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PubMedDate not supplied

[Multicenter trials in the treatment of depression: some methodological issues].

In recent year, multicenter psychopharmacological trials have met an increasing interest since through them it has become easier, in a relatively short time, to collect large samples of patients. Methodological problems common to all psychopharmacological trials may be sharpened in this kind of investigation. Others, that are specifically related to multicenter studies, may also arise. Methodological difficulties addressed in this paper are those related to patients selection procedure, to strategies for data analysis and to issues about design or management of the study. Strictly speaking, the results of a such a trial could only be generalised to patients exhibiting the characteristics of the studied sample. Moreover, before pooling the data obtained at each center, preliminary analyses should demonstrate that centers do not differentiate themselves on the basis of patient characteristics. The new drug has to be compared to both a placebo and a reference compound. In this way, and through the replication of the expected difference between the placebo and the reference drug, the methodological validity of the trial could be ascertained. The treatment with a placebo is warranted by the facts that illness natural course and non specific treatment effects have to be taken into account. Satisfactory levels of inter-rater reliability have to be achieved and maintained through training sessions with the participation of all the centers involved in the trial. Statistical analyses generally focus on the intent to treat sample. However, due to the delayed activity of antidepressant drugs, efficacy analyses could be limited to patients treated at least 14 days. Multivariate analysis of variance is particularly well suited for data analysis but can be invalidated by an excess of dropouts. To overcome this problem, other techniques such as survival analysis and random regression models have been proposed. This latter procedure seems to be particularly promising for analysing data of multicenter trials since it can assess treatment difference while adjusting for inter-center variability.

Antidepressive Agents↗
PubMed2006

Reducing inter-scanner variability of activation in a multicenter fMRI study: role of smoothness equalization.

Scanner-to-scanner variability of activation in multicenter fMRI studies is often considered undesirable. The purpose of this investigation was to evaluate the effect of a new procedure, "smoothness equalization", on reducing scanner differences in activation effect size as part of a multicenter fMRI project (FIRST BIRN). Five subjects were sent to 9 centers (10 scanners) and scanned on 2 consecutive days using a sensorimotor fMRI protocol. High-field (4 T and 3 T) and low-field (1.5 T) scanners from three vendors (GE, Siemens, and Picker) were included. The activation effect size of the scanners for the detection of neural activation during a sensorimotor task was evaluated as the percent of temporal variance accounted for by our model (percent of variance accounted for or PVAF). Marked scanner effects were noted for both PVAF as well as the degree of smoothness of the raw and processed images. After smoothness equalization, there was a dramatic (low field) or consistent (high-field) reduction in scanner-to-scanner variation of activation. It was shown that the likely basis of the scanner differences in smoothness was differences in k-space filtering algorithms. This work highlights the need to account for differences in smoothness when comparing scanners on activation effect size in multicenter fMRI studies.

Adult↗
PubMed2005

[Multicenter Castleman disease in AIDS. Its relationship with HHV-8 or herpes virus associated to Kaposi's sarcoma. Study of two cases].

Castleman disease is considered a reactive lymphadenopathic picture with two clinical forms: one localized, frequent in immunocompetent patients and another multicenter one that is more characteristic in immunodepressed patients. Two cases of Castleman disease multicenter in HIV positive patients with Kaposi's sarcoma are presented. Both patients have multiple adenopathies, hepatomegaly and symptoms B on diagnosis. One of them had a favorable response to chemotherapy treatment and another died. A review of the concept of multicenter Castleman disease and its pathogenic relationship to human herpes virus 8 (HHV-8) is done.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Contribution of multicentered short hydrogen bond arrays to potency of active site-directed serine protease inhibitors.

