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Santosh Kumar, Rada, and A. Rama Krishna. "Clinical Endpoint: Substitute for Prediction of Clinical Benefit." Journal of Drug Delivery and Therapeutics 9, no. 4-s (August 29, 2019): 800–802. http://dx.doi.org/10.22270/jddt.v9i4-s.3367.
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An endpoint is a primary or secondary outcome used to judge the effectiveness of a treatment; it is a precisely defined variable intended to reflect an outcome of interest thatis statistically analyzed. An endpoint usually specifies the sort of assessments made, the timing of those assessments, the assessment tools used and possibly other details, as applicable, such as how multiple assessments within an individual are to be combined. There are different types of endpoints used in clinical trails like primary endpoint, secondary endpoint, multiple endpoint and surrogate endpoint. Primary endpoint means the outcome or event that most accurately measures the benefit of the therapy or drug being studied and this is the most clinically important endpoint. Secondary endpoints are related to toxicity and undesired effects of the new therapy to demonstrate additional effects on the disease or condition. Multiple endpoint is useful in determining clinical advantage of drug depending on one illness side. A surrogate endpoint is a laboratory measure or a physical sign supposed to be used as a substitute for a clinically meaningful endpoint which in all fairness possible to predict clinical benefit.
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Maestrini, Ilaria, Marta Altieri, Laura Di Clemente, Edoardo Vicenzini, Patrizia Pantano, Eytan Raz, Mauro Silvestrini, et al. "Longitudinal Study on Low-Dose Aspirin versus Placebo Administration in Silent Brain Infarcts: The Silence Study." Stroke Research and Treatment 2018 (October 3, 2018): 1–9. http://dx.doi.org/10.1155/2018/7532403.
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Background. We investigated low-dose aspirin (ASA) efficacy and safety in subjects with silent brain infarcts (SBIs) in preventing new cerebrovascular (CVD) events as well as cognitive impairment.Methods. We included subjects aged ≥45 years, with at least one SBI and no previous CVD. Subjects were followed up to 4 years assessing CVD and SBI incidence as primary endpoint and as secondary endpoints: (a) cardiovascular and adverse events and (b) cognitive impairment.Results. Thirty-six subjects received ASA while 47 were untreated. Primary endpoint occurred in 9 controls (19.1%) versus 2 (5.6%) in the ASA group (p=0.10). Secondary endpoints did not differ in the two groups. Only baseline leukoaraiosis predicts primary [OR 5.4 (95%CI 1.3-22.9, p=0.022)] and secondary endpoint-a [3.2 (95%CI 1.1-9.6, p=0.040)] occurrence.Conclusions. These data show an increase of new CVD events in the untreated group. Despite the study limitations, SBI seems to be a negative prognostic factor and ASA preventive treatment might improve SBI prognosis.EU Clinical trialis registered with EudraCT Number:2005-000996-16; Sponsor Protocol Number: 694/30.06.04.
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O'Neill, Robert T. "Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance." Controlled Clinical Trials 18, no. 6 (December 1997): 550–56. http://dx.doi.org/10.1016/s0197-2456(97)00075-5.
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Le Tourneau, C., S. Michiels, H. Gan, and L. Siu. "Reporting of endpoints and tracking of failures in randomized trials of radiotherapy or concurrent chemoradiotherapy for locally advanced head and neck squamous cell cancer (LA-HNSCC)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 6072. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.6072.
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6072 Background: Due to their anatomical complexity, the interactive effects of multiple treatment modalities, the difficulties in differentiating scar tissues versus residual disease and second cancers versus tumor recurrence, LA-HNSCC represent a challenging disease for the reporting of endpoints and the tracking of failures. Methods: We retrieved all randomized trials that began accrual on or after 1978, and enrolled previously untreated nonmetastatic HNSCC patients receiving primary (chemo)radiotherapy. The reporting of endpoints and the tracking of failures in these trials were analyzed. Failures were defined as events meeting a pre-specified endpoint definition. Results: Forty trials involving 13,892 patients fulfilled our inclusion criteria. A total of 125 endpoints were identified: primary versus secondary = 34:91, survival-based (e.g., overall survival [OS]) versus surrogate (e.g. locoregional control [LRC]) = 47:78. In 6 trials, no primary endpoint was identified. LRC and OS accounted for 70% of primary endpoints. All but one trial reported at least one secondary endpoint, with a median of 2 per trial (range: 0–5), and as many as 17 different types of secondary endpoints were reported. Among 72 endpoints tracking locoregional failures, 21/72 (29%) did not define locoregional failure, while 46/72 (64%) specified the absence of complete response as a failure. Whether salvage surgery or elective node dissection was performed or not was reported in less than half of the trials. Furthermore, it was usually not specified if residual disease found during these procedures would account for failure or not. The means (i.e. clinical and/or radiological examinations) to ascertain failures and the protocol-specified timing to track failures were reported in 41% and 67% of surrogate endpoints, respectively. The tracking of other types of failure beyond the first failure is not reported by any of the trials. The reporting of second cancers was found in 15/40 (38%) trials, whereas the duration of follow-up was quantified in 31/40 (78%) trials. Conclusions: These results demonstrate the vast heterogeneity in endpoint reporting and tracking of failures in clinical trials of LA-HNSCC. No significant financial relationships to disclose.
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O'Mahony, Denis, Adalsteinn Gudmundsson, Roy L. Soiza, Mirko Petrovic, Alfonso Jose Cruz-Jentoft, Antonio Cherubini, Richard Fordham, et al. "Prevention of adverse drug reactions in hospitalized older patients with multi-morbidity and polypharmacy: the SENATOR* randomized controlled clinical trial." Age and Ageing 49, no. 4 (June 2, 2020): 605–14. http://dx.doi.org/10.1093/ageing/afaa072.
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Abstract Background Multi-morbidity and polypharmacy increase the risk of non-trivial adverse drug reactions (ADRs) in older people during hospitalization. Despite this, there are no established interventions for hospital-acquired ADR prevention. Methods We undertook a pragmatic, multi-national, parallel arm prospective randomized open-label, blinded endpoint (PROBE) controlled trial enrolling patients at six European medical centres. We randomized 1,537 older medical and surgical patients with multi-morbidity and polypharmacy on admission in a 1:1 ratio to SENATOR software-guided medication optimization plus standard care (intervention, n = 772, mean number of daily medications = 9.34) or standard care alone (control, n = 765, mean number of daily medications = 9.23) using block randomization stratified by site and admission type. Attending clinicians in the intervention arm received SENATOR-generated advice at a single time point with recommendations they could choose to adopt or not. The primary endpoint was occurrence of probable or certain ADRs within 14 days of randomization. Secondary endpoints were primary endpoint derivatives; tertiary endpoints included all-cause mortality, re-hospitalization, composite healthcare utilization and health-related quality of life. Results For the primary endpoint, there was no difference between the intervention and control groups (24.5 vs. 24.8%; OR 0.98; 95% CI 0.77–1.24; P = 0.88). Similarly, with secondary and tertiary endpoints, there were no significant differences. Among attending clinicians in the intervention group, implementation of SENATOR software-generated medication advice points was poor (~15%). Conclusions In this trial, uptake of software-generated medication advice to minimize ADRs was poor and did not reduce ADR incidence during index hospitalization.
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Lupón, Josep, Evelyn Santiago-Vacas, Germán Cediel, Pau Codina, Mar Domingo, Elena Revuelta-López, Elisabet Zamora, et al. "Circulating neprilysin hypothesis: A new opportunity for sacubitril/valsartan in patients with heart failure and preserved ejection fraction?" PLOS ONE 16, no. 5 (May 14, 2021): e0249674. http://dx.doi.org/10.1371/journal.pone.0249674.
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Background Circulating Neprilysin (sNEP) has emerged as a potential prognostic biomarker in heart failure (HF). In PARAGON-HF benefit of sacubitril/valsartan was only observed in patients with left ventricular ejection fraction (LVEF) ≤57%. We aimed to assess the prognostic value of sNEP in outpatients with HF and LVEF >57%, in comparison with patients with LVEF ≤57%. Methods Consecutive HF outpatients were included from May-2006 to February-2016. The primary endpoint was the composite of all-cause death or HF hospitalization and the main secondary endpoint was the composite of cardiovascular death or HF hospitalization. For the later competing risk methods were used. Results sNEP was measured in 1428 patients (age 67.7±12.7, 70.3% men, LVEF 35.8% ±14), 144 of which had a LVEF >57%. sNEP levels did not significantly differ between LVEF groups (p = 0.31). During a mean follow-up of 6±3.9 years, the primary endpoint occurred in 979 patients and the secondary composite endpoint in 714 (in 111 and 84 of the 144 patients with LVEF >57%, respectively). sNEP was significantly associated with both composite endpoints. Age- and sex- adjusted Cox regression analyses showed higher hazard ratios for sNEP in patients with LVEF >57%, both for the primary (HR 1.37 [1.16–1.61] vs. 1.04 [0.97–1.11]) and the secondary (HR 1.38 [1.21–1.55] vs. 1.11 [1.04–1.18]) composite endpoints. Conclusions sNEP prognostic value in patients with HF and LVEF >57% outperforms that observed in patients with lower LVEF. Precision medicine using sNEP may identify HF patients with preserved LVEF that may benefit from treatment with sacubitril/valsartan.
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Davis, C. E. "Secondary endpoints can be validly analyzed, even if the primary endpoint does not provide clear statistical significance." Controlled Clinical Trials 18, no. 6 (December 1997): 557–60. http://dx.doi.org/10.1016/s0197-2456(96)00133-x.
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Easton, J. Donald, Hans Denison, Scott R. Evans, Mikael Knutsson, Pierre Amarenco, Gregory W. Albers, Per Ladenvall, et al. "Estimated treatment effect of ticagrelor versus aspirin by investigator-assessed events compared with judgement by an independent event adjudication committee in the SOCRATES trial." International Journal of Stroke 14, no. 9 (May 15, 2019): 908–14. http://dx.doi.org/10.1177/1747493019851282.
