Risk, Results, and Costs: Optimizing Clinical Trial Efficiency through Prognostic Enrichment.
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ABSTRACT:
SUBMITTER: Viele K
PROVIDER: S-EPMC7958522 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The analysis was performed in 2 parts: a descriptive analysis of the response within each adjuvant group and an analysis at the individual subject level. We used blood transcriptional modules to perform interpretation of the results.
2020-11-15 | GSE116975 | GEO
Project description:Little is known on how to best prioritize various tele-ICU specific tasks and workflows to maximize operational efficiency. We set out to: 1) develop an operational model that accurately reflects tele-ICU workflows at baseline, 2) identify workflow changes that optimize operational efficiency through discrete-event simulation and multi-class priority queuing modeling, and 3) implement the predicted favorable workflow changes and validate the simulation model through prospective correlation of actual-to-predicted change in performance measures linked to patient outcomes.SettingTele-ICU of a large healthcare system in New York State covering nine ICUs across the spectrum of adult critical care.PatientsSeven-thousand three-hundred eighty-seven adult critically ill patients admitted to a system ICU (1,155 patients pre-intervention in 2016Q1 and 6,232 patients post-intervention 2016Q3 to 2017Q2).InterventionsChange in tele-ICU workflow process structure and hierarchical process priority based on discrete-event simulation.Measurements and main resultsOur discrete-event simulation model accurately reflected the actual baseline average time to first video assessment by both the tele-ICU intensivist (simulated 132.8 ± 6.7 min vs 132 ± 12.2 min actual) and the tele-ICU nurse (simulated 128.4 ± 7.6 min vs 123 ± 9.8 min actual). For a simultaneous priority and process change, the model simulated a reduction in average TVFA to 51.3 ± 1.6 min (tele-ICU intensivist) and 50.7 ± 2.1 min (tele-ICU nurse), less than the added simulated reductions for each change alone, suggesting correlation of the changes to some degree. Subsequently implementing both changes simultaneously resulted in actual reductions in average time to first video assessment to values within the 95% CIs of the simulations (50 ± 5.5 min for tele-intensivists and 49 ± 3.9 min for tele-nurses).ConclusionsDiscrete-event simulation can accurately predict the effects of contemplated multidisciplinary tele-ICU workflow changes. The value of workflow process and task priority modeling is likely to increase with increasing operational complexities and interdependencies.
| S-EPMC7063929 | biostudies-literature
Project description:Osteoporosis and cardiovascular disease may share common biological pathways, with inflammation playing a role in the development of both. Although observational studies have suggested that statin use is associated with a lower risk of fractures, randomized trial data addressing this issue are scant.To determine whether statin therapy reduces the risk of fracture and, in a secondary analysis, whether baseline levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) are associated with the risk of fracture.The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial was an international, randomized, double-blind, placebo-controlled study enrolling 17,802 men older than 50 years and women older than 60 years with hs-CRP level of at least 2 mg/L. Participants were screened from 2003 to 2006 and observed prospectively for up to 5 years (median follow-up, 1.9 years).Rosuvastatin calcium, 20 mg daily, or placebo.Incident fracture was a prespecified secondary end point of JUPITER. Fractures were confirmed by radiographs, computed tomography, bone scan, or other methods. Cox proportional hazards models were used to calculate hazard ratios (HRs) and associated 95% confidence intervals for the risk of fracture according to randomized treatment assignment, as well as increasing tertiles of hs-CRP, controlling for potential confounders.During the study, 431 incident fractures were reported and confirmed. Among participants allocated to rosuvastatin, 221 fractures were confirmed, compared with 210 among those allocated to placebo, such that the incidence of fracture in the rosuvastatin and placebo groups was 1.20 and 1.14 per 100 person-years, respectively (adjusted HR, 1.06 [95% CI, 0.88-1.28]; P = .53). Overall, increasing baseline hs-CRP level was not associated with an increased risk of fractures (adjusted HR for each unit increase in hs-CRP tertile, 1.06 [95% CI, 0.94-1.20]; P for trend, .34).Among men and women with elevated hs-CRP level enrolled in a large trial of rosuvastatin therapy for cardiovascular disease, statin therapy did not reduce the risk of fracture. Higher baseline hs-CRP level was not associated with an increased risk of incident fracture.clinicaltrials.gov Identifier: NCT00239681.
| S-EPMC4578729 | biostudies-other
Project description:Clinical trial planning and site selection require an accurate estimate of the number of eligible patients at each site. In this study, we developed a tool to calculate the proportion of patients who would meet a specific trial's age, baseline severity, and time to treatment inclusion criteria.From a sample of 1322 consecutive patients with acute ischemic cerebrovascular syndromes, we developed regression curves relating the proportion of patients within each range of the 3 variables. We used half the patients to develop the model and the other half to validate it by comparing predicted vs actual proportions who met the criteria for 4 current stroke trials.The predicted proportion of patients meeting inclusion criteria ranged from 6% to 28% among the different trials. The proportion of trial-eligible patients predicted from the first half of the data were within 0.4% to 1.4% of the actual proportion of eligible patients. This proportion increased logarithmically with National Institutes of Health Stroke Scale score and time from onset; lowering the baseline limits of the National Institutes of Health Stroke Scale score and extending the treatment window would have the greatest impact on the proportion of patients eligible for a stroke trial.This model helps estimate the proportion of stroke patients eligible for a study based on different upper and lower limits for age, stroke severity, and time to treatment, and it may be a useful tool in clinical trial planning.
| S-EPMC2974263 | biostudies-other
Project description:For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in "basket" trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.
| S-EPMC6071856 | biostudies-other
Project description:The current commonly used single-guide RNA (sgRNA) structure has a shortened duplex compared with the native bacterial clustered regularly interspaced short palindromic repeats RNA (crRNA)–transactivating crRNA (tracrRNA) duplex. Here we show that modifying the sgRNA structure by extending the duplex length and mutating the fourth T of the continuous sequence of Ts (which is the pause signal for RNA polymerase III [pol III]) to C or G significantly, and sometimes dramatically, improves knockout efficiency in cells. In addition, the new sgRNA structure also significantly increases the efficiency of more challenging genome-editing procedures, such as gene deletion, which is important for inducing a loss-of-function in non-coding genes.