We describe and compare the pH dependencies of the potencies and of the bound structures of two inhibitor isosteres that form multicentered short hydrogen bond arrays at the active sites of trypsin, thrombin, and urokinase type plasminogen activator (urokinase or uPA) over certain ranges of pH. Depending on the pH, short hydrogen bond arrays at the active site are mediated by two waters, one in the oxyanion hole (H(2)O(oxy)) and one on the other (S2) side of the inhibitor (H(2)O(S2)), by one water (H(2)O(oxy)), or by no water. The dramatic variation in the length of the active site hydrogen bonds as a function of pH, of inhibitor, and of enzyme, along with the involvement or absence of ordered water, produces a large structural manifold of active site hydrogen bond motifs. Diverse examples of multicentered and two-centered short hydrogen bond arrays, both at and away from the active site, recently discovered in several protein crystal systems, suggest that short hydrogen bonds in proteins may be more common than has been recognized. The short hydrogen bond arrays resemble one another with respect to ionic nature, highly polar environment, multitude of associated ordinary hydrogen bonds, and disparate pK(a) values of participating groups. Comparison of structures and K(i) values of trypsin complexes at pH values where the multicentered short hydrogen bond arrays mediating inhibitor binding are present or absent indicate that these arrays have a minor effect on inhibitor potency. These features suggest little covalent nature within the short hydrogen bonds, despite their extraordinary shortness (as short as 2.0 A).

Binding Sites↗
PubMed1981

Quality of institutional participation in multicenter clinical trials.

We studied the relation between an institution's degree of participation in a multicenter clinical trial and the quality of its participation. The quality of participation was judged on the basis of the percentage of patients entered into the trial who were in fact eligible, who were treated in accordance with the protocol, and for whom the appropriate forms were received. Those who satisfied these criteria were termed "valid" patients. Institutions were divided into two groups, "major participants" and "minor participants," according to the number of patients they entered in the trial. In a detailed analysis of a multicenter trial of chemotherapy for soft-tissue sarcoma, we found that major participants had a significantly higher percentage of valid patients than did minor participants (81 per cent vs. 39 per cent) and that the minor participants were actually detrimental to the study from both scientific and administrative viewpoints. These results suggest that institutions should not participate in multicenter studies unless they can enter some predetermined minimal number of patients per year.

Antineoplastic Agents↗
PubMed1985

Famotidine: nocturnal administration for gastric ulcer healing. Results of multicenter trials in Austria and Germany.

We conducted an 8-week, double-blind, randomized, placebo-controlled multicenter trial (Austria and Germany) to determine whether famotidine would speed healing or relief of symptoms in patients with benign gastric ulcer. Of the 65 patients who completed the trial, 32 received famotidine 40 mg once at night, and 33 received placebo. At 4, 6, and 8 weeks after entry, ulcers had healed in a larger percentage of patients treated with famotidine than in those treated with placebo (German multicenter trial: 65 vs. 46%, 95 vs. 71%, and 95 vs. 79%; Austrian multicenter trial: 42 vs. 44%, 67 vs. 44%, and 92 vs. 44%). In the famotidine group, healing had occurred significantly more often after 6 weeks (p less than 0.05). Famotidine was not superior to placebo in relieving ulcer symptoms. The findings suggest that famotidine in a single evening dose significantly hastens the healing of benign gastric ulcers.

Adolescent↗
PubMed1987

[Advantages and problems of multicenter therapy studies exemplified by a study of the treatment of metastasizing renal cell carcinoma with recombinant interferon-alpha-2c].

The advantages of multicenter trials are numerous: quicker recruitment of the necessary number of patients, clearer results which are more convincing and whose acceptance is higher, as the patient sample of multicenter trials is supposed to be representative. However, multicenter trials require strong efforts for quality assurance concerning admission, treatment and follow-up, thus a highly developed coordinating center is needed. Data on recruitment and protocol compliance, i.e. deviations from the study protocol, are presented for the study of the treatment of metastatic renal cell carcinoma and discussed with respect to their impact on the results of the study. 102 patients were randomized either for IFN alpha-2C or IFN alpha-2C plus medroxyprogesteroneacetate. 16% of the patients violated inclusion criteria and essential data were missing in 16% of the patients. Overall treatment results (remission rate of 5.6%, median survival time of 7 months) and the data on adverse events have been biased by lack of protocol compliance. However, the results concerning the lack of differences between treatments remain valid.

