Collaborative Multicenter Trials Research Articles

National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: scientific opportunities in extracorporeal photopheresis.

The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresis's capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECP's induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012.

Collaborative multicenter trials in Latin America: challenges and opportunities in orthopedic and trauma surgery

CONTEXT AND OBJECTIVE Orthopedic research agendas should be considered from a worldwide perspective. Efforts should be planned as the means for obtaining evidence that is valid for health promotion with global outreach. DESIGN AND SETTING Exploratory study conducted at Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil, and McMaster University, Hamilton, Canada. METHODS We identified and analyzed collaborative and multicenter research in Latin America, taking into account American and Canadian efforts as the reference points. We explored aspects of the data available from official sources and used data from traffic accidents as a model for discussing collaborative research in these countries. RESULTS The evaluation showed that the proportion of collaborative and multicenter studies in our setting is small. A brief analysis showed that the death rate due to traffic accidents is very high. Thus, it seems clear to us that initiatives involving collaborative studies are important for defining and better understanding the patterns of injuries resulting from orthopedic trauma and the forms of treatment. Orthopedic research may be an important tool for bringing together orthopedic surgeons, researchers and medical societies for joint action. CONCLUSIONS We have indicated some practical guidelines for initiatives in collaborative research and have proposed some solutions with a summarized plan of action for conducting evidence-based research involving orthopedic trauma.

Dealing with heterogeneous populations in randomized wound trials: Challenges and potential solutions

Chronic wounds have a great variety of etiologies and manifestations that influence wound healing. Such heterogeneity potentially threatens the validity and clinical usefulness of trials if not considered appropriately. In 82 randomized wound trials retrieved from 10 Cochrane reviews, we assessed if and how authors considered wound and other prognostically important characteristics in the conduct and analysis of wound trials. We assessed whether these characteristics were discussed, reflected in the eligibility criteria, used for prestratification or for adjustments to ensure comparability of treatment groups, and whether subgroup analyses were conducted to identify heterogeneity of treatment effects. Nine percent of all trials explicitly discussed characteristics that influence wound healing in the introduction and 43% in the Discussion section. Ninety percent of trials had at least one prognostically important characteristic as eligibility criterion. Only 11% of trials used prestratification, and 6% adjusted the results for imbalances between treatment groups. Twenty-seven percent performed subgroup analyses with prognostically important characteristics defining subgroups. Chronic wound trials use simple randomization, but rarely adapt the study design and analysis to take the heterogeneity of patients into consideration. Collaborative multicenter trials would overcome many of the limitations and provide statistical power to detect important treatment effects both overall and in subgroups.

Neuroanesthesia: from bench to bed

It has been over 40years since the term "neuroanesthesia" emerged. The anesthesiologists specializing in neuroanesthesia have actively conducted basic research on cerebral ischemia as well as on cerebral blood flow and metabolism. However, translating the results of basic research using experimental animals into clinical applications has been often unsuccessful, especially in the area of cerebral ischemia. The negative results produced by a series of hugely costly and time-consuming collaborative multicenter trials have disappointed many researchers. It could be argued that discrepancies in the efficacy of an agent ought to be viewed in the context of the differences between experimental animals and humans since they have considerably different higher-order functions, and consequently the relevance of using experimental animals is brought into question. Nevertheless, the accuracy of basic research can be improved by taking measures to reduce bias. Taking such measures may enable more careful judgments to be made at the basic research stage and prevent unnecessary clinical studies. Although it could be seen as taking a slight detour, it is advisable to create a system that facilitates confirmation of the original findings by a multicenter basic research project before starting a collaborative multicenter clinical trial.