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Background Adjudication of endpoints is a standard procedure in cardiovascular clinical trials. However, several studies indicate that the benefit of adjudication in estimating treatment effect may be limited. Aims This post hoc analysis of SOCRATES (NCT01994720) compared the treatment effects and investigated the agreement of clinical event assessment by site investigators and independent adjudicators. Methods SOCRATES compared ticagrelor and aspirin in 13,199 patients with acute minor stroke or high-risk transient ischemic attack. The primary endpoint was stroke, myocardial infarction, or death. Stroke was the major component of the primary endpoint and a secondary endpoint. The endpoints were adjudicated by a blinded independent committee. We compared the treatment effect on the primary endpoint and stroke alone based on the investigators' and adjudicators' assessments, and investigated the agreement rate on the stroke endpoint and major hemorrhages. Results The hazard ratios (95% confidence interval) for ticagrelor versus aspirin therapy for the primary endpoint were 0.89 (0.78–1.01) when calculated on adjudicator-assessed events and 0.88 (0.78–1.00) for investigator-assessed events. The hazard ratios (95% confidence intervals) for stroke were 0.86 (0.75–0.99) based on the adjudicators' diagnoses and 0.85 (0.75–0.97) based on the investigators' diagnoses. The overall agreement between adjudicator- and investigator-diagnosed stroke was 91%, and for major hemorrhages was 88%. Conclusions In SOCRATES, there was no clinically meaningful difference in the estimated treatment effect, on either the primary endpoint or stroke, by using investigator- or adjudicator-assessed events. Double-blind treatment outcome studies with stroke endpoints may not benefit from adjudication. Trial Registration ClinicalTrials.gov Identifier: NCT01994720.
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Li, Huiling, Jianming Wang, Xiaolong Luo, Janis Grechko, and Christopher Jennison. "Improved two-stage group sequential procedures for testing a secondary endpoint after the primary endpoint achieves significance." Biometrical Journal 60, no. 5 (June 7, 2018): 893–902. http://dx.doi.org/10.1002/bimj.201700231.
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Hoh, Brian L., Yan Gong, Caitrin W. McDonough, Michael F. Waters, Adrienne J. Royster, Tiffany O. Sheehan, Ben Burkley, et al. "CYP2C19 and CES1 polymorphisms and efficacy of clopidogrel and aspirin dual antiplatelet therapy in patients with symptomatic intracranial atherosclerotic disease." Journal of Neurosurgery 124, no. 6 (June 2016): 1746–51. http://dx.doi.org/10.3171/2015.6.jns15795.
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OBJECT Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients. METHODS Genotype testing for CYP2C19*2, *3, *8, *17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months. RESULTS The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03–0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08–0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06–1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint (HR 0.22, 95% CI 0.05–1.04, p = 0.056). CONCLUSIONS This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations.
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Sodimu, Adetoun, Sonja Bartolome, Oluwatosin P. Igenoza, and Kelly M. Chin. "Hemodynamic effects of fluoxetine in pulmonary arterial hypertension: an open label pilot study." Pulmonary Circulation 10, no. 4 (October 2020): 204589402097195. http://dx.doi.org/10.1177/2045894020971954.
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In order to evaluate the therapeutic potential of fluoxetine in pulmonary arterial hypertension, 13 patients with pulmonary arterial hypertension underwent catheterization before and after 12 (N = 5) or 24 (N = 8) weeks fluoxetine therapy. No change was seen in the primary endpoint of pulmonary vascular resistance, other hemodynamic values, or any secondary endpoints.
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Wen, Patrick, Yazmin Odia, Minesh Mehta, Samuel Goldlust, Sharon Tamir, Sharon Shacham, Hongwei Wang, Heidi Sheehan, and Kai Li. "RTID-08. A PHASE 1/2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA (ndGBM OR rGBM)." Neuro-Oncology 22, Supplement_2 (November 2020): ii195. http://dx.doi.org/10.1093/neuonc/noaa215.813.
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Abstract BACKGROUND GBM is the most common and most aggressive primary brain tumor with poor prognosis and median overall survival (mOS) of patients with ndGBM and rGBM being 15 vs 5-7 months, respectively. Selinexor is a first-in class, oral, selective nuclear export inhibitor which forces nuclear retention and reactivation of many tumor suppressor proteins. Selinexor with low dose dexamethasone was recently approved for patients with triple-class refractory multiple myeloma. Additionally, selinexor monotherapy has demonstrated broad activity in other hematologic and solid malignancies. In a Phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. Preclinical GBM studies showed synergy when combining selinexor with radiation, temozolomide and lomustine. METHOD This is a phase 1 (PH-1) dose finding study followed by a 1:1 randomized phase 2 (PH-2; n= 350) efficacy exploration trial to independently evaluate 3 different combination regimens: Arm A: radiation +/- selinexor in uMGMT ndGBM; Arm B: radiation and temozolomide +/- selinexor in MGMT ndGBM; Arm C:omustine +/- selinexor in first relapse rGBM following frontline radiation and temozolomide. The PH-1 primary endpoint is MTD/RP2D, with secondary endpoints of ORR per modified RANO, duration of response (DOR), PFS, and OS. The PH-2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS6, ORR, DOR. For Arm C, the PH-2 primary endpoint is OS while key secondary endpoints are PFS, PFS6, ORR, DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy for arms A & B, and 80% power to detect a hazard ratio of 0.70 for arm C. We are currently enrolling patients nationwide. Clinical trial identifier: NCT04421378
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Müller, Kai I., Karl B. Alstadhaug, and Svein I. Bekkelund. "A randomized trial of telemedicine efficacy and safety for nonacute headaches." Neurology 89, no. 2 (June 14, 2017): 153–62. http://dx.doi.org/10.1212/wnl.0000000000004085.
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Objective:To evaluate long-term treatment efficacy and safety of one-time telemedicine consultations for nonacute headaches.Methods:We randomized, allocated, and consulted nonacute headache patients via telemedicine (n = 200) or in a traditional manner (n = 202) in a noninferiority trial. Efficacy endpoints, assessed by questionnaires at 3 and 12 months, included change from baseline in Headache Impact Test–6 (HIT-6) (primary endpoint) and pain intensity (visual analogue scale [VAS]) (secondary endpoint). The primary safety endpoint, assessed via patient records, was presence of secondary headache within 12 months after consultation.Results:We found no differences between telemedicine and traditional consultations in HIT-6 (p = 0.84) or VAS (p = 0.64) over 3 periods. The absolute difference in HIT-6 from baseline was 0.3 (95% confidence interval [CI] −1.26 to 1.82, p = 0.72) at 3 months and 0.2 (95% CI −1.98 to 1.58, p = 0.83) at 12 months. The absolute change in VAS was 0.4 (95% CI −0.93 to 0.22, p = 0.23) after 3 months and 0.3 (95% CI −0.94 to 0.29, p = 0.30) at 12 months. We found one secondary headache in each group at 12 months. The estimated number of consultations needed to miss one secondary headache with the use of telemedicine was 20,200.Conclusion:Telemedicine consultation for nonacute headache is as efficient and safe as a traditional consultation.ClinicalTrials.gov identifier:NCT02270177.Classification of evidence:This study provides Class III evidence that a one-time telemedicine consultation for nonacute headache is noninferior to a one-time traditional consultation regarding long-term treatment outcome and safety.
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Ezhov, Marat V., Narek A. Tmoyan, Olga I. Afanasieva, Marina I. Afanasieva, and Sergei N. Pokrovsky. "Lipoprotein(a) and Cardiovascular Outcomes after Revascularization of Carotid and Lower Limbs Arteries." Biomolecules 11, no. 2 (February 10, 2021): 257. http://dx.doi.org/10.3390/biom11020257.
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Background: Despite high-intensity lipid-lowering therapy, there is a residual risk of cardiovascular events that could be associated with lipoprotein(a) (Lp(a)). It has been shown that there is an association between elevated Lp(a) level and cardiovascular outcomes in patients with coronary heart disease. Data about the role of Lp(a) in the development of cardiovascular events after peripheral revascularization are scarce. Purpose: To evaluate the relationship of Lp(a) level with cardiovascular outcomes after revascularization of carotid and lower limbs arteries. Methods: The study included 258 patients (209 men, mean age 67 years) with severe carotid and/or lower extremity artery disease, who underwent successful elective peripheral revascularization. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The secondary endpoint was the composite of primary endpoint and repeated revascularization. Results: For 36-month follow-up, 29 (11%) primary and 128 (50%) secondary endpoints were registered. There was a greater risk of primary (21 (8%) vs. 8 (3%); hazard ratio (HR), 3.0; 95% confidence interval (CI) 1.5–6.3; p < 0.01) and secondary endpoints (83 (32%) vs. 45 (17%), HR, 2.8; 95% CI 2.0–4.0; p < 0.01) in patients with elevated Lp(a) level (≥30 mg/dL) compared to patients with Lp(a) < 30 mg/dL. Multivariable-adjusted Cox regression analysis revealed that Lp(a) was independently associated with the incidence of cardiovascular outcomes. Conclusions: Patients with peripheral artery diseases have a high risk of cardiovascular events. Lp(a) level above 30 mg/dL is significantly and independently associated with cardiovascular events during 3-year follow-up after revascularization of carotid and lower limbs arteries.
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Petricciuolo, Serena, Maria Grazia Delle Donne, Alberto Aimo, Antonio Chella, Giacinta Guarini, and Raffaele De Caterina. "76 Pre-treatment high-sensitivity troponin T for the short-term prediction of cardiac outcomes in patients on immune checkpoint inhibitors." European Heart Journal Supplements 22, Supplement_N (December 1, 2020): N19—N23. http://dx.doi.org/10.1093/eurheartj/suaa193.
