Therapy Trials (therapy + trials)

Distribution by Scientific Domains

Kinds of Therapy Trials

  • gene therapy trials

  • Selected Abstracts

    Baseline Characteristics of Patients Randomized in the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) Study

    Cecilia Linde MD
    The Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study is a randomized controlled trial currently assessing the safety and efficacy of cardiac resynchronization therapy in patients with asymptomatic left ventricular (LV) dysfunction with previous symptoms of mild heart failure. This paper describes the baseline characteristics of randomized patients; 610 patients with New York Heart Association (NYHA) class II (82.3%) heart failure or asymptomatic (NYHA class I) LV dysfunction with previous symptoms (17.7%) were randomized in 73 centers. The mean age was 62.511.0 years, the mean LV ejection fraction was 26.7%7.0%, and the mean LV end-diastolic diameter was 66.98.9 mm. A total of 97% of patients were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and 95.1% were taking ,-blockers, which were at the target dose in 35.1% of patients. Compared with previous randomized cardiac resynchronization therapy trials, REVERSE patients are on better pharmacologic treatment, are younger, and have a narrower QRS width despite similar LV dysfunction. [source]

    Home management of haemophilia

    HAEMOPHILIA, Issue 2 2004
    J. M. Teitel
    Summary., The demonstrated benefits of home care for haemophilia include improved quality of life, less pain and disability, fewer hospitalizations, and less time lost from work or school. Although reduced mortality has not been demonstrated, the substantial increase in longevity since the early 1980s correlates with the introduction of home treatment and prophylaxis programmes. These programmes must be designed and monitored by haemophilia treatment centres (HTC), which are staffed with professionals with broad and complementary expertise in the disease and its complications. In return, patients and their families must be willing to accept the reciprocal responsibilities that come from administering blood products or their recombinant equivalents at home. Patients with inhibitors to factors VIII or IX pose special challenges, but these complications do not obviate participation in home care programmes. Home care was an essential prerequisite to the introduction of effective prophylactic factor replacement therapy. Prophylaxis offers significant improvements in quality of life, but requires a substantial commitment. The use of implantable venous access devices can eliminate some of the difficulty and discomfort of peripheral venous access in small children, but brings additional risks. The future holds the promise of factor concentrates for home use that have longer half-lives, or can be administered by alternate routes. Knowledge of patient genotypes may allow treatments tailored to avoid complications such as inhibitor development. Gene therapy trials, which are currently ongoing, will ultimately lead to gene-based treatments as a complement to traditional protein-based therapy. [source]

    Cautionary tales in the interpretation of systematic reviews of therapy trials

    I. Scott
    Abstract This is the second in a series of articles emphasizing the cautions in the interpretation of health-care studies. Systematic reviews are presented as comprehensive, unbiased summaries of evidence and are often referred to by clinicians, guideline developers and health policy-makers. Their strengths and limitations, and how their results can be subject to bias and misinterpretation, are discussed. [source]

    Duloxetine for the Management of Diabetic Peripheral Neuropathic Pain: Response Profile

    PAIN MEDICINE, Issue 5 2007
    Yili L. Pritchett PhD
    ABSTRACT Objective., The current analysis examines the response profile in patients receiving duloxetine for the management of diabetic peripheral neuropathic pain (DPNP). Patients/Design., Data were pooled from three double-blind, randomized, placebo-controlled 12-week acute therapy trials of patients with DPNP of at least 6 months' duration. Study 1 (N = 457) had treatment groups of duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), and placebo; Studies 2 (N = 334) and 3 (N = 348) compared duloxetine 60 mg QD and 60 mg BID with placebo. The primary efficacy measure in each study was the weekly mean score of the 24-hour average pain severity. Treatment response was defined as a 30% reduction in pain severity, although some analyses were repeated using alternative response criteria (50% reduction, or 2-point reduction, in pain severity). Results., Consistently across the three studies, response rates at endpoint were significantly higher among patients receiving duloxetine (60 mg QD or 60 mg BID) than among those receiving placebo, regardless of the chosen response criterion (30% reduction, 50% reduction, or 2-point reduction in weekly mean of 24-hour average pain severity). The proportion of patients achieving pain relief in the duloxetine treatment groups was significantly greater than that in the placebo group at Week 1 and at all subsequent study visits to the end of acute phase therapy. Using diary data (24-hour average pain severity) from the first 7 days of treatment, the first significant separation from placebo in pain severity reduction for duloxetine 60 mg QD occurred at Day 1 (Study 1), Day 2 (Study 2), and Day 4 (Study 3), while significant separation in response rates first occurred at Day 3 when using pooled data. Conclusions., Patients with DPNP receiving duloxetine 60 mg QD or 60 mg BID had significantly higher rates of treatment response, when compared with patients receiving placebo, regardless of the chosen response criterion. Response to duloxetine treatment tended to occur early in therapy. [source]