Carcinoma, Renal Cell↗
PubMed1996

Ambulatory monitoring of the blood pressure in multicenter clinical trials.

By reducing measurement error associated with clinic (or casual) blood pressure, ambulatory blood pressure measurement (ABPM) potentially enhances the precision of blood pressure estimation. Enhanced precision leads to lower sample size requirements or increased statistical power, or both, in clinical trials. Thus, by virtue of its increased numbers of measurements and improved reproducibility, ABPM can differentiate among active antihypertensive therapies when clinic blood pressure measurements do not. Additional benefits of ABPM can include identification of white-coat hypertensives, removal of observer bias, a marked reduction in placebo effects and evaluation of the circadian blood pressure pattern. By identifying circadian patterns, ABPM aids in the evaluation of the diurnal and nocturnal effects of a therapeutic regimen. ABPM has found more frequent application in the assessment of antihypertensive therapies in multicenter trials in recent years. However, using ABPM in multicenter trials might increase the complexities of the conduct of the trial relevant to the maintenance of homogeneity in study methods. Special concerns for multicenter trials involving ABPM include device use and validation, experience of study coordinators or research technicians and patient compliance. In recent years in the USA, ambulatory blood pressure values have been used to serve as secondary 'cut-off' criteria before random allocation in a trial (after primary entry criteria based on clinical blood pressure values have been satisfied). Sponsors of trials have become highly selective in recruiting study sites with substantial experience in ABPM. These practices may create a more homogeneous cohort in the trial and make the population less representative of the general hypertensive population.

Journal Article↗
PubMedDate not supplied

Issues in the design and implementation of multicenter studies in pediatric nephrology.

Multicenter studies in pediatric nephrology have been acknowledged in recent years to be an important means of studying renal disease in children. This review examines a number of issues that are important in the design and performance of a successful trial, with special emphasis on their significance for prospective clinical trials of antihypertensive medications in children and adolescents. Some issues to be covered include the most frequent difficulties that are encountered with multicenter studies, an historical perspective, specific design problems, the importance of close networking and communication, and the problems that may be anticipated with regards to authorship and financial reimbursement for time and effort. The paper concludes with a brief analysis of how multicenter studies involving hypertension protocols in children and adolescents might be conducted during the next few years.

Antihypertensive Agents↗
PubMed1986

Quantitative analysis of stress thallium-201 myocardial scintigrams: a multicenter trial.

Previously we validated a method for quantification of 201TI myocardial stress distribution and washout in which the patient's stress and washout circumferential profiles are compared with observed normal limits. The present study reports the results of a multicenter trial in which this method, utilizing normal limits from our institution, was employed to evaluate the presence, location, and extent of coronary artery disease (CAD). The normal limits utilized were generated from 49 patients having a low likelihood of CAD. The study population included 157 patients from four centers in the United States and Canada as well as a comparative prospective population from Cedars-Sinai Medical Center (CSMC) of 51 patients with CAD, 30 patients with normal coronary arteriograms, and 30 additional low-likelihood normals. The results in the combined centers regarding overall detection of CAD revealed a sensitivity of 84% and a frequency of test normality in the patients with low likelihood of CAD of 88%, compared to a sensitivity of 82% and true normalcy rate of 83% obtained in the prospective CSMC population. The sensitivity for detecting disease increased according to the extent of angiographic CAD in both the multicenter sites and the prospective CSMC group. Regarding localization of disease, similar sensitivities and specificities for detecting disease in individual coronary arteries were found in the multicenter sites and the prospective CSMC population. The results indicate that our method for quantifying 201TI stress-redistribution scintigrams utilizing standard normal limits can be applied at other institutions using a variety of scintillation cameras with similar accuracy to that currently obtained at our institution.

Adult↗
PubMed2004

Reliability of brain volumes from multicenter MRI acquisition: a calibration study.

