafiban/ticlopidine placebo twice daily, and high-dose sibrafiban/ticlopidine placebo twice daily. After the second interim safety assessment by the Data and Safety Monitoring Board the stent regimen for the low-dose group was modified to include ticlopidine 250 mg twice daily. END POINTS: The primary efficacy end point of SYMPHONY was the 90-day incidence of a composite of all-cause mortality, myocardial infarction or reinfarction, and severe recurrent ischemia. A clinical events classification committee was established to determine the end points of reinfarction and severe recurrent ischemia. The primary safety end points were the incidence of major bleeding or minor bleeding and the combined incidence of major and minor bleeding. Bleeding classification was done by computer algorithm. Tolerability was assessed by the rate of study drug discontinuation from bleeding.

Angina, Unstable↗

PubMed2000

Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment.

OBJECTIVE: Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries. STUDY DESIGN: The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available. RESULTS: The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis. CONCLUSION: None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Abnormalities, Drug-Induced↗

PubMed1995

Data handling in clinical trials: an ongoing debate.

Data handling is a crucial phase in controlled clinical trials. In this paper we conceive the process of data handling in a broad sense, encompassing monitoring, analysis and publication of data. We discuss basic ethical principles underlying adequate data handling and suggest some modifications of the Good Clinical Practice guidelines. As to data monitoring, we underline the corporate responsibilities and argue in favour of an independent Data and Safety Monitoring Board (DSMB). Data analysis should be performed in independent institutions, and there is a moral obligation to perform an interim analysis. Regarding accessibility of data, the raw data should be made available to participating researchers and independent scientific institutions, and both positive and negative results should be published, in agreement with a Report on Drug Information by the World Health Organization. To meet these requirements, commercial sponsors should have initiatives for independent DSMBs, interim analysis and complete data availability, and conceive corresponding contracts. The investigators can improve the quality of data handling by forming an Investigators Liaison Panel that represents them in the contacts with the sponsor. Finally, ethics committee and drug regulatory agencies should see to it that newly gained insights are being put into practice.

Clinical Trials as Topic↗

PubMed2004

When "minimal risk" research yields clinically-significant data, maybe the risks aren't so minimal.

Surveys and routine clinical procedures applied in research protocols are typically considered only minimally risky to participants. The apparent benign nature of "minimal risk" tasks increases the chance that investigators and Institutional Review Boards (IRBs) will overlook the probability that clinical tools will identify signs, symptoms, or definitive test results that are clinically-relevant to subjects' welfare. "Minimal risk" procedures may also pose a particular hazard to participants in clinical research by increasing the therapeutic misconception because the tasks mimic clinical care and are often conducted in clinical settings. Investigators should anticipate which measures could yield clinically-important findings and should describe explicit plans for data monitoring, disclosure, and follow-up. Protocols that include reliable and valid clinical measures should prompt a more detailed risk assessment by the IRB, even when the tasks meet the regulatory criteria for minimal physical, psychological, or emotional risk.

Behavioral Research↗

PubMed2001

Operational aspects of terminating the doxazosin arm of The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, practice-based trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI). The double-blind, active-controlled component of ALLHAT was designed to determine whether the rate of the primary outcome-a composite of fatal coronary heart disease and nonfatal myocardial infarction-differs between diuretic (chlorthalidone) treatment and each of three other classes of antihypertensive drugs: a calcium antagonist (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin) in high-risk hypertensive persons ages 55 years and older. In addition, 10,377 ALLHAT participants with mild to moderate hypercholesterolemia were also enrolled in a randomized, open-label trial designed to determine whether lowering serum LDL cholesterol with an HMG CoA reductase inhibitor (pravastatin) will reduce all-cause mortality as compared to a control group receiving "usual care." In January 2000, an independent data review committee recommended discontinuing the doxazosin treatment arm. The NHLBI director promptly accepted the recommendation. This article discusses the steps involved in the orderly closeout of one arm of ALLHAT and the dissemination of trial results. These steps included provisional preparations; the actual decision process; establishing a timetable; forming a transition committee; preparing materials and instructions; informing 65 trial officers and coordinators, 628 active clinics and satellite locations, 313 institutional review boards, over 42,000 patients, and the general public; reporting detailed trial results; and monitoring the closeout process. Control Clin Trials 2001;22:29-41