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Abstract Aims Immune checkpoint inhibitors (ICIs) are an emerging option for several advanced metastatic cancers, but have been associated with cardiotoxicity. The prognostic value of high-sensitivity troponin T (hs-TnT) measured before treatment start has never been investigated. Methods and results Thirty consecutive patients underwent measurement of hs-TnT before starting ICI therapy (pembrolizumab, 23%; nivolumab, 12%; atezolizumab, 6%; durvalumab, 5%). The primary endpoint was a composite of cardiovascular death, stroke or transient ischaemic attack, pulmonary embolism and new-onset heart failure. The secondary endpoint was progression of cardiac involvement according to the CARDIOTOX staging system. Patients (median age 68 years, 77% men, 13% with coronary artery disease, 90% current or former smokers, 67% overweight or obese, and 43% hypertensive) had a median hs-TnT of 12 ng/L (interquartile interval 8-23). At the 3-month timepoint, 7 patients (23%) had experienced the primary endpoint, and 13 (43%) the secondary endpoint. Area under the curve values were 0.909 for the primary, and 0.757 for the secondary endpoint. The best troponin-T cut-off was 14 ng/L for both the primary (100% sensitivity, 73% specificity) and secondary endpoint (sensitivity 75%, specificity 77%). Over a median follow-up duration of 2.6 months (2.0-3.6), survival free from the primary endpoint was shorter in patients with hs-TnT ≥14 ng/L (Log-rank: 10.3, p = 0.001), and all patients developing the primary endpoint had hs-TnT ≥14 ng/L at baseline. Conclusion In patients on ICIs, baseline hs-TnT predicts a composite cardiovascular endpoint and the progression of cardiac involvement at 3 months, with 14 ng/L as the best cut-off.
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Fernández-Cisnal, Agustín, Ernesto Valero, Sergio García-Blas, Vicente Pernias, Adela Pozo, Arturo Carratalá, Jessika González, et al. "Clinical History and Detectable Troponin Concentrations below the 99th Percentile for Risk Stratification of Patients with Chest Pain and First Normal Troponin." Journal of Clinical Medicine 10, no. 8 (April 20, 2021): 1784. http://dx.doi.org/10.3390/jcm10081784.
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Decision-making is challenging in patients with chest pain and normal high-sensitivity cardiac troponin T (hs-cTnT; <99th percentile; <14 ng/L) at hospital arrival. Most of these patients might be discharged early. We investigated clinical data and hs-cTnT concentrations for risk stratification. This is a retrospective study including 4476 consecutive patients presenting to the emergency department with chest pain and first normal hs-cTnT. The primary endpoint was one-year death or acute myocardial infarction, and the secondary endpoint added urgent revascularization. The number of primary and secondary endpoints was 173 (3.9%) and 252 (5.6%). Mean hs-cTnT concentrations were 6.9 ± 2.5 ng/L. Undetectable (<5 ng/L) hs-cTnT (n = 1847, 41%) had optimal negative predictive value (99.1%) but suboptimal sensitivity (90.2%) and discrimination accuracy (AUC = 0.664) for the primary endpoint. Multivariable analysis was used to identify the predictive clinical variables. The clinical model showed good discrimination accuracy (AUC = 0.810). The addition of undetectable hs-cTnT (≥ or <5 ng/L; HR, hazard ratio = 3.80; 95% CI, confidence interval 2.27–6.35; p = 0.00001) outperformed the clinical model alone (AUC = 0.836, p = 0.002 compared to the clinical model). Measurable hs-cTnT concentrations (between detection limit and 99th percentile; per 0.1 ng/L, HR = 1.13; CI 1.06–1.20; p = 0.0001) provided further predictive information (AUC = 0.844; p = 0.05 compared to the clinical plus undetectable hs-cTnT model). The results were reproducible for the secondary endpoint and 30-day events. Clinical assessment, undetectable hs-cTnT and measurable hs-cTnT concentrations must be considered for decision-making after a single negative hs-cTnT result in patients presenting to the emergency department with acute chest pain.
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King, Martin T., David R. Wise, Lawrence M. Scala, Neil M. Mariados, Amanda Whitbeck, Mark Pomerantz, Sharon Bober, Elai Davicioni, Glenn Bubley, and Paul L. Nguyen. "INTREPId (INTermediate Risk Erection PreservatIon Trial): A randomized trial of radiation therapy and darolutamide for prostate cancer." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): TPS384. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.tps384.
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TPS384 Background: Men with intermediate risk prostate cancer are often recommended external beam radiation therapy (EBRT) with or without 4-6 months of androgen deprivation therapy (ADT). However, ADT can be associated with prolonged erectile dysfunction due to delayed testosterone recovery. Darolutamide is a second-generation androgen receptor with low blood-brain barrier penetration. We hypothesize that men who receive Darolutamide with RT rather than ADT with RT are able to achieve surrogate PSA endpoints indicative of long-term disease control while preserving erectile function. Methods: This is an open label, phase 2B, multi-center, randomized controlled trial. Eligibility criteria include intermediate risk prostate cancer, good erectile quality per the EPIC-26 questionnaire, and archival tissue suitable for submission to Decipher Biosciences (San Diego, CA). Men will be stratified by Decipher score (low/intermediate vs high), RT modality (EBRT vs Brachytherapy/stereotactic body radiation therapy/combination RT), and age (>65 vs <65). Men with a Decipher high score will be strongly encouraged to undergo extreme RT dose-escalation. The primary endpoint is PSA nadir ≤ 0.5 within 6 months from end of treatment (EOT). The hierarchical endpoint is maintenance of good erectile quality at 3 months from EOT. The key secondary endpoint is interval to PSA failure at 3 years from EOT. Endpoints will be analyzed in a fixed-sequence hierarchical method. 220 patients will be accrued over 3 years. Non-inferiority margins for the primary and key secondary endpoints are 9% (90% power) and 4.9% (80% power), respectively. Men will be randomized to 6 months of GnRH agonist plus bicalutamide 50 mg daily with RT or 6 months of darolutamide 600 mg twice daily with RT. Assessments will occur at baseline, during treatment, EOT, and at regularly scheduled intervals up to 36 months from EOT. Correlative endpoints include discovering transcriptomic and radiomic predictors of response. Clinical trial information: NCT04025372.
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Su, Bo, Junhan Yang, Lijuan Li, and Yu Wang. "Secondary parallel automatic parking of endpoint regionalization based on genetic algorithm." Cluster Computing 22, S3 (February 6, 2018): 7515–23. http://dx.doi.org/10.1007/s10586-018-1809-8.
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Unruh, Terry, Joseph Adjei Boachie, and Eduardo Smith-Singares. "Feasibility of laparoscopic abdominal wall reconstruction in an outpatient community-hospital setting using cPTFE prosthetic mesh: a prospective, multicenter case series." Journal of International Medical Research 44, no. 6 (November 10, 2016): 1506–13. http://dx.doi.org/10.1177/0300060516667321.
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Objective This study investigated the use of prosthetic condensed polytetrafluoroethylene (cPTFE) for laparoscopic ventral hernia repair (LVHR) in an outpatient community-hospital setting. Methods Patients underwent LVHR with cPTFE at one of three community hospitals. Primary endpoint was hernia recurrence at 1-year postoperatively. Secondary endpoints included pain, surgical site infection, medical/surgical complications, and patient-reported outcomes. Results This study included 65 females and 52 males, aged 46.6 ± 13.2 years (mean ± SD; range 18–84 years). Mean prosthetic size was 413.8 ± 336.11 cm2 (range 165–936 cm2). Mean follow-up was 30 months (range 12–46 months). Hernia recurrence rate was 4.3%. Rate of hospitalization in the first postoperative week was 2.6%. Early and late secondary endpoint complication rates were 24.8% and 27.4%, respectively; pain was the most common complication, followed by seroma (8.5%). Conclusions Outpatient LVHR using cPTFE is feasible in community hospitals. Complication rates were similar to previous reports, and the seroma rate was markedly lower.
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Martin, Paul J., Barry E. Storer, Scott D. Rowley, Mary E. D. Flowers, Stephanie J. Lee, Paul A. Carpenter, John R. Wingard, et al. "Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease." Blood 113, no. 21 (May 21, 2009): 5074–82. http://dx.doi.org/10.1182/blood-2009-02-202937.
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AbstractWe conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versus-host disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00089141 on August 4, 2004.
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Vander, M. A., E. A. Lyasnikova, L. A. Belyakova, M. A. Trukshina, V. L. Galenco, I. M. Kim, T. A. Lelyavina, et al. "Two-year follow-up of patients with heart failure with reduced ejection fraction receiving cardiac contractility modulation." Russian Journal of Cardiology 25, no. 7 (August 15, 2020): 3853. http://dx.doi.org/10.15829/1560-4071-2020-3853.
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Aim. To assess the 2-year prognosis of patients with heart failure with reduced ejection fraction (HFrEF) receiving cardiac contractility modulation (CCM).Material and methods. This single-center observational study included 55 patients (46 men, mean age 53±11 years) with NYHA class II-III HFrEF receiving optimal medical therapy, with sinus rhythm, QRS <130 ms or QRS<150 ms with nonspecific intraventricular conduction delay. NYHA class II and III were established in 76% and 24% of patients, respectively. All patients were implanted with CCM devices between October 2016 and September 2017. Follow-up visits were carried out every 3 months during the 1st year and every 6 months during the 2nd year of observation. The primary composite endpoint was mortality and heart transplantation. Secondary composite endpoints included death, heart transplantation, paroxysmal ventricular tachycardia/ ventricular fibrillation, hospitalizations due decompensated HFResults. The one-year and two-year survival rate was 95% and 80%, respectively. Primary endpoint was observed in 20% of patients. NYHA class III and higher levels of N-terminal pro-brain natriuretic peptide (NTproBNP) were associated with unfavorable prognosis (p=0,014 and p=0,026, respectively). NTproBNP was an independent predictor of survival (p=0,018). CCM contributed to a significant decrease in hospitalizations due to decompensated HF (p<0,0001). The secondary endpoint was observed in 18 (33%) of patients during the 1st year. The predictor for the secondary composite endpoint was NTproBNP (p=0,047).Conclusion. CCM is associated with a significant decrease in hospitalization rate due to decompensated HF. The 2-year survival rate of patients with NYHA class II-III HF receiving CCM was 80%. The NTproBNP level was an independent predictor of survival in patients receiving CMM for 2 years. Further longer-term studies of the CCM efficacy are required.