Multicenter studies can provide additional information over single center studies because of their increased statistical power. Because similar acquisition protocols are being used internationally for structural magnetic resonance imaging (MRI) studies of the human brain, volumetric MRI data studies seem suitable for this purpose. Possible systematic differences between sites should be avoided, however, particularly when subtle differences in tissue volume are being searched for, such as in neuropsychiatric diseases. In this calibration study, the brains of six healthy volunteers were (re)scanned with MR scanners from four different manufacturers at five different sites, using the local acquisition protocols. The images were segmented at a central reference site. The intraclass correlation coefficient (ICC) was determined for the whole brain, gray and white matter, cerebellum, and lateral and third ventricle volumes. When required, the processing algorithms were calibrated for each site. Calibration of the histogram analysis was needed for segmentation of total brain volume at one site and for gray and white matter volume at all sites. No (additional) calibration was needed for cerebellum and ventricle volumes. The ICCs were > or = 0.96 for total brain, > or = 0.92 for cerebellum, > or = 0.96 for lateral ventricle, > or = 0.21 for third ventricle, > or = 0.84 for gray matter, and > or = 0.78 for white matter volume. Calibration of segmentation procedures allows morphologic MRI data acquired at different research sites to be combined reliably in multicenter studies.

Adult↗
PubMed2003

Computerized heart allograft-recipient monitoring: a multicenter study.

Computerized heart allograft recipient monitoring (CHARM) is a unique concept of patient surveillance after heart transplantation (HTx), based on the evaluation of intramyocardial electrograms (IEGMs) recorded non-invasively with telemetric pacemakers. Previous open, single-center studies had indicated a high correlation between CHARM results and clinical findings. The present study was initiated to assess the suitability of CHARM for monitoring the absence of rejection in a blind, multicenter context. During the HTx procedure, telemetric pacemakers and two epimyocardial leads were implanted in 44 patients at four European HTx centers. IEGMs during pacing were recorded and transferred via the Internet to the CHARM computer center, for automatic data processing and extraction of diagnostically relevant information, i.e., the maximum slew rate of the descending part of the repolarization phase of the ventricular evoked response (VER T-slew). The study period comprised the first 6 months after HTx, during which the transplant centers were blind to the CHARM results. A single threshold diagnosis model was prospectively defined to assess the ability of the VER T-slew to indicate clinically significant rejection, which was defined as an endomyocardial biopsy (EMB) grade greater than or equal to 2, according to the grading system of the International Society for Heart and Lung Transplantation. All EMB slides from three centers were reviewed blind by the pathologist of the fourth center in order that agreement among the histological diagnoses at the various centers could be assessed. Totals of 839 follow-ups and 366 EMBs were obtained in 44 patients. Thirty-seven patients were alive at the end of the study period. Age at HTx, EMB grade distribution, and rejection prevalence varied significantly between the centers. Review of the EMB results showed considerable differences with respect to classification of significant rejection. Comparison of average VER T-slew values with and without rejection in the 15 patients who exhibited both states revealed significantly lower values under the influence of rejection (97+/-13% vs 79+/-15%, P<0.0001). Twenty out of the 25 cases with significant rejection were correctly identified by VER T-slew values below a threshold of 98% (sensitivity =80%, specificity =50%, negative predictive value =97%, positive predictive value =11%; P<0.0005). Of the EMBs, 48% could have been saved if the diagnosis model had been used to indicate the need for EMB. A high negative predictive value for the detection of cases with significant rejection has been obtained in a prospective, blind, multicenter study. The presented method can, therefore, be used to supplement patient monitoring after HTx non-invasively, in particular to indicate the need for EMBs. In centers with patient management similar to the ones who participated in the study, this may allow a reduction in the number of surveillance EMBs.

Decision Making, Computer-Assisted↗
PubMed1988

Diabetic autonomic neuropathy--Part I. Autonomic nervous system data analysis by a computerized central unit in a multicenter trial.