    A phase I clinical trial of interferon-beta gene therapy for high-grade glioma: novel findings from gene expression profiling and autopsy

    Toshihiko Wakabayashi
    Background High-grade gliomas are highly lethal neoplasms representing approximately 20% of all intracranial tumors. Cationic liposome-mediated interferon-beta (IFN- ,) gene transfer has been found to induce regression of experimental glioma. We have previously performed a pilot clinical trial to evaluate the safety and effectiveness of this IFN- , gene therapy in five patients with high-grade glioma. Two patients showed more than 50% reduction while others had stable disease 10 weeks after treatment initiation. Methods To identify alterations in gene expression in brain tumors 2 weeks after the gene therapy trial, we used a microarray technology and Gene Ontology analysis. The results were validated by patients' clinical course and findings of histology and autopsy. Results and conclusions Using hierarchical clustering and principal component analysis, five series of gene therapy trials were classified according to the response to IFN- , gene therapy. Significant changes in gene expression related to immunoresponse and apoptosis were observed. Moreover, novel patterns of altered gene expression, such as inhibition of neovascularization, were identified, suggesting the involvement of pathways reported previously as not involved. Autopsy and histological examinations revealed dramatic changes in the tumor tissues after therapy in all patients. Many tumor cells showed necrotic changes, and immunohistochemistry identified numerous CD8-positive lymphocytes and macrophages infiltrating the tumor and surrounding tissues; these were probably the effects of therapy. Simultaneously, CD34-immunoreactive vessels were notably decreased in the vector-injected brain. This study facilitates the understanding of the antitumor mechanism and helps identify candidate target molecules for new approaches. However, additional clinical trials are warranted. Copyright 2008 John Wiley & Sons, Ltd. [source]

    Gene therapy legislation in The Netherlands

    D. A. Bleijs
    Abstract Several regulatory organisations are involved in the assessment of clinical gene therapy trials involving genetically modified organisms (GMOs) in The Netherlands. Medical, ethical and scientific aspects are, for instance, evaluated by the Central Committee on Research Involving Human Subjects (CCMO). The Ministry of Housing, Spatial Planning and the Environment (VROM) is the competent authority for the environmental risk assessment according to the deliberate release Directive 2001/18/EC. A Gene Therapy Office has been established in order to streamline the different national review processes and to enable the official procedures to be completed as quickly as possible. Although the Gene Therapy Office improved the application process at the national level, there is a difference of opinion between the EU member states with respect to the EU Directive according to which gene therapy trials are assessed, that urges for harmonisation. This review summarises the gene therapy legislation in The Netherlands and in particular The Netherlands rationale to follow Directive 2001/18/EC for the environmental risk assessment. Copyright 2007 John Wiley & Sons, Ltd. [source]