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Waldén, Katarina, Anders Jeppsson, Salmir Nasic, and Martin Karlsson. "Fibrinogen Concentrate to Cardiac Surgery Patients with Ongoing Bleeding does not Increase the Risk of Thromboembolic Complications or Death." Thrombosis and Haemostasis 120, no. 03 (January 15, 2020): 384–91. http://dx.doi.org/10.1055/s-0039-3402759.
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Abstract Background We investigated whether fibrinogen concentrate administration to bleeding patients is associated with an increased risk of thromboembolic complications and death. Methods All consecutive patients who underwent first-time cardiac surgery at Sahlgrenska University Hospital from 2009 to 2014 were included. Patients, who had received fibrinogen concentrate, were compared with those who had not received fibrinogen concentrate. The primary endpoint was a composite of thromboembolic complications and death within 1 year after surgery. Secondary endpoints included the composite and mortality within 30 days and mortality within 1 year after surgery. Multivariable logistic regression and Cox regression models were used to compare the groups. Propensity score (PS)-matched models were used for sensitivity analyses. Results A total of 5,408 patients were included in the present study, of which 564 (10.4%) received fibrinogen concentrate. The composite endpoint occurred in 3.5% of patients at 30 days and 10.5% at 1 year. There was no significant difference between the groups in the composite endpoint at 1 year (adjusted hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.84–1.46, p = 0.45) or in the secondary endpoints, that is, mortality at 1 year (adjusted HR: 1.38, 95% CI: 0.93–2.04, p = 0.11), composite at 30 days (adjusted odds ratio [OR]: 1.07, 95% CI: 0.64–1.81, p = 0.79) and mortality at 30 days (adjusted OR: 1.00, 95% CI: 0.51–1.96, p = 0.50). The results of the sensitivity analyses were consistent with those of main analyses. Conclusion Perioperative administration of fibrinogen concentrate to bleeding cardiac surgery patients is not associated with an increased risk of thromboembolic complications or death.
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Choudhury, Anirban, Scot Garg, Jamie Smith, Andrew Sharp, Sergio Nabais de Araujo, Anoop Chauhan, Nikhil Patel, Benjamin Wrigley, Sudipta Chattopadhyay, and Azfar G. Zaman. "Prospective evaluation of an ultrathin strut biodegradable polymer-coated sirolimus-eluting stent: 12 months’ results from the S-FLEX UK registry." BMJ Open 9, no. 10 (October 2019): e026578. http://dx.doi.org/10.1136/bmjopen-2018-026578.
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ObjectiveTo prospectively evaluate safety and efficacy of the ultrathin strut biodegradable polymer-coated Supraflex sirolimus-eluting stent (S-SES) in ‘real world’ patient population requiring percutaneous coronary intervention (PCI).MethodsNational, prospective, multicentre, single-arm, all-comers, observational registry of 469 patients treated with S-SES from July 2015 and November 2016 in 11 centres in UK. Primary endpoint was target lesion failure (TLF) at 12 months (cardiac death, target vessel myocardial infarction (MI) or clinically driven target lesion revascularisation (TLR)). Secondary endpoints included safety and performance outcomes at 12 months—overall stent thrombosis (ST), all-cause mortality, any MI, target vessel failure (TVF) and major adverse cardiac events (MACE—composite of cardiac death, MI, emergent or repeat revascularisation).ResultsAt 12 months, the primary endpoint occurred in 11 (2.4%) of 466 patients, consisting of 4 (0.9%) cardiac deaths, 3 (0.6%) target vessel MI and 7 (1.5%) TLR. Secondary endpoints findings included all-cause mortality in 6 (1.3%), TVF of 14 (3%), no definite ST, 1 (0.2%) probable ST and 3 (0.6%) possible ST. Overall MACE was observed in 18 (3.9%).ConclusionsThe S-FLEX UK registry showed that the S-SES is safe with a low incidence of TLF in routine clinical practise in patients with coronary artery disease being treated by PCI.
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Martischnig, Amadea M., Julinda Mehilli, Janina Pollak, Tobias Petzold, Anette K. Fiedler, Katharina Mayer, Stefanie Schulz-Schüpke, et al. "Impact of Dabigatran versus Phenprocoumon on ADP Induced Platelet Aggregation in Patients with Atrial Fibrillation with or without Concomitant Clopidogrel Therapy (the Dabi-ADP-1 and Dabi-ADP-2 Trials)." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/798486.
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Background.A relevant number of patients receive triple therapy with clopidogrel, aspirin, and oral anticoagulation. Clopidogrel’s efficacy on ADP induced platelet function may be influenced by concomitant antithrombotic therapies. Data regarding the effect of dabigatran on platelet function is limited toin vitrostudies and healthy individuals.Methods.The “Dabi-ADP-1” and “Dabi-ADP-2” trials randomized patients with atrial fibrillation to either dabigatran or phenprocoumon for a 2-week period. In Dabi-ADP-1 (n=70) patients with clopidogrel therapy were excluded and in Dabi-ADP-2 (n=46) patients had to be treated concomitantly with clopidogrel. The primary endpoint was ADP-induced platelet aggregation between dabigatran and phenprocoumon at 14 days. Secondary endpoints were ADPtest HS-, TRAP-, and COL-induced platelet aggregation.Results.There was no significant difference regarding the primary endpoint between both groups in either trial (Dabi-ADP-1: Dabigatran: 846 [650–983] AU × min versus phenprocoumon: 839 [666–1039] AU × min,P=0.90and Dabi-ADP-2: 326 [268–462] versus 350 [214–535],P=0.70) or regarding the secondary endpoints, ADPtest HS-, TRAP-, and COL-induced platelet aggregation.Conclusion.Dabigatran as compared to phenprocoumon has no impact on ADP-induced platelet aggregation in atrial fibrillation patients neither with nor without concomitant clopidogrel therapy.
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McCahill, Laurence E., Greg Yothers, Saima Sharif, Nicholas J. Petrelli, Samia H. Lopa, Michael J. O'Connell, and Norman Wolmark. "A phase II trial of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy plus bevacizumab (bev) for patients (pts) with unresectable stage IV colon cancer and a synchronous asymptomatic primary tumor: Updated results of NSABP C-10 with definitive survival analysis." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 468. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.468.
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468 Background: Surgical resection of asymptomatic primary colon tumor for pts presenting with synchronous yet unresectable metastatic disease is controversial. We published results for the primary endpoint in JCO in September 2012. Here we update the primary endpoint and present definitive survival results. Methods: Eligible pts had ECOG Performance 0 or 1, an asymptomatic colon tumor and unresectable distant metastases. Primary endpoint (PE) was major morbidity, defined as surgical resection or death related to the intact primary tumor. Major morbidity rate of 25% was considered acceptable and the trial had 85% power to rule out a rate of 40%. Secondary endpoints were overall survival and morbidity related to the intact primary requiring hospitalization, transfusion, or interventional procedure. Results: Between March 2006-June 2009, 90 pts were registered and 86 eligible pts with follow-up comprise this analysis. 52% were female and 47% were age 60+. Median follow-up was 61.5 mos. There were 15 (17.4%) major morbidity events, 12 (14.0%) required surgery: obstruction (9), perforation (2), and pain (1). Three (3.5%) resulted in pt death: perforation (2), obstruction (1). Cumulative incidence of major morbidity at 42 mos was 17.7% (95% CI 9.5-26.0%). Fourteen other primary tumor resections were performed: attempted cure (11), other reasons (3). There were 6 secondary endpoint events: 4 obstructions (2 required stents, 2 resolved with conservative management), 2 pts with suspected perforation required percutaneous drainage (1) and hospitalization and antibiotics (1). Median survival was 18.3 mos (95% CI 15.2-24.2). Two year OS rate was 38.7% and 3 year OS rate was 15.1%. Conclusions: The primary endpoint holds with the updated analysis justifying observation for asymptomatic primary colon cancers even in patients with a good clinical response of distant metastases. Clinical trial information: NCT 00321828.
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Péron, Julien, Thibaut Reverdy, Colette Smenteck, Marion Cortet, Benoît You, and Gilles Freyer. "Methods and Designs of Modern Breast Cancer Confirmatory Trials." Cancers 13, no. 11 (June 2, 2021): 2757. http://dx.doi.org/10.3390/cancers13112757.
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Background: The benefit–risk assessments of new drugs for breast cancer (BC) face several challenges, as all stakeholders do not agree on the evidence bar required for market authorization, and by the fragmentation of breast cancer diagnosis. The aim of this study was to describe the changes in methods and designs of breast cancer confirmatory trials. Methods: All phase III randomized trials published between 2001 and 2020 and assessing systemic BC therapies were included. Trials’ main characteristics, endpoints, and statistical methods were collected using a standardized data extraction form. Results: A total of 347 randomized controlled trials (RCTs) met the inclusion criteria. While most older trials (79%) included all subtypes of breast cancer, most recent trials populations were limited to one large intrinsic BC subgroup (69%). The use of gatekeeping testing strategies increased dramatically from 9% to 71%. The use of overall survival (OS) as an endpoint in the trials increased over time, but its use as a primary endpoint remained infrequent. The inclusion of OS testing in a hierarchical sequence in case of positive testing of a tumor-centered or composite endpoint appeared to have become the new standard. Conclusion: Our findings indicate some improvements in the quality of the evidence-base supporting new breast cancer drugs. The rigorous assessment of patient-relevant endpoints has increased over time, but this improvement is mainly related to the analysis of OS as a secondary endpoint analyzed in a hierarchical sequence.