Adverse Drug Reaction Reporting Systems↗

PubMed2004

The PAV trial: does lactobacillus prevent post-antibiotic vulvovaginal candidiasis? Protocol of a randomised controlled trial [ISRCTN24141277].

BACKGROUND: Complementary and alternative medicines are used by many consumers, and increasingly are being incorporated into the general practitioner's armamentarium. Despite widespread usage, the evidence base for most complementary therapies is weak or non-existent. Post-antibiotic vulvovaginitis is a common problem in general practice, for which complementary therapies are often used. A recent study in Melbourne, Australia, found that 40% of women with a past history of vulvovaginitis had used probiotic Lactobacillus species to prevent or treat post-antibiotic vulvovaginitis. There is no evidence that this therapy is effective. This study aims to test whether oral or vaginal lactobacillus is effective in the prevention of post-antibiotic vulvovaginitis. METHODS/DESIGN: A randomised placebo-controlled blinded 2 x 2 factorial design is being used. General practitioners or pharmacists approach non-pregnant women, aged 18-50 years, who present with a non-genital infection requiring a short course of oral antibiotics, to participate in the study. Participants are randomised in a four group factorial design either to oral lactobacillus powder or placebo and either vaginal lactobacillus pessaries or placebo. These interventions are taken while on antibiotics and for four days afterwards or until symptoms of vaginitis develop. Women self collect a vaginal swab for culture of Candida species and complete a survey at baseline and again four days after completing their study medications. The sample size (a total of 496--124 in each factorial group) is calculated to identify a reduction of half in post-antibiotic vulvovaginitis from 23%, while allowing for a 25% drop-out. An independent Data Monitoring Committee is supervising the trial. Analysis will be intention-to-treat, with two pre-specified main comparisons: (i) oral lactobacillus versus placebo and (ii) vaginal lactobacillus versus placebo.

Adult↗

PubMed1997

An extension of stochastic curtailment for incompletely reported and classified recurrent events: the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH).

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), a double-blind randomized clinical trial, compared the frequency of acute vaso-occlusive (painful) crises during 2 yr of follow-up in 299 patients randomly assigned to hydroxyurea or placebo. Most patients had more than one crisis; all crises reported were included in the primary outcome analysis. A total of 7,229 follow-up medical contact reports were classified as crises/not crises by a Crisis Review Committee. Because of the time required to report, document, and classify contacts, interim analyses were prepared with incomplete data. If a stopping boundary were crossed, early termination could be advised only after assessing the potential impact of the incomplete data. In an extension of stochastic curtailment methods, simulation procedures were used to estimate the probability of detecting differences when group crisis rates projected to the end of the study were compared using a rank test. To account for medical contacts not yet reported and the future occurrence of crises, Poisson process models assuming no treatment effect on crisis rates were used for these simulations. The number of unclassified contacts that would be classified as crises was simulated as a binomial random variable. These methods may be useful for interim monitoring in other studies of recurrent events with ongoing event reporting and classification.

Anemia, Sickle Cell↗

PubMed2005

Contested ground: how should qualitative evidence inform the conduct of a community intervention trial?

