Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.
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ABSTRACT:
SUBMITTER: Paganoni S
PROVIDER: S-EPMC7820979 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundA randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001.MethodsSurvival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity.ResultsA significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001.ConclusionsAnalysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).
| S-EPMC8388186 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE39642: NanoString nCounter immune-related gene expression in blood sorted CD14+CD16- monocytes from sALS, fALS and HC subjects GSE39643: NanoString miRNA profiling of peripheral blood sorted CD14+CD16- monocytes from amyotrophic lateral sclerosis, multiple sclerosis and healthy control subjects Refer to individual Series
2012-07-25 | E-GEOD-39644 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2012-07-26 | GSE39644 | GEO
Project description:Identification of amyotrophic lateral sclerosis (ALS) associated genes. Post mortem spinal cord grey matter from sporadic and familial ALS patients compared with controls. Keywords: other
2003-11-14 | GSE833 | GEO
Project description:In the Prostate Cancer Prevention Trial (PCPT), finasteride significantly reduced the risk of prostate cancer but was associated with an increased risk of high-grade disease. With up to 18 years of follow-up, we analyzed rates of survival among all study participants and among those with prostate cancer.We collected data on the incidence of prostate cancer among PCPT participants for an additional year after our first report was published in 2003 and searched the Social Security Death Index to assess survival status through October 31, 2011.Among 18,880 eligible men who underwent randomization, prostate cancer was diagnosed in 989 of 9423 (10.5%) in the finasteride group and 1412 of 9457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% confidence interval [CI], 0.65 to 0.76; P<0.001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3.0%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1.00 to 1.37; P=0.05). Of the men who died, 2538 were in the finasteride group and 2496 were in the placebo group, for 15-year survival rates of 78.0% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride group was 1.02 (95% CI, 0.97 to 1.08; P=0.46). Ten-year survival rates were 83.0% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73.0% and 73.6%, respectively, for those with high-grade prostate cancer.Finasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of follow-up, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer. (Funded by the National Cancer Institute.).
| S-EPMC4141537 | biostudies-other
Project description:OBJECTIVES:To conduct a geographically defined, UK-based case-control study, to examine any association between physical activity (PA) and amyotrophic lateral sclerosis (ALS). METHODS:A novel historical PA questionnaire was designed, validated, and subsequently administered in individual face-to-face interviews of 175 newly diagnosed sporadic ALS cases and 317 age- and sex-matched community controls. Historical PA energy expenditure and time spent in vigorous-intensity PA were derived from questionnaire data and compared between cases and controls. RESULTS:Participation in an extra 10kJ/kg/day of PA (equivalent to approximately 45minutes brisk walking) was consistently associated with an increased risk of ALS, with the strongest association observed for adulthood exercise-related PA (OR 1.47, 95% CI 1.10-1.97). An extra 10mins/day of vigorous PA was also associated with the odds of ALS (OR 1.03, 95% CI 1·01-1·05). Results were slightly attenuated following adjustment for smoking and educational attainment. CONCLUSIONS:To our knowledge this is the first study to demonstrate a positive association between ALS and PA participation using a specifically designed and validated historical PA questionnaire. Despite the well-established health benefits of PA, a high activity lifestyle may also be associated with elevated risk of ALS. Large-scale prospective studies in the future may help to confirm this association.
| S-EPMC4950417 | biostudies-literature
Project description:amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to death within a few years after diagnosis. Malnutrition and weight loss are frequent and are indexes of poor prognosis. Total body fat and fat distribution have not been studied in ALS patients.Our aim was to describe adipose tissue content and distribution in ALS patients.We performed a cross-sectional study in a group of ALS patients (n?=?62, mean disease duration 22 months) along with age and gender matched healthy controls (n?=?62) using a MRI-based method to study quantitatively the fat distribution.Total body fat of ALS patients was not changed as compared with controls. However, ALS patients displayed increased visceral fat and an increased ratio of visceral to subcutaneous fat. Visceral fat was not correlated with clinical severity as judged using the ALS functional rating scale (ALS-FRS-R), while subcutaneous fat in ALS patients correlated positively with ALS-FRS-R and disease progression. Multiple regression analysis showed that gender and ALS-FRS-R, but not site of onset, were significant predictors of total and subcutaneous fat. Increased subcutaneous fat predicted survival in male patients but not in female patients (p<0.05).Fat distribution is altered in ALS patients, with increased visceral fat as compared with healthy controls. Subcutaneous fat content is a predictor of survival of ALS patients.
