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A Real-World Observational Cohort of Patients with Hepatocellular Carcinoma: Design and Rationale for TARGET-HCC.
Cabrera, R, Singal, AG, Colombo, M, Kelley, RK, Lee, H, Mospan, AR, Meyer, T, Newell, P, Parikh, ND, Sangro, B, et al
Hepatology communications. 2021;(3):538-547
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Abstract
This study describes the design of the TARGET-hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET-HCC is a 5-year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice. Patients can complete patient-reported outcome measures and provide biological specimens for future translational studies. The TARGET-HCC study includes adults with histologic, cytologic, or radiologic diagnosis of HCC from academic and community centers in both the United States and Europe. A total of 1,841 participants were enrolled between January 9, 2017, and July 23, 2019, at 67 sites in the United States and Europe. To date, the most common liver disease etiology in the cohort continues to be hepatitis C, although nearly half had a nonviral etiology, including alcohol-related liver disease or nonalcoholic steatohepatitis. Most included patients were diagnosed at an early stage (Barcelona Clinic Liver Cancer Stage [BCLC] 0/A), but only approximately one third underwent curative treatment. Systemic therapy has been used in 7.3% of enrolled patients, including 45.7% of those with BCLC stage C tumors. Conclusion: Overall, the TARGET-HCC cohort allows for the assessment of patient characteristics and investigation of new treatment paradigms and sequencing with existing agents as well as novel regimens for HCC.
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Early score fluctuation and placebo response in a study of major depressive disorder.
Targum, SD, Cameron, BR, Ferreira, L, MacDonald, ID
Journal of psychiatric research. 2020;:118-125
Abstract
Early score fluctuation in double-blind, placebo-controlled studies may affect the reliability of the baseline measurement and adversely affect the eventual study outcome. We examined the effect of early score fluctuation during a 2-week double-blind placebo lead-in period in a phase II, double-blind, placebo-controlled trial of adjunctive s-adenosyl methionine (MSI-195) in MDD subjects who had had an inadequate response to ongoing antidepressant treatment. The overall study failed to meet its specified endpoints. We examined the score trajectories of all placebo-assigned subjects during the double-blind placebo lead-in period and subsequent 6-week treatment period. Placebo-assigned subjects with ≥20% HamD17 or MADRS score fluctuations (improvement or worsening) during the double-blind placebo lead-in period (prior to randomization) had significantly higher rates of placebo response and remission at week 8 compared to subjects with <20% response. A post-hoc analysis of evaluable subjects taken from the ITT population that excluded subjects with ≥20% early score response yielded higher effect sizes for both the HamD17 and MADRS sub-groups and statistical significance for MSI-195 over placebo in the MADRS sub-group (p = 0.012) with an effect size of 0.404. A reliable baseline measure is an asset for signal detection. These post-hoc findings suggest that study designs that anticipate and attempt to manage early response prior to randomization may yield more meaningful outcome data for trials of MDD and possibly other disorders as well.
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Individualised nutritional support in medical inpatients at nutritional risk: a randomised clinical trial.