This paper presents issues which arose in the conduct of qualitative evaluation research within a cluster-randomized, community-level, preventive intervention trial. The research involved the collection of narratives of practice regarding the intervention by community development officers working in eight communities over a two-year period. The community development officers were largely responsible for implementing the intervention. We discuss the challenges associated with the collection of data as the intervention unfolded, in particular, the disputes over cues to revise and adjust the intervention (i.e. to use the early data formatively). We explore the ethical uncertainties that arise when multiple parties have different views on the legitimacy of types of knowledge and the appropriate role of research and theory in various trial stages. These issues are discussed drawing on the fields of ethnography, community psychology, epidemiology, qualitative methodology and notions of research reflexivity. We conclude by arguing that, in addition to the usual practice of having an outcome data-monitoring committee, community intervention trials also require a process data-monitoring committee as a forum for debate and decision-making. Without such a forum, the relevance, ethics and position of qualitative evaluation research within randomized controlled trials are destined to be a point of contention rather than a source of insight.

Cluster Analysis↗

PubMed1998

Monitoring pregnancy outcomes following prenatal drug exposure through prospective pregnancy registries and passive surveillance: a pharmaceutical company commitment.

Objectives: Glaxo Wellcome (G.W.) becomes aware of prenatal exposures to its medications from as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all G.W. medicines has been developed utilizing a passive surveillance system and, for specific products, pregnancy registries. Additionally, G.W. jointly sponsors the multi-company Antiretroviral and North American Antiepileptic Drug (AED) Pregnancy Registries.Study Design: The registries are observational, case-registration and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. Pregnancies are registered prospectively following prenatal exposure to the registry medication. An advisory committee for each registry reviews data and assists in dissemination of information. Committee members include independent scientists with expertise in fields such as obstetrics, teratology, epidemiology, pediatrics, and the relevant therapeutic areas.Results: The following data are from the prospective first-trimester exposures in each registry. Through December 1996, the proportion of outcomes in the Acyclovir Pregnancy Registry with birth defects (n = 17/505) is 3.4% (95% CI 2.0%, 5.4%). Through March 1997, the proportion of outcomes in the Lamotrigine Pregnancy Registry with birth defects (n = 4/76) is 5.3% (95% CI 1.7%, 13.6%). Through April 1997, the proportion of outcomes in the Sumatriptan Pregnancy Registry with birth defects (n = 5/148) is 3.4% (95% CI 1.3%, 8.1%). The newer Valacyclovir and Bupropion Pregnancy Registries have insufficient data for analysis. None of the registries have provided a risk estimate exceeding that expected in the general population, and no pattern of defects has been observed.Conclusions: The outcomes accumulated to date represent a sample of insufficient size for reaching conclusions regarding the possible teratogenic risk of using these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies and to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the OB/GYN community to notify the registries of prenatal exposures.

Journal Article↗

PubMed1999

The impact of an end-point committee in a large multicentre, randomized, placebo-controlled clinical trial: results with and without the end-point committee's final decision on end-points.

BACKGROUND: A multicentre study permits rapid recruitment of a large number of patients. However, there is a risk of heterogeneities in end-point evaluations, as complex definitions of criteria are interpreted by several local investigators from different hospitals. Reports discussing end-point evaluation are sparse. The TRIM trial was a multicentre trial of a thrombin inhibitor in patients with unstable angina or non-Q myocardial infarction. In this study, an independent end-point committee evaluated all the reported events of death, acute myocardial infarction and refractory angina pectoris in order to obtain uniform judgements of major end-points. STUDY AIMS: To describe the work of the end-point committee, to analyse its possible effect on the final study results and to discuss the impact on the design of future trials. METHOD: The end-point committee consisted of four members, one from each participating country. After the data were processed by the study monitors, completed case record forms and patient files for patients with reported end-points were mailed to the national member of the end-point committee for judgement. The end-point committee met regularly and made final decisions about the end-points. The work of the end-point committee was documented on a separate case record form. RESULTS: The end-point committee assessed 246 events of death, acute myocardial infarction and refractory angina pectoris in 187 of the 1209 patients (15.5%) in the TRIM trial. Misinterpretation of the index event, an inclusion myocardial infarction, as an early cardiac event was found in 12 patients. After end-point committee judgements, the number of patients with acute myocardial infarction or refractory angina pectoris during 30 days of follow-up was reduced from 177 to 153 (13. 6% reduction). The classification of events was changed in 53 of 187 patients (28.3%) with death, acute myocardial infarction or refractory angina pectoris. The data assessed by the safety committee was significantly different from the final database after end-point committee judgements. CONCLUSION: The end-point committee corrected misinterpretations in such a high proportion of cases that the final results differed significantly from the preliminary results delivered to the safety committee. End-point judgements by an end-point committee should be performed in multicentre clinical trials to improve the quality and reliability of study results.