    An inventory of shedding data from clinical gene therapy trials

    Ellen A. M. Schenk-Braat
    Abstract Viruses are the most commonly used vectors for clinical gene therapy. The risk of dissemination of a viral vector into the environment via excreta from the treated patient, a phenomenon called shedding, is a major safety concern for the environment. Despite the significant number of clinical gene therapy trials that have been conducted worldwide, there is currently no overview of actual shedding data available. In this article, an inventory of shedding data obtained from a total of 100 publications on clinical gene therapy trials using retroviral, adenoviral, adeno-associated viral and pox viral vectors is presented. In addition, the experimental set-up for shedding analysis including the assays used and biological materials tested is summarized. The collected data based on the analysis of 1619 patients in total demonstrate that shedding of these vectors occurs in practice, mainly determined by the type of vector and the route of vector administration. Due to the use of non-quantitative assays, the lack of information on assay sensitivity in most publications, and the fact that assay sensitivity is expressed in various ways, general conclusions cannot be made as to the level of vector shedding. The evaluation of the potential impact and consequences of the observations is complicated by the high degree of variety in the experimental design of shedding analysis between trials. This inventory can be supportive to clinical gene therapy investigators for the establishment of an evidence-based risk assessment to be included in a clinical protocol application, as well as to national regulatory authorities for the ongoing development of regulatory guidelines regarding gene therapy. Copyright 2007 John Wiley & Sons, Ltd. [source]

    Limb-girdle muscular dystrophy type 2D gene therapy restores ,-sarcoglycan and associated proteins,,

    ANNALS OF NEUROLOGY, Issue 3 2009
    Jerry R. Mendell MD
    Objective ,-Sarcoglycan deficiency results in a severe form of muscular dystrophy (limb-girdle muscular dystrophy type 2D [LGMD2D]) without treatment. Gene replacement represents a strategy for correcting the underlying defect. Questions related to this approach were addressed in this clinical trial, particularly the need for immunotherapy and persistence of gene expression. Methods A double-blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into the extensor digitorum brevis muscle was conducted. Control sides received saline. A 3-day course of methylprednisolone accompanied gene transfer without further immune suppression. Results No adverse events were encountered. SGCA gene expression increased 4,5-fold over control sides when examined at 6 weeks (2 subjects) and 3 months (1 subject). The full sarcoglycan complex was restored in all subjects, and muscle fiber size was increased in the 3-month subject. Adeno-associated virus serotype 1 (AAV1)-neutralizing antibodies were seen as early as 2 weeks. Neither CD4+ nor CD8+ cells were increased over contralateral sides. Scattered foci of inflammation could be found, but showed features of programmed cell death. Enzyme-linked immunospot (ELISpot) showed no interferon-, response to ,-SG or AAV1 capsid peptide pools, with the exception of a minimal capsid response in 1 subject. Restimulation to detect low-frequency capsid-specific T cells by ELISpot assays was negative. Results of the first 3 subjects successfully achieved study aims, precluding the need for additional enrollment. Interpretation The finding of this gene replacement study in LGMD2D has important implications for muscular dystrophy. Sustained gene expression was seen, but studies over longer time periods without immunotherapy will be required for design of vascular delivery gene therapy trials. Ann Neurol 2009;66:290,297 [source]

    Tubular carcinoma of the breast: Prognosis and response to adjuvant systemic therapy

    ANZ JOURNAL OF SURGERY, Issue 1 2001
    P. R. B. Kitchen
    Background: Tubular carcinoma of the breast is an uncommon and usually small tumour, and is thought to have a favourable prognosis. The present study examined the long-term prognosis of patients with tubular breast carcinoma and the roles of axillary dissection and adjuvant therapy. Methods: Eighty-six tubular cases were identified from a large worldwide database of 9520 breast carcinoma patients entered into randomized adjuvant therapy trials run by the International Breast Cancer Study Group from 1978 to 1999. These patients were followed for a median of 12 years. Results: Forty-two (49%) cases were node-positive, of which 33 (79%) had 1,3 nodes involved. Ten (32%) of the 31 smaller tumours (, 1 cm in size) were node-positive. Patients with node-positive tubular carcinoma had a significantly better 10-year relapse-free survival (P = 0.006) and survival (P < 0.0001) compared with non-tubular node-positive cases. Overall survival was similar for node-positive and node-negative tubular carcinoma. Overall, 71 patients (83%) received some form of adjuvant systemic therapy. Of the 86 cases, 43 (50%) received more than one course of chemotherapy. There was an 85% decrease in the risk of death for patients who received more than one course of chemotherapy compared to those who did not (hazard ratio 0.15, 95% confidence interval (CI): 0.03,0.82; P = 0.03). Conclusions: Compared to other histological types of breast cancer, tubular carcinoma has a better long-term prognosis. Adjuvant chemotherapy may further improve prognosis and involvement of axillary nodes may not be an indicator for early death due to breast carcinoma. [source]