Schuetz, P, Fehr, R, Baechli, V, Geiser, M, Deiss, M, Gomes, F, Kutz, A, Tribolet, P, Bregenzer, T, Braun, N, et al
Lancet (London, England). 2019;(10188):2312-2321
Abstract
BACKGROUND Guidelines recommend the use of nutritional support during hospital stays for medical patients (patients not critically ill and not undergoing surgical procedures) at risk of malnutrition. However, the supporting evidence for this recommendation is insufficient, and there is growing concern about the possible negative effects of nutritional therapy during acute illness on recovery and clinical outcomes. Our aim was thus to test the hypothesis that protocol-guided individualised nutritional support to reach protein and caloric goals reduces the risk of adverse clinical outcomes in medical inpatients at nutritional risk. METHODS The Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) is a pragmatic, investigator-initiated, open-label, multicentre study. We recruited medical patients at nutritional risk (nutritional risk screening 2002 [NRS 2002] score ≥3 points) and with an expected length of hospital stay of more than 4 days from eight Swiss hospitals. These participants were randomly assigned (1:1) to receive either protocol-guided individualised nutritional support to reach protein and caloric goals (intervention group) or standard hospital food (control group). Randomisation was done with variable block sizes and stratification according to study site and severity of malnutrition using an interactive web-response system. In the intervention group, individualised nutritional support goals were defined by specialist dietitians and nutritional support was initiated no later than 48 h after admission. Patients in the control group received no dietary consultation. The composite primary endpoint was any adverse clinical outcome defined as all-cause mortality, admission to intensive care, non-elective hospital readmission, major complications, and decline in functional status at 30 days, and it was measured in all randomised patients who completed the trial. This trial is registered with ClinicalTrials.gov, number NCT02517476. FINDINGS 5015 patients were screened, and 2088 were recruited and monitored between April 1, 2014, and Feb 28, 2018. 1050 patients were assigned to the intervention group and 1038 to the control group. 60 patients withdrew consent during the course of the trial (35 in the intervention group and 25 in the control group). During the hospital stay, caloric goals were reached in 800 (79%) and protein goals in 770 (76%) of 1015 patients in the intervention group. By 30 days, 232 (23%) patients in the intervention group experienced an adverse clinical outcome, compared with 272 (27%) of 1013 patients in the control group (adjusted odds ratio [OR] 0·79 [95% CI 0·64-0·97], p=0·023). By day 30, 73 [7%] patients had died in the intervention group compared with 100 [10%] patients in the control group (adjusted OR 0·65 [0·47-0·91], p=0·011). There was no difference in the proportion of patients who experienced side-effects from nutritional support between the intervention and the control group (162 [16%] vs 145 [14%], adjusted OR 1·16 [0·90-1·51], p=0·26). INTERPRETATION In medical inpatients at nutritional risk, the use of individualised nutritional support during the hospital stay improved important clinical outcomes, including survival, compared with standard hospital food. These findings strongly support the concept of systematically screening medical inpatients on hospital admission regarding nutritional risk, independent of their medical condition, followed by a nutritional assessment and introduction of individualised nutritional support in patients at risk. FUNDING The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau, Switzerland.
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Generalizability of the FOURIER trial to routine clinical care: Do trial participants represent patients in everyday practice?
Yao, X, Gersh, BJ, Lopez-Jimenez, F, Shah, ND, Noseworthy, PA
American heart journal. 2019;:54-62
Abstract
BACKGROUND In the FOURIER trial, evolocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, reduced cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). We aimed to examine how closely patients in routine practice resemble the FOURIER trial participants and to assess the observed cardiovascular risks based on trial eligibility and underrepresentativeness. METHODS Using a large US administrative database with linked laboratory data, we identified adult patients with ASCVD between January 1, 2012, and December 31, 2016. We identified the excluded and underrepresented populations and examined the risk of cardiovascular events (a composite endpoint of myocardial infarction [MI], stroke, angina, and coronary revascularization) based on trial eligibility and underrepresentativeness. RESULTS Only 15.2% of 233,977 patients met the FOURIER eligibility. Nearly 60% of the ineligible patients met at least 2 exclusion criteria. Among trial-eligible patients, elderly patients, women, minorities, and those without prior MI were underrepresented in FOURIER. Patients who would have been excluded from FOURIER had a diverse risk profile but, on average, had a lower cardiovascular risk than those who would have qualified (hazard ratio [HR] 0.84 [0.81-0.88], P < .001). Among the underrepresented patients, women and patients without prior MI had a lower cardiovascular risk (HR 0.77 [0.71-0.82], P < .001; HR 0.67 [0.63-0.72], P < .001, respectively). Only 47.2% of patients were on moderate-/high-intensity statins. CONCLUSIONS One in 7 ASCVD patients in practice would have qualified for FOURIER. The excluded and underrepresented populations were at a particularly low or high cardiovascular risk. Statin therapy was underused, and physicians may need to evaluate adherence before adding a proprotein convertase subtilisin-kexin type 9 inhibitor.