Cardiac allograft vasculopathy in children — treatment challenges

Cardiomyopathy in children accounts for greater than 50% of the cases of end-stage cardiac disease leading to heart transplantation in children. While early survival is excellent, late survival is limited with an average graft half-life of approximately 15 years in children. Cardiac allograft vasculopathy is a not uncommon complication of transplantation and is the leading cause of late graft loss and retransplantation in pediatric populations. Studies of the United Network of Organ Sharing database and the Pediatric Heart Transplant Study group report rates of coronary vasculopathy that increase from 5% at 2 years to 35% at 10 years. Coronary artery vasculopathy is a complex process caused by both immune mediated endothelial dysfunction and vascular changes as well as typical cardiovascular risk factors. Unfortunately, despite vigilant surveillance protocols, new onset graft dysfunction and sudden cardiac death can be the presenting symptoms of new disease. In recent years multiple medical and adjuvant therapies have been studied in relation to potential management to minimize this disease process. Further research and collaborative multi-center trials will be the most effective means of developing strategies for the prevention and treatment of coronary vasculopathy in pediatric heart transplant patients.

Tumor Biology Influences the Prognosis of Nephroblastoma Patients With Primary Pulmonary Metastases

To analyze the outcome of Wilms' tumor patients with primary lung metastases. Radiotherapy and/or surgery are used for local control of primary pulmonary Wilms' tumor metastases. A widely accepted treatment standardization is still lacking. Data for 210 patients with Wilms' tumor and primary lung metastases from the collaborative multicenter trials SIOP 93-01/GPOH and SIOP 2001/GPOH of the German Society of Pediatric Oncology and Hematology were reviewed. Analyses included patient data, tumor characteristics, local treatment, outcome and possible prognostic factors. Five-year overall survival (OS) was 83.3% and 5-year event free survival (EFS) was 72.3% for all children. Survival was significantly poorer in children with high risk primary tumor histology (OS 44.4%) compared to low risk (OS 100.0%) and intermediate risk histology (OS 89.2%, P < 0.001). Within the high risk group, tumors of the blastemal subtype (OS 56.5%) were associated with a significantly better outcome than those presenting with diffuse anaplasia (OS 22.2%, P = 0.02). Further, prognostic markers were lacking response to chemotherapy (P = 0.011), persistence of metastases after local treatment (P = 0.007), and vitality of metastases (P = 0.01). The prognosis of children with primary Wilms' tumor lung metastases mainly depends on the biology of primary tumors and metastases and is excellent with adequate treatment. Pulmonary metastasectomy is indicated if complete remission can be achieved to avoid lung irradiation. In the future a standardized local approach to nonresponding lung metastases (metastasectomy, irradiation, or both) will have to be prospectively evaluated regarding outcome, acute toxicity, and late effects.

Conducting industry-partnered trials in orthopaedic surgery

We have seen an emergence of larger scale collaborative multi-center trials in surgery. These larger trials have the advantage of increased generalisability of the results and the potential for large scale and efficient recruitment (1000 patients or more). It is estimated that the average cost of bringing a new drug to market approximates 500 million dollars. The funding limitations in most national peer-reviewed agencies provides a compelling rationale for industry co-sponsors. To limit biases associated with industry-sponsored research, researchers should develop specific protocols to ensure accurate and transparent reporting of funding sources, design and implementation of surgical trials, manuscript preparation and the criteria for authorship.

THE EDMONTON EXPERIENCE WITH VENOVENOUS (VV) EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) † 1562

VV ECMO is not widely used. A recent collaborative multicenter trial of neonatal ECMO showed that only 25% of the patients received VV ECMO (Lancet 1996;348:75-82). We retrospectively reviewed the charts of all neonatal ECMO candidates admitted to the NICU at the RAH since the introduction of VV ECMO in March 1993 to December 1996. Sixty-five near-term and term neonates were supported with ECMO during this period. Fifty-seven (88%) were initially supported by VV ECMO and 8 (12%) by venoarterial (VA) ECMO. Five (9%) of those initially supported by VV ECMO required conversion to VA ECMO for myocardial dysfunction. Six of the 8 VA ECMO neonates were placed on VA ECMO due to cannulation failure (small jugular vein) and the other two because of myocardial dysfunction. The neonates placed on VV ECMO were unstable with an oxygenation index of 89 ± 40 (mean ± SD), and requiring inotropic support of dopamine at 18 ± 7 mcg/kg/min and epinephrine at 1.2 ± 1 mcg/kg/min. The following table compares survival between the RAH and the Extracorporeal Life Support Organization(ELSO) data (January 1996) according to diagnosis when only VV ECMO was used. Fisher's exact test was employed.