2015-11-17 | GSE74766 | GEO
Project description:AIM:The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin-to-creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. METHODS:Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75?mL/min/1.73?m2 and UACR between 300 and 5000?mg/g were enrolled. After a run-in period, eligible patients received 0.75?mg/d of atrasentan for 6?weeks. A total of 2648 responder patients in whom UACR decreased by ?30% compared to baseline were enrolled, as were 1020 non-responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3?kg and in whom brain natriuretic peptide exceeded ?300?pg/mL, or who experienced an increase in serum creatinine >20% (0.5?mg/dL), were not randomized. RESULTS:Baseline characteristics were similar for atrasentan responders and non-responders. Upon entry to the study, median UACR was 802?mg/g in responders and 920?mg/g in non-responders. After 6?weeks of treatment with atrasentan, the UACR change in responders was -48.8% (95% CI, -49.8% to -47.9%) and in non-responders was -1.2% (95% CI, -6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non-responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. CONCLUSIONS:The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection.
| S-EPMC6055730 | biostudies-literature
Project description:Lentiviral vector (LV)-based hematopoietic stem cell (HSC) gene therapy is becoming a promising clinical strategy for the treatment of genetic blood diseases. However, the current approach of modifying 1 × 108 to 1 × 109 CD34+ cells per patient requires large amounts of LV, which is expensive and technically challenging to produce at clinical scale. Modification of bulk CD34+ cells uses LV inefficiently, because the majority of CD34+ cells are short-term progenitors with a limited post-transplant lifespan. Here, we utilized a clinically relevant, immunomagnetic bead (IB)-based method to purify CD34+CD38- cells from human bone marrow (BM) and mobilized peripheral blood (mPB). IB purification of CD34+CD38- cells enriched severe combined immune deficiency (SCID) repopulating cell (SRC) frequency an additional 12-fold beyond standard CD34+ purification and did not affect gene marking of long-term HSCs. Transplant of purified CD34+CD38- cells led to delayed myeloid reconstitution, which could be rescued by the addition of non-transduced CD38+ cells. Importantly, LV modification and transplantation of IB-purified CD34+CD38- cells/non-modified CD38+ cells into immune-deficient mice achieved long-term gene-marked engraftment comparable with modification of bulk CD34+ cells, while utilizing ?7-fold less LV. Thus, we demonstrate a translatable method to improve the clinical and commercial viability of gene therapy for genetic blood cell diseases.
| S-EPMC5589063 | biostudies-literature
Project description:Patients with hypertension continue to have less than optimal blood pressure control, with nearly one in five Canadian adults having hypertension. Pharmacist prescribing is gaining favor as a potential clinically efficacious and cost-effective means to improve both access and quality of care. With Alberta being the first province in Canada to have independent prescribing by pharmacists, it offers a unique opportunity to evaluate outcomes in patients who are prescribed antihypertensive therapy by pharmacists.The study is a randomized controlled trial of enhanced pharmacist care, with the unit of randomization being the patient. Participants will be randomized to enhanced pharmacist care (patient identification, assessment, education, close follow-up, and prescribing/titration of antihypertensive medications) or usual care. Participants are patients in rural Alberta with undiagnosed/uncontrolled blood pressure, as defined by the Canadian Hypertension Education Program. The primary outcome is the change in systolic blood pressure between baseline and 24 weeks in the enhanced-care versus usual-care arms. There are also three substudies running in conjunction with the project examining different remuneration models, investigating patient knowledge, and assessing health-resource utilization amongst patients in each group.To date, one-third of the required sample size has been recruited. There are 15 communities and 17 pharmacists actively screening, recruiting, and following patients. This study will provide high-level evidence regarding pharmacist prescribing.Clinicaltrials.gov NCT00878566.
| S-EPMC3199859 | biostudies-literature
Project description:Recent clinical trials in mild Alzheimer disease (AD) have enriched for amyloid-specific positron emission tomography (PET) imaging and used extended versions of the AD Assessment Scale-Cognitive Subscale (ADAS-Cog) in an effort to increase the sensitivity to detect treatment effects. We used data from mild AD participants in the AD Neuroimaging Initiative to model trial effect sizes for 12- and 24-month trials using 3 versions of the ADAS-Cog and increased standardized uptake value ratio (SUVR) cutoffs for amyloid imaging inclusion criteria. For 12-month trials, extended ADAS-Cog versions improved effect sizes. The ADAS-Cog11 elicited larger effect sizes when enriching for SUVR 1.1 only, whereas the ADAS-Cog12 and ADAS-Cog13 were associated with larger effect sizes with higher SUVR thresholds. For 24-month trials, extended ADAS-Cog versions increased effect sizes for trials not enriched for amyloid and trials enriched for SUVR 1.1. Only enriching for higher SUVR thresholds (1.3 and 1.4, not 1.1) increased trial power. We conclude that extended versions of the ADAS-Cog improve mild AD trial effect sizes for both 12- and 24-month long studies, whereas amyloid imaging criteria may be most valuable for 12-month trials.
| S-EPMC5116001 | biostudies-literature