Anticoagulants↗

PubMed2002

Auditing of clinical research ethics in a children's and women's academic hospital.

OBJECTIVE: Canadian and international guidelines for research ethics practices have advocated that research ethics boards (REBs) should implement mechanisms to review and monitor human research. Despite this, few Canadian REBs fulfil this expectation. The objective of this report is to summarize the results of 6 audits of clinical research ethics conducted between 1992 and 2000 in a children's and women's academic hospital in Canada in an effort to guide other academic centres planning a similar process. DESIGN: Research audits were conducted by members of a research audit review committee made up of REB volunteers. With use of random and selective processes, approximately 10% of research protocols were audited through interviews with research investigators and research coordinators and by sampling research records. Predetermined criteria were used to assess evidence of good record keeping, data monitoring, adherence to protocol, consents and the recording of adverse events during the research study. An estimate of time required to undertake an audit was made by recall of participants and records. RESULTS: Thirty-five research studies were reviewed including 16 multicentre clinical trials and 19 single-site clinical studies. Review of record keeping and research practice revealed some deficiencies: researchers failed to maintain original authorization (7%) or renewal documentation (9%); there was 1 instance of improper storage of medication; in 5% of 174 participants for whom consent was reviewed, an outdated consent form had been used, and in 4% the signature of the enrolee was not properly shown. Other deficiencies in consent documentation occurred in less than 2% of cases. Nineteen recommendations were made with respect to deficiencies and process issues. A total of 9 to 20 person-hours are required to review each protocol in a typical audit of this type. CONCLUSIONS: Information from research audits has been useful to develop educational programs to correct deficiencies identified through the audits. The research audit is a valuable tool in improving research ethics performance but requires considerable resources.

Biomedical Research↗

PubMed2004

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial.

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1996

A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). The RANTTAS Investigators.

BACKGROUND AND PURPOSE: Tirilazad mesylate, a nonglucocorticoid 21-aminosteroid lipid peroxidation inhibitor, has shown promise as a neuroprotectant in experimental models of focal cerebral ischemia. METHODS: To test whether early treatment with tirilazad, 6 mg/kg per day for 3 days, would improve functional outcome after acute human stroke, 27 North American centers conducted a prospective, randomized, double-blinded, vehicle-controlled trial in patients with acute stroke treated within 6 hours of onset. The primary outcome measures were disability as measured by the Glasgow Outcome Scale and activities of daily living by the Barthel Index determined 3 months after stroke. RESULTS: From May 1993 through December 1994, 660 patients were randomized. The trial was prematurely terminated on the advice of an independent monitoring committee after review of outcome data at a preplanned interim analysis. In 556 fully eligible patients (276 tirilazad, 280 vehicle), the odds ratio of a favorable outcome in favor of tirilazad was 0.87 (95% confidence interval [CI], 0.60 to 1.25) for the Glasgow Outcome Scale and 0.87 (95% CI, 0.60 to 1.25) for the Barthel Index, after adjustment for imbalances between the groups in preexisting disability, prior stroke, and diabetes. CONCLUSIONS: These observations suggest that tirilazad, 6 mg/kg per day for 3 days administered beginning at a median of 4.3 hours after stroke, does not improve overall functional outcome.

Activities of Daily Living↗