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Bar-Zohar, D., F. Agosta, D. Goldstaub, and M. Filippi. "Magnetic resonance imaging metrics and their correlation with clinical outcomes in multiple sclerosis: a review of the literature and future perspectives." Multiple Sclerosis Journal 14, no. 6 (July 2008): 719–27. http://dx.doi.org/10.1177/1352458507088102.
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Magnetic resonance imaging (MRI) has revolutionized the diagnosis and management of patients with multiple sclerosis (MS). Conventional MRI metrics are employed as primary endpoints in proof-of-concept clinical trials evaluating new drugs for MS and as secondary endpoints in definitive phase III trials. Metrics derived from non-conventional MRI techniques are now emerging and hold significant promise since they appear to be more correlated with the most disabling features of MS. However, none of these has been approved for use as a surrogate endpoint for accumulation of physical disability, which is the most important clinical endpoint of this disease. Taking into account the large numbers of patients needed, the extensive exposure to placebo, and the relatively long duration required for phase III clinical trials to show a meaningful effect on progression of disability, the need for a valid, reliable, and objective paraclinical marker of disease evolution cannot be overemphasized. This paper reviews the most up-to-date data regarding MRI techniques, their relationship with central nervous system pathology, as well as with clinical endpoints, and proposes future insights into the use of MRI metrics as surrogate endpoints in clinical trials of MS.
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Tamhane, Ajit C., Cyrus R. Mehta, and Lingyun Liu. "Testing a Primary and a Secondary Endpoint in a Group Sequential Design." Biometrics 66, no. 4 (March 11, 2010): 1174–84. http://dx.doi.org/10.1111/j.1541-0420.2010.01402.x.
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Hothorn, Ludwig A., and Gernot Wassmer. "Analyzing Randomized Dose Finding Studies with a Primary and a Secondary Endpoint." Journal of Biopharmaceutical Statistics 13, no. 2 (January 4, 2003): 301–5. http://dx.doi.org/10.1081/bip-120019273.
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van der Heijde, Désirée, Atul Deodhar, James C. Wei, Edit Drescher, Dona Fleishaker, Thijs Hendrikx, David Li, Sujatha Menon, and Keith S. Kanik. "Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study." Annals of the Rheumatic Diseases 76, no. 8 (January 27, 2017): 1340–47. http://dx.doi.org/10.1136/annrheumdis-2016-210322.
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ObjectivesTo compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis).MethodsIn this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored.ResultsEmax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; p<0.001); tofacitinib 2 and 10 mg twice daily demonstrated greater response rate than placebo (51.9% and 55.8%, respectively; not significant). Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10 mg twice daily than placebo. Objective (including MRI) endpoints demonstrated clear dose response. Adverse events were similar across treatment groups with no unexpected safety findings. Dose-dependent laboratory outcome changes returned close to baseline by week 16.ConclusionsTofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications.Trial registration numberNCT01786668.
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Kim, Woo Young, Jae Bok Lee, Hoon Yub Kim, Pyoung Jae Park, Seung Pil Jung, Hye Yoon Lee, Jae-Gu Cho, Kyoung Sik Park, and Min Jeng Cho. "Prospective, Randomized, Double Blind, Multicenter Study for an Autocrosslinked Polysaccharide Gel to Evaluate Antiadhesive Effect and Safety Compared to Poloxamer/Sodium Alginate After Thyroidectomy." International Surgery 103, no. 9 (September 1, 2019): 452–60. http://dx.doi.org/10.9738/intsurg-d-17-00065.1.
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The aim of the study was to compare the efficacy and safety between an autocrosslinked polysaccharide (ACP) gel (Hyalobarrier) and a poloxamer/sodium alginate (P/SA: Guardix-SG) in preventing adhesions after thyroidectomy and demonstrate the noninferiority of ACP gel to P/SA. To identify differences of antiadhesive efficacy and safety between the ACP gel and P/SA, we investigated various variables such as the proportion of normal esophageal motility as assessed using marshmallow esophagography, swallowing impairment, adhesion severity and so on. This prospective, randomized, double-blinded, multicenter, phase III study investigated the antiadhesive efficacy and safety of ACP gel compared with those of P/SA for 12 weeks. Subjects were randomly assigned to receive either ACP gel (n = 97) or P/SA (n = 96). The primary endpoint was the proportion of normal esophageal motility as assessed using marshmallow esophagography, while the secondary endpoints included swallowing impairment, adhesion severity, laryngoscopic assessment of the vocal cords, and voice range profile. Safety endpoints included adverse events. There was no significant difference between the ACP gel and P/SA groups in the proportion of normal esophageal motility as the primary endpoint (P = 0.7428). In addition, there were no differences in the secondary or safety endpoints between the 2 groups. It was demonstrated that ACP gel was not inferior to P/SA. ACP gel appears both effective and safe for use in preventing adhesions after thyroidectomy.
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Cosentino, Nicola, Jeness Campodonico, Marco Moltrasio, Claudia Lucci, Valentina Milazzo, Mara Rubino, Monica De Metrio, et al. "Mitochondrial Biomarkers in Patients with ST-Elevation Myocardial Infarction and Their Potential Prognostic Implications: A Prospective Observational Study." Journal of Clinical Medicine 10, no. 2 (January 13, 2021): 275. http://dx.doi.org/10.3390/jcm10020275.
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Background: Mitochondrial biomarkers have been investigated in different critical settings, including ST-elevation myocardial infarction (STEMI). Whether they provide prognostic information in STEMI, complementary to troponins, has not been fully elucidated. We prospectively explored the in-hospital and long-term prognostic implications of cytochrome c and cell-free mitochondrial DNA (mtDNA) in STEMI patients undergoing primary percutaneous coronary intervention. Methods: We measured cytochrome c and mtDNA at admission in 466 patients. Patients were grouped according to mitochondrial biomarkers detection: group 1 (−/−; no biomarker detected; n = 28); group 2 (−/+; only one biomarker detected; n = 283); group 3 (+/+; both biomarkers detected; n = 155). A composite of in-hospital mortality, cardiogenic shock, and acute pulmonary edema was the primary endpoint. Four-year all-cause mortality was the secondary endpoint. Results: Progressively lower left ventricular ejection fractions (52 ± 8%, 49 ± 8%, 47 ± 9%; p = 0.006) and higher troponin I peaks (54 ± 44, 73 ± 66, 106 ± 81 ng/mL; p = 0.001) were found across the groups. An increase in primary (4%, 14%, 19%; p = 0.03) and secondary (10%, 15%, 23%; p = 0.02) endpoint rate was observed going from group 1 to group 3. The adjusted odds ratio increment of the primary endpoint from one group to the next was 1.65 (95% CI 1.04–2.61; p = 0.03), while the adjusted hazard ratio increment of the secondary endpoint was 1.55 (95% CI 1.12–2.52; p = 0.03). The addition of study group allocation to admission troponin I reclassified 12% and 22% of patients for the primary and secondary endpoint, respectively. Conclusions: Detection of mitochondrial biomarkers is common in STEMI and seems to be associated with in-hospital and long-term outcome independently of troponin.
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Shore, Neal D., Andrew J. Armstrong, Russell Zelig Szmulewitz, Daniel Peter Petrylak, Jeffrey Holzbeierlein, Arnauld Villers, Arun Azad, et al. "Efficacy of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) by pattern of metastatic spread: ARCHES post hoc analyses." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 5547. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.5547.
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5547 Background: ENZA + ADT significantly reduced the risk of radiographic progression or death in men with mHSPC (NCT02677896). Here, we assess how pattern of metastatic spread impacts the efficacy of ENZA + ADT in patients enrolled in ARCHES. Methods: Patients with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT, stratified by disease volume and prior docetaxel treatment. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included time to prostate-specific antigen (PSA) progression, time to first symptomatic skeletal event (SSE), time to castration resistance, and time to initiation of new antineoplastic therapy. Post hoc analyses were performed by pattern of metastatic spread at study entry. Results: Of the overall population with known metastases at screening (n=1146), the largest patient subgroups were those with bone metastases only (n=513) and those with bone and soft-tissue metastases only (n=351); there were fewer M0 patients or patients with soft-tissue metastases only (n=154) and patients with visceral ± bone metastases (n=128). ENZA + ADT reduced the risk of rPFS and other secondary endpoint measures versus PBO + ADT across all subgroups, with greater relative efficacy observed in patients without visceral metastases (Table). Conclusions: ENZA + ADT provides improvements in rPFS and other secondary endpoints versus PBO + ADT in patients with mHSPC regardless of pattern of metastatic spread, particularly in patients without visceral metastases. These results highlight the importance of patient/physician discussion regarding the use of ENZA in the treatment of mHSPC. Clinical trial information: NCT02677896 . [Table: see text]
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Kavia, RBC, D. De Ridder, CS Constantinescu, CG Stott, and CJ Fowler. "Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis." Multiple Sclerosis Journal 16, no. 11 (September 9, 2010): 1349–59. http://dx.doi.org/10.1177/1352458510378020.