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Childhood adversities, negative life events and outcomes of non-pharmacological treatments for depression in primary care: A secondary analysis of a randomized controlled trial.
Yacaman-Mendez, D, Hallgren, M, Forsell, Y
Journal of psychiatric research. 2019;:152-158
Abstract
Non-pharmacological treatments for depression are effective and available in primary care, but useful prognostic factors are lacking. Childhood adversities (CA) and negative recent life events (RLE) increase the risk and severity of depression, though their effect on treatment outcomes remains understudied. Using a sample of 737 adult participants of a multicenter randomized controlled trial receiving physical exercise, internet based cognitive-behavioral therapy or treatment as usual, alone or in combination with antidepressants, this prospective study aimed to determine the impact of CA, RLE and their interaction as predictors of outcomes of non-pharmacological treatments for mild-moderate depression in primary care. Outcomes were depression severity (MADRS score) and response to treatment (≥50% reduction in MADRS score) after three months. Linear regression and modified Poisson regression were used, interaction was assessed with a product term (CA*RLE) and epidemiological measures of interaction. The number of CA and RLE were associated with higher depression severity at follow-up (CA: β = 0.79, 95% CI: 0.14 to 1.44 and RLE: β = 0.52, 95% CI: 0.14 to 0.72) and showed a trend towards lower rates of response to treatment (RR = 0.94, 95% CI: 0.86 to 1.03; and RLE: RR = 0.95, 95% CI: 0.90 to 0.99). Interaction between CA and RLE was not significant for depression severity (β = 0.10, 95% CI: -2.12 to 0.41) nor for response to treatment (RERI = -0.05, 95% CI = -0.33 to 0.24). CA and RLE are associated with worse outcomes of non-pharmacological treatments in primary care. Further studies to identify predictors of outcomes of non-pharmaological treatments for depression are needed.
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Serious Adverse Events Associated with Readmission Through One Year After Vertebral Augmentation with Either a Polyetheretherketone Implant or Balloon Kyphoplasty.
Beall, DP, Coe, JD, McIlduff, M, Bloch, D, Hornberger, J, Warner, C, Tutton, S
Pain physician. 2017;(6):521-528
Abstract
BACKGROUND The KAST (Kiva Safety and Efficacy) investigation device exempt (IDE) study indicated that the majority of patients responded equally well to vertebral augmentation using either an implant-based approach or balloon kyphoplasty (BK). Additional investigation has suggested that a subset of patients may benefit further by avoiding repeated readmissions due to serious adverse events (SAEs) if they receive one vertebral augmentation approach over another. OBJECTIVES The primary aim was to assess the effect of 2 different augmentation procedures on readmission rates for SAEs. STUDY DESIGN The KAST trial is a pivotal, multicenter, randomized, controlled trial conducted to evaluate an implant-based vertebral augmentation approach (implant) against BK. Post-hoc analysis was performed to evaluate SAEs and readmission rates. SETTING Twenty-one sites in North America and Europe. METHODS The treatment effect of vertebral implant versus BK on SAEs requiring unplanned readmission was evaluated by estimating the risk of SAEs associated with readmissions in KAST while controlling for key baseline covariates using multivariate Poisson regression modeling. RESULTS Forty (27.8%) patients with implants had 69 SAEs associated with readmission compared to 44 (31.2%) patients with BK having 103 events. The risk for all SAEs leading to readmission was 34.4% lower with the implant than for BK (95% confidence interval = 11.1%, 51.7%; P < 0.01). Multivariate analysis showed that the risk of SAEs associated with readmission was decreased in subjects treated with the implant compared to BK, and increased in patients with prior histories of vertebral compression fractures (VCFs) or significant osteoporosis. LIMITATIONS The power of the KIVA study was based on clinical efficacy criteria to meet FDA requirements and recommendations for equivalency or noninferiority. The primary endpoint in this post-hoc analysis is SAEs associated with readmissions; as a result, the sample size is underpowered, although the results remain significant. CONCLUSION The augmentation approaches compared here have similar pain relief and quality of life effects; the implant showed a lower risk of readmissions. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01123512. Key words: Vertebral compression fracture, kiva implant, balloon kyphoplasty, vertebroplasty, health economics, osteoporosis.