    Re-calibration and external validation of an existing nomogram to predict aggressive recurrences after radical prostatectomy

    BJU INTERNATIONAL, Issue 12 2010
    Florian R. Schroeck
    Study Type , Prognosis (case series) Level of Evidence 4 OBJECTIVE To re-calibrate the previously published Duke Prostate Center (DPC) nomogram for the prediction of biochemical recurrence (BCR) after radical prostatectomy (RP) to not only predict overall BCR but also the clinically more relevant endpoint of an aggressive recurrence (i.e. a BCR with a postoperative PSA doubling time (PSADT) of <9 months). PATIENTS AND METHODS Using the established point-scale system based upon the previously published DPC nomogram, we re-calibrated this point system to predict not just BCR, but also aggressive BCR within 2599 men treated with RP from the DPC database. PSADT was computed on all patients meeting the recurrence definition who had a minimum of two PSA values, separated by at least 3 months, and ,2 years after recurrence. External validation was performed using data from 1695 men treated with RP within the Shared Equal Access Regional Cancer Hospital (SEARCH) database by calculating the concordance index c and by plotting calibration curves. RESULTS The median follow-up for patients with no BCR was 56 and 47 months for DPC and SEARCH, respectively. In the DPC modelling cohort and the SEARCH validation cohort, 645 (25%) and 557 (33%) men had BCR, while 83 (3.2%) and 71 (4.2%) patients had an aggressive recurrence. In external validation, predictive accuracy for an aggressive BCR was high (c = 0.83) and the nomogram showed good calibration. CONCLUSIONS We re-calibrated an existing nomogram to not only predict overall BCR after RP but also aggressive recurrence after RP. Our new tool can provide valuable information for patient counselling and patient selection for adjuvant therapy trials. [source]

    Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients

    CANCER, Issue 7 2010
    Frank Sinicrope MD
    Abstract BACKGROUND: Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5-fluorouracil,based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data. METHODS: TNM stage II and III colon carcinomas (n = 982) from 6 5-fluorouracil,based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor-infiltrating lymphocytes (TILs) were quantified (n = 326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status. RESULTS: Defective MMR was detected in 147 (15%) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3%; 13 of 468); proximal tumors had a greater likelihood (26%; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic = 0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51% for defective MMR. In a patient subset (n = 326), a model including proximal site, TILs (>2/high-power field), and female sex showed even better discrimination (c statistic = 0.86), with a PPV of 81%. CONCLUSIONS: Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51% of tumors with defective MMR; substituting TILs for grade increases the PPV to 81%. These data can increase the efficiency of MMR testing to assist in clinical decisions. Cancer 2010. 2010 American Cancer Society. [source]

    Cationic Liposome Conjugation to Recombinant Adenoviral Vector Reduces Viral Antigenicity

    CANCER SCIENCE, Issue 4 2000
    Atsushi Natsume
    Adenoviral (Ad) vectors are commonly used in gene therapy trials because of their efficiency in gene transfer. However, their use is limited by immune responses that reduce transgene expression and decrease the efficacy of repeated vector administration. In this study, we demonstrated that conjugation of Ad vector with our novel cationic liposomes could reduce viral antigenicity in vivo. Mice subcutaneously injected with liposome-conjugated Ad vector showed a 6.5-fold reduction of anti-Ad antibodies with neutralizing activity, compared to those with unconjugated Ad vector. Interestingly, we also found that the conjugated vector is less susceptible to inactivation by neutralizing antibodies in vitro and in vivo. Our results suggest that liposome conjugation reduces viral antigenicity, shields vectors from neutralizing antibody, and may allow repeated Ad vector administration. [source]