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Background: Bladder dysfunction is a common feature of multiple sclerosis (MS). Objective: In this study we aimed to assess the efficacy, tolerability and safety of Sativex® (nabiximols) as an add-on therapy in alleviating bladder symptoms in patients with MS. Methods: We undertook a 10-week, double-blind, randomized, placebo-controlled, parallel-group trial in 135 randomized subjects with MS and overactive bladder (OAB). Results: The primary endpoint was the reduction in daily number of urinary incontinence episodes from baseline to end of treatment (8 weeks). Other endpoints included incidence of nocturia and urgency, overall bladder condition (OBC), daytime frequency, Incontinence Quality of Life (I-QOL), Patient’s Global Impression of Change (PGIC) and volume voided. The primary endpoint showed little difference between Sativex and placebo. Four out of seven secondary endpoints were significantly in favour of Sativex: number of episodes of nocturia (adjusted mean difference -0.28, p = 0.010), OBC (-1.16, p = 0.001), number of voids/day (-0.85, p = 0.001) and PGIC ( p = 0.005). Of the other endpoints, number of daytime voids was statistically significantly in favour of Sativex (-0.57, p = 0.044). The improvement in I-QOL was in favour of Sativex but did not reach statistical significance. Conclusions: Although the primary endpoint did not reach statistical significance, we conclude that Sativex did have some impact on the symptoms of overactive bladder in patients with MS, providing evidence of some improvement in symptoms associated with bladder dysfunction in these subjects.
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Dodick, David W., Peter J. Goadsby, Christian Lucas, Rigmor Jensen, Jennifer N. Bardos, James M. Martinez, Chunmei Zhou, et al. "Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment." Cephalalgia 40, no. 9 (February 12, 2020): 935–48. http://dx.doi.org/10.1177/0333102420905321.
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Objective To report efficacy and safety of galcanezumab in adults with chronic cluster headache. Background Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity. Methods This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if patients were on a stable dose for 2 months prior to the prospective baseline period. Patients were randomized 1:1 to monthly subcutaneous galcanezumab (300 mg) or placebo. The primary endpoint was overall mean change from baseline in weekly attack frequency with galcanezumab compared to placebo. Key secondary endpoints were ≥50% response rate and percentage of patients meeting sustained response. Results from the double-blind treatment period are reported. Results A total of 237 patients were randomized and treated (120 placebo; 117 galcanezumab). At baseline, the mean age was 45 years and 63% were using ≥1 preventive drug. The primary endpoint was not met; mean change in weekly attack frequency was −4.6 placebo versus −5.4 galcanezumab ( p = 0.334). Key secondary endpoints also were not met. Injection site-related treatment-emergent adverse events were more common in the galcanezumab than the placebo group, with significantly more injection site erythema. Conclusion Treatment with galcanezumab 300 mg did not achieve its primary and key secondary endpoints. This study underscores the potential distinct biology of cCH as well as the significant unmet need for safe, effective, and well-tolerated preventive treatment. The safety profile of galcanezumab in cCH is consistent with that observed in trials of episodic CH and migraine. Trial registration NCT02438826; https://www.clinicaltrials.gov/ct2/show/NCT02438826 .
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Bjelland, Thor W., Thomas G. R. Yates, Morten W. Fagerland, Jan K. Frøyen, Karl R. Lysebråten, and Ulrich J. Spreng. "Quadratus lumborum block for postoperative analgesia after full abdominoplasty: a randomized controlled trial." Scandinavian Journal of Pain 19, no. 4 (October 25, 2019): 671–78. http://dx.doi.org/10.1515/sjpain-2019-0013.
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Abstract Background and aims The quadratus lumborum block (QLB) provides regional analgesia of the anterior abdominal wall, theoretically matching the postoperative pain after postbariatric standard full abdominoplasty. We investigated the effectiveness of a QLB as an addition to the current multimodal analgesia regimen in postbariatric patients treated with standard full abdominoplasty. Methods Randomized, placebo-controlled, triple blinded study (n = 50). All patients received perioperative paracetamol and intraoperative local anesthetic infiltration. QLB was administered bilaterally before induction of general anesthesia with 2 × 20 mL of either ropivacaine 3.75 mg/mL (n = 25) or placebo (saline 9 mg/mL) (n = 25). Patients received intravenous patient controlled opioid analgesia postoperatively. The primary endpoint was opioid use during the first 24 postoperative hours. Secondary endpoints were acute and chronic postoperative pain, postoperative nausea and vomiting, and other side effects. Results Patient characteristics were similar between groups. The primary endpoint in morphine equivalent units was similar between groups during the first 24 h with mean (SD) of 26 (25) vs. 33 (33) mg (p = 0.44) in the ropivacaine and placebo group, respectively. The observed effect was smaller, and SD larger than assumed in the sample size estimation. Linear mixed effects modeling indicated a minimal inter-group difference. No differences were found for secondary endpoints. Conclusions The QLB did not provide significant additional benefit in terms of reduced opioid requirements or secondary endpoints when administered as part of a multimodal pain regimen to postbariatric patients undergoing standard full abdominoplasty. A minimal difference of little clinical importance the first 12 postoperative hours may have been missed. Implications Including the QLB in the current multimodal pain regimen cannot be recommended based on these findings. The study does not preclude QLB use in individual cases where the multimodal regimen is inadequate or contraindicated. The effectiveness of the QLB for supraumbilical pain remains undocumented.
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Kalantzi, Kallirroi I., Ioannis V. Ntalas, Vasileios G. Chantzichristos, Maria E. Tsoumani, Dimitrios Adamopoulos, Christos Asimakopoulos, Adamantios Bourdakis, et al. "Comparison of Triflusal with Aspirin in the Secondary Prevention of Atherothrombotic Events; Α Randomised Clinical Trial." Current Vascular Pharmacology 17, no. 6 (October 2, 2019): 635–43. http://dx.doi.org/10.2174/1570161116666180605090520.
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Background: Triflusal has demonstrated an efficacy similar to aspirin in the prevention of vascular events in patients with acute myocardial infarction (ΜΙ) and ischaemic stroke but with less bleeding events. Objective: We performed a randomised, multicentre, phase 4 clinical trial to compare the clinical efficacy and safety of triflusal versus aspirin, administered for 12 months in patients eligible to receive a cyclooxygenase-1 (COX-1) inhibitor. Methods: Patients with stable coronary artery disease or with a history of non-cardioembolic ischaemic stroke were randomly assigned to receive either triflusal 300 mg twice or 600 mg once daily or aspirin 100 mg once daily for 12 months. The primary efficacy endpoint was the composite of: (a) ΜΙ, (b) stroke (ischaemic or haemorrhagic), or, (c) death from vascular causes for the entire follow-up period. The primary safety endpoints were the rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria. Results: At 12-month follow-up, an equivalent result was revealed between the triflusal (n=559) and aspirin (n=560) in primary efficacy endpoint. Specifically, the combined efficacy outcome rate (i.e. MI, stroke or death from vascular causes) difference was equal to -1.3% (95% confidence interval -1.1 to 3.5) and lied within the a-priori defined equivalence interval (p<0.001). Regarding the primary safety endpoints, patients on triflusal treatment were 50% less likely to develop bleeding events according to the BARC criteria, and especially any clinically overt sign of haemorrhage that requires diagnostic studies, hospitalisation or special treatment (BARC type 2). Conclusion: The efficacy of triflusal in the secondary prevention of vascular events is similar to aspirin when administered for 12 months. Importantly, triflusal significantly reduced the incidence of ΜΙ and showed a better safety profile compared with aspirin. : (ASpirin versus Triflusal for Event Reduction In Atherothrombosis Secondary prevention, ASTERIAS trial; Clinical Trials.gov Identifier: NCT02616497).
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Rothenberg, Marc E., Gerald J. Gleich, Florence E. Roufosse, Lanny J. Rosenwasser, and Peter F. Weller. "Steroid-Sparing Effects of Anti-IL-5 Monoclonal Antibody (Mepolizumab) Therapy in Patients with HES: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial." Blood 108, no. 11 (November 16, 2006): 373. http://dx.doi.org/10.1182/blood.v108.11.373.373.
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Abstract An international, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial has evaluated the effects of mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, on therapeutic prednisone dose requirements, eosinophil levels, signs and symptoms of disease in patients with hypereosinophilic syndrome (HES). The trial enrolled 85 patients (mean age 48.1 years) with HES (blood eosinophil count >1500/μl with evidence of eosinophil-related organ involvement or dysfunction and no known cause of eosinophilia), who tested negative for the FIP1L1-PDGFRα gene rearrangement and required 20–60 mg/day prednisone monotherapy to maintain blood eosinophils at <1000 cells/μL during a run-in period of ≤6 weeks. Patients were randomized to treatment with intravenous mepolizumab 750 mg (n=43) or saline (placebo; n=42) every 4 weeks for 36 weeks (final infusion at Week 32). The prednisone dose was tapered at weekly intervals following the first infusion according to a predefined algorithm based on blood eosinophil counts and HES clinical activity criteria. A total of 84% of patients in the mepolizumab group vs 43% in the placebo group (P<0.001) achieved the primary endpoint (≤10 mg/day prednisone for ≥8 consecutive weeks within the 36-week treatment period). Time to achievement of the primary endpoint, a post-hoc analysis, was significantly shorter in mepolizumab- vs placebo-treated patients (P=0.002). Significantly higher proportions of patients on mepolizumab achieved pre-defined secondary steroid-sparing and eosinophil endpoints vs placebo (Table). Initial assessments of cutaneous disease (based on pruritus visual analog scales and erythema/edema scores) did not differ between the treatment groups. This study, the largest placebo-controlled trial to be conducted in patients with HES to date, has shown that mepolizumab is more effective than placebo at reducing therapeutic prednisone use and stabilizing eosinophil counts in patients with HES. Importantly, a significantly higher proportion of HES patients treated with mepolizumab than placebo achieved the primary endpoint and required ≤10 mg/day prednisone for at least 8 consecutive weeks. These findings indicate that mepolizumab will be an effective therapy for FIP1L1-PDGFRα negative patients with HES. Primary and secondary endpoints Endpoint Placebo (n=42) Mepolizumab (n=43) P-value (95% CI) Patients on ≤10 mg/day prednisone for ≥8 weeks (primary endpoint), % 43% 84% <0.001 (2.69, 23.78) Patients with eosinophils <600 μL for ≥8 weeks, % 45% 95% <0.001 (4.74, 75.17) Primary endpoint in patients on ≤30 mg/day prednisone at baseline, % 57% (n=30) 87% (n=30) 0.011 (1.39, 17.82) Primary endpoint in patients on >30 mg/day prednisone at baseline, % 8% (n=12) 77% (n=13) <0.001 (3.26, 412.26) Patients achieving ≤7.5 mg/day prednisone during the treatment period, % 50% 86% <0.001 (2.04, 15.00) Mean (±SE) prednisone dose at Week 36 (adjusted), mg/day 21.8±1.92 6.2±1.87 <0.001
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Parimi, Sunil, Soundouss Raissouni, Yongtao Lin, Jose Gerard Monzon, Patricia A. Tang, and Vincent Channing Tam. "Trends in the design and interpretation of metastatic colorectal cancer phase III clinical trials." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 692. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.692.