To determine the feasibility of utilizing a central, computerized unit to analyze autonomic nervous system function tests for a 10-year, multicenter, clinical trial, the Autonomic Nervous System Reading Center was established. The Reading Center selected and standardized testing methods, designed the testing protocol, developed testing equipment, computerized data analysis, and instituted measures to monitor data quality. Three cardiovascular testing methods, RR-variation, Valsalva maneuver, and postural testing, were selected because each is a simple, non-invasive, quantitative, sensitive, and reproducible test. Furthermore, a hierarchy of sensitivity has been established with these cardiovascular autonomic nervous system measurements: RR-variation, Valsalva maneuver, and finally postural testing. Confounding variables were minimized by prescribing eligibility criteria. Testing equipment, designed to record time between RR intervals in a form easily read into a computer, has been in 21 clinics for three years and a total of 54 technicians have been trained. Over 85 percent of the autonomic nervous system tests performed have been usable at initial testing. A central reading center is an efficient and necessary means of collecting and analyzing data for a multicenter clinical trial.

Autonomic Nervous System Diseases↗
PubMed2003

Effect of trapidil on cardiovascular events in patients with coronary artery disease (results from the Japan Multicenter Investigation for Cardiovascular Diseases-Mochida [JMIC-M]).

A large-scale study was conducted to assess the effect of long-term administration of trapidil on the prognosis of patients with angiographic evidence of coronary artery disease (CAD). A large-scale, multicenter study, the Japan Multicenter Investigation for Cardiovascular Diseases-Mochida was an open-label, randomized trial of 1,743 patients with CAD who were < or =70 years old and had angiographic evidence of >25% stenosis in any coronary artery. We randomly assigned the patients to receive medical treatment either with trapidil 100 mg 3 times daily (trapidil group, n = 873) or without trapidil (control group, n = 870). The mean follow-up period was 924 days. The incidence of cardiovascular events, including cardiac death, nonfatal myocardial infarction, angina pectoris/heart failure requiring hospitalization, and cerebrovascular events was 11.1% in the trapidil group and 14.9% in the control group (relative risk 0.75, 95% confidence interval 0.58 to 0.98, p = 0.036). Thus, long-term intervention with trapidil in CAD reduces the incidence of cardiovascular events and improves the prognosis of patients with CAD.

Angina Pectoris↗
PubMed1990

The prognostic significance of first myocardial infarction type (Q wave versus non-Q wave) and Q wave location. The Multicenter Diltiazem Post-Infarction Research Group.

The prognostic significance of the type of first acute myocardial infarction (Q wave versus non-Q wave) and Q wave location (anterior versus inferoposterior) was determined from a multicenter data base involving 777 placebo-treated patients who were participants in the Multicenter Diltiazem Post-Infarction Trial. There were 224 patients (29%) with a non-Q wave infarction, 326 (42%) with an inferoposterior Q wave infarction and 227 (29%) with an anterior Q wave infarction. Mean left ventricular ejection fraction was significantly (p less than 0.001) lower in patients with an anterior Q wave infarction than in the other two groups (anterior Q wave 0.39; inferior Q wave 0.52; non-Q wave 0.53). Nevertheless, the total cardiac mortality rate during the follow-up period (average 25 months per patient) was only marginally higher (p = 0.42) in the anterior Q wave group (8.4%) than in the other two groups (inferoposterior Q wave 7.1%; non-Q wave 6.3%). The total first recurrent cardiac event was somewhat higher (p = 0.08) in the anterior Q wave group (18.1%) than in the other two groups (inferoposterior Q wave 11.7%; non-Q wave 15.6%). Survivorship analyses extending over 3 years revealed that electrocardiographic classification of the type of first infarction and Q wave location did not make significant independent contributions to the risk of postinfarction cardiac death or first recurrent cardiac event, either before or after adjustment for baseline clinical variables.

Adult↗
PubMed2005

Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial.