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Predictors of Functional Decline in Early Parkinson's Disease: NET-PD LS1 Cohort.
Bega, D, Kim, S, Zhang, Y, Elm, J, Schneider, J, Hauser, R, Fraser, A, Simuni, T
Journal of Parkinson's disease. 2015;(4):773-82
Abstract
BACKGROUND Data on predictors of decline in PD are largely based on de-novo populations and limited to the use of motor outcomes that fail to capture the full scope of disease. OBJECTIVE Determine the clinical predictors of decline in early treated PD using a novel multi-domain measure. METHODS Data from NINDS Exploratory Trials in PD Long-Term Study 1 (NET-PD LS1), a multicenter Phase 3 study of creatine in early treated PD, were analyzed. Functional decline was defined by a global outcome metric (GO) that consisted of: Schwab and England ADL scale, PD 39-item Questionnaire, Unified PD Rating Scale, Ambulatory Capacity Score, Symbol Digit Modalities Test, and Modified Rankin Scale. Univariate and multivariate models were used to test the association of predictors of interest with a standardized rank-sum of the GO. RESULTS 765 of 1741 participants completed five-year assessments and were included. Older age at disease onset (p < 0.0001), higher baseline levodopa equivalent dose (p = 0.01), and worse Scales for Outcomes of Parkinson's Disease Cognition score (p = 0.001) at baseline were the strongest predictors of functional decline in multivariate analysis. PD symptom subtype was not a significant predictor of outcome (p = 0.42). The full model was only a modest predictor of change in GO (R2 = 0.186). CONCLUSIONS This is the largest study to systematically assess predictors of functional decline in early treated PD over several years, and the first to use a multi-domain outcome measure of decline. Older age at disease onset and worse cognition, and not PD subtype, were predictors of decline.
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Assessment of abdominal pain through global outcomes and recent FDA recommendations in children: are we ready for change?
Mohammad, S, Di Lorenzo, C, Youssef, NN, Miranda, A, Nurko, S, Hyman, P, Saps, M
Journal of pediatric gastroenterology and nutrition. 2014;(1):46-50
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Abstract
OBJECTIVES Irritable bowel syndrome is a multisymptom construct, with abdominal pain (AP) acting as the driving symptom of patient-reported severity. The Food and Drug Administration considers a >30% decrease in AP as satisfactory improvement, but this has not been validated in children. We investigated the correspondence of 2 measures for AP assessment, ≥30% improvement in AP and global assessment of improvement. METHODS Secondary analysis of data from 72 children who completed a randomized clinical trial for abdominal pain-associated functional gastrointestinal disorders. Children completed daily assessment of AP intensity, functional disability inventory (FDI), question regarding pain's interference with activities, and 2 global assessment questions. We measured the extent to which ≥30% improvement of AP and global assessment questions correlated with each other and with disability. RESULTS The global questions correlated with each other (r=0.74; P<0.0001) and with a ≥30% improvement in AP (P<0.01). Global outcomes were satisfaction with treatment was inversely related to the child's report of interference with activities (P<0.01) and symptom relief was positively associated with ≥30% improvement in FDI scores (P<0.009). A 30% change in FDI scores was associated with global questions of symptom relief (P=0.009) but not with satisfaction with treatment (P=0.07). The association of AP improvement with interference with activities (P=0.14) or change in FDI scores (P=0.27) did not reach significance. CONCLUSIONS Currently used global assessments are significantly associated with decreased pain intensity, decreased interference with daily activities, and a ≥30% change in FDI scores, whereas recommended 30% improvement in pain intensity is not as comprehensive.