| S-EPMC3694869 | biostudies-other
Project description:Objective: The heterogeneity of amyotrophic lateral sclerosis (ALS) survival duration, which varies from <1 year to >10 years, challenges clinical decisions and trials. Utilizing data from 801 deceased ALS patients, we: (1) assess the underlying complex relationships among common clinical ALS metrics; (2) identify which clinical ALS metrics are the "best" survival predictors and how their predictive ability changes as a function of disease progression. Methods: Analyses included examination of relationships within the raw data as well as the construction of interactive survival regression and classification models (generalized linear model and random forests model). Dimensionality reduction and feature clustering enabled decomposition of clinical variable contributions. Thirty-eight metrics were utilized, including Medical Research Council (MRC) muscle scores; respiratory function, including forced vital capacity (FVC) and FVC % predicted, oxygen saturation, negative inspiratory force (NIF); the Revised ALS Functional Rating Scale (ALSFRS-R) and its activities of daily living (ADL) and respiratory sub-scores; body weight; onset type, onset age, gender, and height. Prognostic random forest models confirm the dominance of patient age-related parameters decline in classifying survival at thresholds of 30, 60, 90, and 180 days and 1, 2, 3, 4, and 5 years. Results: Collective prognostic insight derived from the overall investigation includes: multi-dimensionality of ALSFRS-R scores suggests cautious usage for survival forecasting; upper and lower extremities independently degenerate and are autonomous from respiratory decline, with the latter associating with nearer-to-death classifications; height and weight-based metrics are auxiliary predictors for farther-from-death classifications; sex and onset site (limb, bulbar) are not independent survival predictors due to age co-correlation. Conclusion: The dimensionality and fluctuating predictors of ALS survival must be considered when developing predictive models for clinical trial development or in-clinic usage. Additional independent metrics and possible revisions to current metrics, like the ALSFRS-R, are needed to capture the underlying complexity needed for population and personalized forecasting of survival.
| S-EPMC6010549 | biostudies-literature
Project description:BackgroundBetter predictors of amyotrophic lateral sclerosis disease course could enable smaller and more targeted clinical trials. Partially to address this aim, the Prize for Life foundation collected de-identified records from amyotrophic lateral sclerosis sufferers who participated in clinical trials of investigational drugs and made them available to researchers in the PRO-ACT database.MethodsIn this study, time series data from PRO-ACT subjects were fitted to exponential models. Binary classes for decline in the total score of amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) (fast/slow progression) and survival (high/low death risk) were derived. Data was segregated into training and test sets via cross validation. Learning algorithms were applied to the demographic, clinical and laboratory parameters in the training set to predict ALSFRS-R decline and the derived fast/slow progression and high/low death risk categories. The performance of predictive models was assessed by cross-validation in the test set using Receiver Operator Curves and root mean squared errors.ResultsA model created using a boosting algorithm containing the decline in four parameters (weight, alkaline phosphatase, albumin and creatine kinase) post baseline, was able to predict functional decline class (fast or slow) with fair accuracy (AUC = 0.82). However similar approaches to build a predictive model for decline class by baseline subject characteristics were not successful. In contrast, baseline values of total bilirubin, gamma glutamyltransferase, urine specific gravity and ALSFRS-R item score-climbing stairs were sufficient to predict survival class.ConclusionsUsing combinations of small numbers of variables it was possible to predict classes of functional decline and survival across the 1-2 year timeframe available in PRO-ACT. These findings may have utility for design of future ALS clinical trials.
| S-EPMC5390993 | biostudies-literature
Project description:Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.
| S-EPMC7747476 | biostudies-literature