Standardization of sensitive human immunodeficiency virus coculture procedures and establishment of a multicenter quality assurance program for the AIDS Clinical Trials Group. The NIH/NIAID/DAIDS/ACTG Virology Laboratories.

An independent quality assurance program has been established by the Division of AIDS, National Institute of Allergy and Infectious Diseases, for monitoring virologic assays performed by nearly 40 laboratories participating in multicenter clinical trials in the United States. Since virologic endpoints are important in evaluating the timing and efficacy of therapeutic interventions, it is imperative that virologic measurements be accurate and uniform. When the quality assurance program was initially created, fewer than 40% of the laboratories could consistently recover human immunodeficiency virus (HIV) from peripheral blood mononuclear cells (PBMCs) of HIV-infected patients. By comparing coculture procedures in the more competent laboratories with those in laboratories who were struggling to isolate virus, optimal conditions were established and nonessential reagents and practices were eliminated. Changes were rapidly introduced into a laboratory when experience dictated that such modifications would result in a favorable outcome. Isolation of HIV was enhanced by optimizing the numbers and ratios of patient and donor cells used in cultures, by standardizing PBMC separation procedures, by using fresh rather than frozen donor PBMCs, by processing whole blood within 24 h, and by using natural delectinated interleukin 2 instead of recombinant interleukin 2 products in existence at that time. Delays of more than 8 h in the addition of phytohemagglutinin-stimulated donor cells to freshly separated patient PBMCs reduced recovery. Phytohemagglutinin in cocultures and the addition of Polybrene and anti-human alpha interferon to media were not important in HIV isolation. The introduction of a consensus protocol based on this information brought most laboratories quickly into compliance. In addition, monthly monitoring has successfully maintained proficiency among the laboratories, a process that is critical for the scientific integrity of collaborative multicenter trials. Problems which might not be appreciated for months are now being resolved early, before data can be compromised unknowingly. This consensus protocol is recommended for any laboratory attempting to isolate HIV for the purpose of standardizing recovery and for accessing virologic endpoints in clinical trials.

Zoladex vs. Zoladex Plus Cyproterone Acetate in the Treatment of Advanced Prostatic Cancer: A Multicenter Italian Study

A collaborative multicenter trial was conducted by 17 Italian groups to verify whether the so-called total androgen blockade obtained with luteinizing hormone releasing hormone (LHRH) analogs combined with antiandrogens is more effective than conventional monotherapy in the treatment of advanced prostatic cancer. A total of 328 previously untreated patients were evaluated: 163 patients received Zoladex depot alone, 3.6 mg subcutaneously every 28 days, and 165 patients received Zoladex depot plus cyproterone acetate (CPA), 200 mg/day orally. The follow-up period ranged from 41-251 weeks. Treatment was well tolerated, and side-effects in both groups mainly comprised loss of libido and erections, hot flashes and breast swelling and tenderness. There was no significant difference in objective response after 6, 12 and 24 months of treatment between the 2 groups. Median time to disease progression was comparable in both groups: 55 weeks in the Zoladex group and 54 weeks in the Zoladex plus CPA group. The time to disease progression and the survival distribution was comparable in both groups. Although there were no significant differences in the overall subjective response to both treatments, a faster improvement, with respect to pain and performance status was noted in the Zoladex plus CPA group (8 weeks) compared to Zoladex alone (12 weeks). The addition of antiandrogen, by inhibiting the initial elevation of plasma testosterone, may prevent the disease flare-up which occurs in a small number of patients during the first few days of treatment with LHRH analogs alone.(ABSTRACT TRUNCATED AT 250 WORDS)