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The reciprocal effects of pain intensity and activity limitations: implications for outcomes assessment in clinical trials.
Jensen, MP, Molton, IR
The Clinical journal of pain. 2014;(1):9-16
Abstract
OBJECTIVES To examine the reciprocal effects of pain intensity and limitations in physical functioning over time. METHODS This study presents findings from a reanalysis of a 7-center trial conducted in Ontario, Canada, included 209 adults with chronic knee pain secondary to osteoarthritis. Patients were randomized to receive 28 days of therapy with an active solution (1.5% w/w diclofenac sodium in dimethyl sulfoxide) or 1 of 2 control solutions containing no diclofenac. The key outcome measures used in the current analyses were administered throughout the study period and assessed pain intensity, perceived activity limitations, and a composite score measuring both domains. A structural cross-lagged regression approach was used to determine the reciprocal effects of pain and activity limitations over time. RESULTS In both study groups, participants (N=209) experienced significant reductions in mean pain intensity and activity limitations from baseline to weeks 1, 2, 3, and 4 (P<0.001 for both variables). Similarly, there were significant reductions in the activity limitations outcome at weeks 1 and 4 for the active versus control group (P<0.05 for both). Higher levels of perceived activity limitations predicted more future pain at all time points. Cross-lagged associations in which pain predicted subsequent perceived activity limitations were not significant at any time point. All 3 outcome measures evidenced similar responsiveness to the treatment. CONCLUSION These analyses showed that a decrease in activity limitations results in a decrease in pain intensity. However, changes in pain intensity had no effect on subsequent activity limitations in the study sample. None of the 3 outcome variables emerged as being more responsive to treatment than the others.
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Correlates and responsiveness to change of measures of skin and musculoskeletal disease in early diffuse systemic sclerosis.
Wiese, AB, Berrocal, VJ, Furst, DE, Seibold, JR, Merkel, PA, Mayes, MD, Khanna, D
Arthritis care & research. 2014;(11):1731-9
Abstract
OBJECTIVE Skin and musculoskeletal involvement are frequently present early in diffuse cutaneous systemic sclerosis (dcSSc). The current study examined the correlates for skin and musculoskeletal measures in a 1-year longitudinal observational study. METHODS Patients with dcSSc were recruited at 4 US centers and enrolled in a 1-year study. Prespecified and standardized measures included physician and patient assessments of skin involvement, modified Rodnan skin score (MRSS), durometer score, Health Assessment Questionnaire disability index, serum creatine phosphokinase, tender joint counts, and presence/absence of tendon friction rubs, small joint contractures, and large joint contractures. Additionally, physician and patient global health assessments and health-related quality of life assessments were recorded. Correlations were computed among the baseline global assessments, skin variables, and musculoskeletal variables. Using the followup physician and patient anchors, effect sizes were calculated. RESULTS A total of 200 patients were studied: 75% were women, mean ± SD age was 50.0 ± 11.9 years, and mean ± SD disease duration from first non-Raynaud's phenomenon symptom was 1.6 ± 1.4 years. Physician global health assessment had large correlations with MRSS (r = 0.60) and physician-reported skin involvement visual analog scale in the last month (r = 0.74), whereas patient global assessment had large correlations with MRSS, the Short Form 36 health survey physical component scale, skin interference, and skin involvement in the last month (r = 0.37-0.72). Four of 9 skin variables had moderate to large effect sizes (0.51-1.09). CONCLUSION Physician and patient global assessments have larger correlations with skin measures compared to musculoskeletal measures. From a clinical trial perspective, skin variables were more responsive to change than musculoskeletal variables over a 1-year period, although both provide complementary information.