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692 Background: Increasing use of subsequent lines of therapy and crossover in phase III randomized clinical trials (P3 RCTs) has shifted how we perceive the effectiveness of treatments for metastatic colorectal cancer (mCRC). This study aims to characterize the evolution of P3 RCTs in mCRC with respect to clinical trial design and result interpretation. Methods: Abstracts of P3 RCTs of systemic therapy for mCRC conducted between 1980 and 2014 were identified by searching PubMed, Medline, and ASCO abstracts. Data regarding trial design, agent(s) investigated, primary endpoint, secondary endpoint(s), primary endpoint significance and interpretation of the study results (conclusions) were extracted. Results: A total of 422 trials were identified by the search strategy, and 132 eligible trials were included. Over time the sample size of P3 RCTs in mCRC has been increasing and there has been a steady increase in trials studying targeted therapy (see table below for detailed results by decade). A trend towards a smaller percentage of P3 RCTs sponsored by co-operative groups has been observed in recent decades. The most common primary endpoint was overall survival (OS) which was used in 35% of the trials. A decreasing trend in the use of OS was observed since the 1990s. Other common primary endpoints include: progression-free survival (PFS) in 28% and response rate (RR) in 20% of the P3 RCTs. The primary endpoint was met in 45% of the trials. There was discordance between the primary endpoint significance and the authors’ conclusions in 14% of the trials. Conclusions: The design and interpretation of P3 RCTs for mCRC has changed over time from 1980 to present. The use of OS as the primary endpoint is decreasing, while the use of PFS is increasing. [Table: see text]
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Sekfali, Rim, Gérard Mimoun, Salomon Yves Cohen, Giuseppe Querques, Francesco Bandello, Riccardo Sacconi, Eric H. Souied, and Vittorio Capuano. "Switching from ranibizumab to aflibercept in choroidal neovascularization secondary to angioid streaks." European Journal of Ophthalmology 30, no. 3 (March 18, 2019): 550–56. http://dx.doi.org/10.1177/1120672119838133.
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Purpose: To evaluate the efficacy of switching from intravitreal ranibizumab to intravitreal aflibercept in choroidal neovascularization secondary to angioid streaks. Design: Multicenter retrospective interventional case series. Methods: Patients previously treated with intravitreal ranibizumab with at least 12-month follow-up (M12) after switching (M0) to intravitreal aflibercept. Switch to intravitreal aflibercept was decided in cases of refractory or recurrent choroidal neovascularization. Primary endpoint: Change of best-corrected visual acuity using the Early Treatment Diabetic Retinopathy Study letters. Secondary endpoints: Mean change of central macular thickness, absence of intraretinal/subretinal fluid on spectral domain optical coherence tomography and the percentage of eyes with absence of leakage on fluorescein angiography. Results: Fourteen eyes of 13 patients were included. Mean best-corrected visual acuity was 65.0 ± 21.03 letters at M0 and 63.5 ± 17.30 letters at M12 (p = 0.5). Secondary endpoints: Mean central macular thickness was 344 ± 194.65 µm at M0 and 268 ± 79.97 µm at M12 (p = 0.008). Absence of intraretinal/subretinal fluid was observed in 71%. Fluorescein angiography (nine eyes) showed absence of leakage in 77% (seven eyes). Conclusion: Switching from intravitreal ranibizumab to intravitreal aflibercept represents a therapeutic option in patients with refractory or recurrent choroidal neovascularization secondary to angioid streaks.
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Odia, Yazmin, Samuel Aaron Goldlust, Minesh P. Mehta, Andrew B. Lassman, Howard Colman, Priya Kumthekar, Warren P. Mason, et al. "A phase 1/2 study of selinexor in combination with standard of care therapy for newly diagnosed or recurrent glioblastoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS2071. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps2071.
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TPS2071 Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a median overall survival (OS) of 15 months for patients with newly diagnosed GBM (ndGBM) and 5-7 months for patients with recurrent GBM (rGBM). To improve the prognosis of patients with GBM, novel therapies are urgently needed. Selinexor is a first-in class, oral, selective inhibitor of nuclear export that blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing death of cancer cells. Selinexor is an FDA-approved treatment for patients with heavily pretreated multiple myeloma, for patients who received at least one prior therapy, and for patients with relapsed/refractory diffuse large B-cell lymphoma. Increased XPO1 expression in gliomas was associated with higher pathological stage and poorer prognosis. In a phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. In preclinical studies, selinexor showed synergy with radiation, temozolomide, or lomustine. The current trial tests the hypothesis that the addition of selinexor to standard therapy will improve clinical outcomes for patient with ndGBM or rGBM. Methods: This phase 1 dose finding study is followed by a 1:1 randomized phase 2 (n= 350) efficacy exploration trial to independently evaluate 3 regimens: Arm A – radiation +/- selinexor in unmethylated O6-methylguanine-DNA-methyltransferase (uMGMT) ndGBM; Arm B – radiation and temozolomide +/- selinexor in mMGMT ndGBM; Arm C – lomustine +/- selinexor in first relapsed rGBM following frontline radiation and temozolomide. The phase 1 primary endpoint is maximum tolerated dose/recommended phase 2 dose, with secondary endpoints of overall response rate (ORR) per modified Response Assessment in Neuro-Oncology (mRANO), duration of response (DOR), progression free survival (PFS), and OS. The phase 2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS at 6 months, ORR, and DOR. For Arm C, the phase 2 primary endpoint is OS, while key secondary endpoints are PFS, PFS at 6 months, ORR, and DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy in Arms A and B, and 80% power to detect a hazard ratio of 0.70 for Arm C. We are currently enrolling patients nationwide. Clinical trial information: NCT04421378.
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Molica, Matteo, Alessandra Serrao, Roberta Saracino, Irene Zacheo, Christof Stingone, Giuliana Alimena, and Massimo Breccia. "Disappearance of fibrosis in secondary myelofibrosis after ruxolitinib treatment: new endpoint to achieve?" Annals of Hematology 93, no. 11 (May 7, 2014): 1951–52. http://dx.doi.org/10.1007/s00277-014-2096-y.
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Wang, Shao-Li, Cheng-Long Wang, Pei-Li Wang, Hao Xu, Hong-Ying Liu, Jian-Peng Du, Da-Wu Zhang, et al. "Combination of Chinese Herbal Medicines and Conventional Treatment versus Conventional Treatment Alone in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention (5C Trial): An Open-Label Randomized Controlled, Multicenter Study." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/741518.
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Aims.To evaluate the efficacy of Chinese herbal medicines (CHMs) plus conventional treatment in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI).Methods and Results.Participants (n=808) with ACS who underwent PCI from thirteen hospitals of mainland China were randomized into two groups: CHMs plus conventional treatment group (treatment group) or conventional treatment alone group (control group). All participants received conventional treatment, and participants in treatment group additionally received CHMs for six months. The primary endpoint was the composite of cardiac death, nonfatal recurrent MI, and ischemia-driven revascularization. Secondary endpoint was the composite of readmission for ACS, stroke, or congestive heart failure. The safety endpoint involved occurrence of major bleeding events. The incidence of primary endpoint was 2.7% in treatment group versus 6.2% in control group (HR, 0.43; 95% CI, 0.21 to 0.87;P=0.015). The incidence of secondary endpoint was 3.5% in treatment group versus 8.7% in control group (HR, 0.39; 95% CI, 0.21 to 0.72;P=0.002). No major bleeding events were observed in any participant.Conclusion.Treatment with CHMs plus conventional treatment further reduced the occurrence of cardiovascular events in patients with ACS after PCI without increasing risk of major bleeding.
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Lucena, Adson F. de, Luís Henrique de Castro-Afonso, Lucas M. Monsignore, Guilherme S. Nakiri, Soraia R. C. Fábio, Octávio Pontes Neto, and Daniel Giansante Abud. "Carotid artery stenting in the context of endovascular treatment of acute ischemic stroke." Arquivos de Neuro-Psiquiatria 74, no. 3 (March 2016): 212–18. http://dx.doi.org/10.1590/0004-282x20150213.
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ABSTRACT Mechanical thrombectomy as an adjunctive to intravenous thrombolysis is now the standard treatment for acute ischemic stroke (AIS) due to large vessel occlusions. However, the best management of acute carotid tandem occlusions (CTO) remains controversial. Method Twenty patients underwent endovascular treatment of acute CTO. The primary endpoint was the composite rate of complete or partial recanalization without a symptomatic intracranial hemorrhage (sICH). Secondary endpoints were recanalization times, procedure times, and clinical outcomes at three months. Results The primary endpoint was reached in 17 (85%) patients. Recanalization rate was reached in 90% of patients (19/20) and sICH rate was 5% (1/20). At the 3-month follow-up we obtained a mRS ≤ 2 rate of 35% (7/20) and a mortality rate of 20% (4/20). Conclusion Carotid angioplasty stenting and endovascular treatment of AIS due to CTO appears effective with an acceptable rate of sICH.