OBJECTIVE: The objective of this study was to evaluate, in an international multicenter phase III trial, the accuracy, use, and morbidity of intraoperative lymphatic mapping and sentinel node biopsy (LM/SNB) for staging the regional nodal basin of patients with early-stage melanoma. SUMMARY BACKGROUND DATA: Since our introduction of LM/SNB in 1990, this technique has been widely adopted and has become part of the American Joint Committee on Cancer (AJCC) staging system. Eleven years ago, the authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT-I) to compare 2 treatment approaches: wide excision (WE) plus LM/SNB with immediate complete lymphadenectomy (CLND) for sentinel node (SN) metastases, and WE plus postoperative observation with CLND delayed until the subsequent development of clinically evident nodal metastases. METHODS: After each center achieved 85% accuracy of SN identification during a 30-case learning phase, patients with primary cutaneous melanoma (> or =1 mm with Clark level > or =III, or any thickness with Clark level > or =IV) were randomly assigned in a 4:6 ratio to WE plus observation (WEO) with delayed CLND for nodal recurrence, or to WE plus LM/SNB with immediate CLND for SN metastasis. The accuracy of LM/SNB was determined by comparing the rates of SN identification and the incidence of SN metastases in the LM/SNB group versus the subsequent development of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was completed on March 31, 2002, after enrollment of 2001 patients. RESULTS: Initial SN identification rate was 95.3% overall: 99.3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rate of false-negative LM/SNB during the trial phase, as measured by nodal recurrence in a tumor-negative dissected SN basin, decreased with increasing case volume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. There were no operative mortalities. The low (10.1%) complication rate after LM/SNB increased to 37.2% with the addition of CLND; CLND also increased the severity of complications. CONCLUSIONS: LM/SNB is a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma. Even after a 30-case learning phase and 25 additional LM/SNB cases, the accuracy of LM/SNB continues to increase with a center's experience. LM/SNB should become standard care for staging the regional lymph nodes of patients with primary cutaneous melanoma.

Adolescent↗
PubMed1989

Prevention of chronic bronchitis exacerbations with ambroxol (mucosolvan retard). An open, long-term, multicenter study in 5,635 patients.

Different therapies can be applied for the prevention of chronic bronchitis exacerbations: vaccinations, antibiotics, immunomodulating and mucoregulating drugs. Among the latter, ambroxol was tested in a multicenter open study in 5,635 outpatients during a 6-month winter period. The results achieved in a large and heterogeneous number of patients confirm the positive trend already observed in a multicenter double-blind study versus placebo in 214 patients. Particularly significant is the decrease in the number of exacerbations with time, above all in patients with more than 2-3 episodes. In parallel, the improvement in the clinical pattern, observed through the contemporaneous assessment of respiratory signs and symptoms and of the length of antibiotic therapy, confirms the soundness of the results achieved.

Adolescent↗
PubMed1990

Effects of prostaglandin E1 on oxygen delivery and consumption in patients with the adult respiratory distress syndrome. Results from the prostaglandin E1 multicenter trial. The Prostaglandin E1 Study Group.

We wanted to determine the long-term effects of a continuous infusion of PGE1 on DO2 and VO2 in patients with ARDS. Data were obtained from a randomized double-blind multicenter trial, which evaluated the effects of PGE1 on survival in patients with ARDS. Patients were stratified according to treatment and outcome: placebo-died (n = 8); PGE1-died (n = 12); placebo-survived (n = 9); and PGE1-survived (n = 8). In the placebo-died group, elevations occurred in VO2, which were associated with increases in O2ext and a constant DO2. In contrast, in the PGE1-died group, elevations in VO2 were associated with increases in DO2 and an unchanged O2ext. In the placebo-survived group, VO2 and DO2 decreased, whereas in the PGE1-survived group, VO2 and DO2 increased; however, O2ext decreased in both of these groups. Since impaired O2ext occurs in ARDS, PGE1-induced elevations in DO2, rather than compensatory increases in O2ext, may achieve better tissue oxygenation. We conclude that although the recently completed multicenter trial failed to show an enhancing effect of PGE1 on survival in patients with advanced ARDS, PGE1 may have important effects on oxygen transport and, therefore, may still have a role in the treatment of early manifestations of ARDS, either alone or in combination with other agents.

Alprostadil↗