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Geenen, Baggen, Kauling, Koudstaal, Boomars, Boersma, Roos-Hesselink, and van den Bosch. "The Prognostic Value of Soluble ST2 in Adults with Pulmonary Hypertension." Journal of Clinical Medicine 8, no. 10 (September 20, 2019): 1517. http://dx.doi.org/10.3390/jcm8101517.
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Soluble ST2 (sST2) is upregulated in response to myocardial stress and may serve as biomarker in adults with pulmonary hypertension (PH). This prospective cohort study investigated sST2 levels and its association with echocardiographic and hemodynamic measures, and adverse clinical outcomes in adults with PH of different etiologies. sST2 was measured during the diagnostic right heart catheterization for PH, in adult patients enrolled between May 2012 and October 2016. PH due to left heart failure was excluded. The association between sST2 and a primary endpoint composed of death or lung transplantation and a secondary composite endpoint including death, lung transplantation or heart failure, was investigated using Cox regression with adjustment for NT-proBNP. In total 104 patients were included (median age was 59 years, 66% woman, 51% pulmonary arterial hypertension). Median sST2 was 28 [IQR 20–46] ng/mL. Higher sST2 was associated with worse right ventricular dysfunction and higher mean pulmonary and right atrial pressures. Median follow-up was 3.3 [IQR 2.3–4.6] years. The primary and secondary endpoint occurred in 33 (31.7%) and 43 (41.3%) patients, respectively. sST2 was significantly associated with both endpoints (HR per 2-fold higher value 1.53, 95%CI 1.12–2.07, p = 0.007 and 1.45, 95%CI 1.10–1.90, p = 0.008, respectively). However, after adjustment for NT-proBNP, both associations did not reach statistical significance. In conclusions, higher sST2 levels are associated with more severe PH and right ventricular dysfunction and yields prognostic value in adults with PH, although not independently of NT-proBNP.
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Hoertel, Nicolas, Marina Sánchez-Rico, Raphaël Vernet, Anne-Sophie Jannot, Antoine Neuraz, Carlos Blanco, Cédric Lemogne, et al. "Observational study of haloperidol in hospitalized patients with COVID-19." PLOS ONE 16, no. 2 (February 19, 2021): e0247122. http://dx.doi.org/10.1371/journal.pone.0247122.
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Background Haloperidol, a widely used antipsychotic, has been suggested as potentially useful for patients with COVID-19 on the grounds of its in-vitro antiviral effects against SARS-CoV-2, possibly through sigma-1 receptor antagonist effect. Methods We examined the associations of haloperidol use with intubation or death and time to discharge home among adult patients hospitalized for COVID-19 at Assistance Publique-Hôpitaux de Paris (AP-HP) Greater Paris University hospitals. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death and the secondary endpoint was discharge home among survivors in time-to-event analyses. In the primary analyses, we compared these two outcomes between patients receiving and not receiving haloperidol using univariate Cox regression models in matched analytic samples based on patient characteristics and other psychotropic medications. Sensitivity analyses included propensity score analyses with inverse probability weighting and multivariable Cox regression models. Results Of 15,121 adult inpatients with a positive COVID-19 PT-PCR test, 39 patients (0.03%) received haloperidol within the first 48 hours of admission. Over a mean follow-up of 13.8 days (SD = 17.9), 2,024 patients (13.4%) had a primary end-point event and 10,179 patients (77.6%) were discharged home at the time of study end on May 1st. The primary endpoint occurred in 9 patients (23.1%) who received haloperidol and 2,015 patients (13.4%) who did not. The secondary endpoint of discharge home occurred in 16 patients (61.5%) who received haloperidol and 9,907 patients (85.8%) who did not. There were no significant associations between haloperidol use and the primary (HR, 0.80; 95% CI, 0.39 to 1.62, p = 0.531) and secondary (HR, 1.30; 95% CI, 0.74 to 2.28, p = 0.355) endpoints. Results were similar in multiple sensitivity analyses. Conclusion Findings from this multicenter observational study suggest that haloperidol use prescribed at a mean dose of 4.5 mg per day (SD = 5.2) for a mean duration of 8.4 days (SD = 7.2) may not be associated with risk of intubation or death, or with time to discharge home, among adult patients hospitalized for COVID-19.
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Cadavid, Diego, Jeffrey A. Cohen, Mark S. Freedman, Myla D. Goldman, Hans-Peter Hartung, Eva Havrdova, Douglas Jeffery, et al. "The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis." Multiple Sclerosis Journal 23, no. 1 (July 11, 2016): 94–105. http://dx.doi.org/10.1177/1352458516638941.
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Background: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. Objective: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. Methods: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm ( n = 215) data, we analyzed disability progression using a novel progression endpoint, “EDSS-Plus,” defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. Results: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors’ times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. Conclusion: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.
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Zhang, Jun-Jie, Xiao-Fei Gao, Ya-Ling Han, Jing Kan, Ling Tao, Zhen Ge, Damras Tresukosol, et al. "Treatment effects of systematic two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: rationale and design of a prospective, randomised and multicentre DEFINITION II trial." BMJ Open 8, no. 3 (March 2018): e020019. http://dx.doi.org/10.1136/bmjopen-2017-020019.
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IntroductionProvisional stenting (PS) for simple coronary bifurcation lesions is the mainstay of treatment. A systematic two-stent approach is widely used for complex bifurcation lesions (CBLs). However, a randomised comparison of PS and two-stent techniques for CBLs has never been studied. Accordingly, the present study is designed to elucidate the benefits of two-stent treatment over PS in patients with CBLs.Methods and analysisThis DEFINITION II study is a prospective, multinational, randomised, endpoint-driven trial to compare the benefits of the two-stent technique with PS for CBLs. A total of 660 patients with CBLs will be randomised in a 1:1 fashion to receive either PS or the two-stent technique. The primary endpoint is the rate of 12-month target lesion failure defined as the composite of cardiac death, target vessel myocardial infarction (MI) and clinically driven target lesion revascularisation. The major secondary endpoints include all causes of death, MI, target vessel revascularisation, in-stent restenosis, stroke and each individual component of the primary endpoints. The safety endpoint is the occurrence of definite or probable stent thrombosis.Ethics and disseminationThe study protocol and informed consent have been approved by the Institutional Review Board of Nanjing First Hospital, and accepted by each participating centre. Written informed consent was obtained from all enrolled patients. Findings of the study will be published in a peer-reviewed journal and disseminated at conferences.Trial registration numberNCT02284750; Pre-results.
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Cloughesy, Timothy, Kevin Petrecca, Tobias Walbert, Nicholas Butowski, Michael Salacz, James Perry, Denise Damek, et al. "LTBK-08. TOCA 511 & TOCA FC VERSUS STANDARD OF CARE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi284. http://dx.doi.org/10.1093/neuonc/noz219.1199.
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Abstract BACKGROUND Toca 511 (vocimagene amiretrorepvec) is a cancer-selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5-fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. Three Ph1 studies in patients with recurrent high grade glioma have demonstrated a tolerable safety profile and encouraging efficacy. METHODS Toca 5 is a multi-national, randomized, open-label Ph3 trial (NCT02414165) of Toca 511 & Toca FC versus standard of care (SOC) options that comprises Investigator’s choice of single agent chemotherapy (lomustine, temozolomide) or bevacizumab in patients who have undergone resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. 403 patients were randomized 1:1 to the Toca arm or the SOC arm and stratified by IDH1 status, KPS, and geographic region. Primary endpoint was overall survival (OS), and secondary endpoints were durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. The study used group sequential design including 2 interim analyses and 1 final analysis, and the stratified log-rank test are used for the analysis. RESULTS 271 events were observed for this analysis. Median follow-up was 22.8 months, and the Toca arm missed the primary endpoint (OS) compared to the SOC arm (11.1 months median compared to 12.2 months, HR=1.06, p=0.6154). All secondary endpoints showed no meaningful difference between the arms of the trial. The safety, tolerability and adverse event profile of Toca 511 and Toca FC was as expected for this patient population, with low incidences of Grade 3–4 adverse events. Pre-planned subgroup analyses showed compelling OS improvement in patients with secondary recurrence, and favorable trends in IDH1 mutant and AA population. Detailed data will be presented at the time of the conference.
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Magri, Caroline J., Alaide Chieffo, Alessandro Durante, Azeem Latib, Matteo Montorfano, Francesco Maisano, Michela Cioni, et al. "Impact of Mean Platelet Volume on Combined Safety Endpoint and Vascular and Bleeding Complications following Percutaneous Transfemoral Transcatheter Aortic Valve Implantation." BioMed Research International 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/645265.
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Background. Vascular and bleeding complications remain important complications in patients undergoing percutaneous transfemoral transcatheter aortic valve implantation (TF-TAVI). Platelets play an important role in bleeding events. Mean platelet volume (MPV) is an indicator of platelet activation. The objective of this study was to assess whether low MPV is an indicator of major vascular and bleeding complications following TF-TAVI.Methods. A retrospective cohort study of 330 subjects undergoing TF-TAVI implantation was performed. The primary study endpoint was the occurrence of combined safety endpoint (CSEP); secondary endpoints included major vascular complications and life-threatening bleeding. Endpoints were defined according to Valve Academic Research Consortium 2.Results. The CSEP at 30 days was reached in 30.9%; major vascular complications were observed in 14.9% while life-threatening bleeding occurred in 20.6%. Logistic Euroscore and MPV were independent predictors of CSEP. Predictors of vascular complications were female sex, previous myocardial infarction, red blood cell distribution width (RDW), and MPV while predictors of life-threatening bleeding were peripheral arterial disease, RDW, and MPV.Conclusion. A low baseline MPV was shown for the first time to be a significant predictor of CSEP, major vascular complications, and life-threatening bleeding following TF-TAVI.