scholarly journals Positive predictive value of sustained virologic response 4 weeks posttreatment for achieving sustained virologic response 12 weeks posttreatment in patients receiving glecaprevir/pibrentasvir in Phase 2 and 3 clinical trials

2021 ◽  
Author(s):  
Edward Gane ◽  
Victor Ledinghen ◽  
Douglas E. Dylla ◽  
Giuliano Rizzardini ◽  
Mitchell L. Shiffman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Positive Predictive Value ◽  
Predictive Value ◽  
Sustained Virologic Response ◽  
Virologic Response ◽  
Phase 2

LP06 : Sustained virologic response after ACH-3102 and sofosbuvir treatment for 8 or 6 weeks: A phase 2 “proxy” study

2015 ◽  
Vol 62 ◽  
pp. S266 ◽  
Author(s):  
E. Gane ◽  
C. Schwabe ◽  
M. Mader ◽  
V. Suri ◽  
M. Donohue ◽  
...  
Keyword(s):  
Sustained Virologic Response ◽  
Virologic Response ◽  
Phase 2

scholarly journals Comparability of Event Adjudication Versus Administrative Billing Claims for Outcome Ascertainment in the DAPT Study

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kamil F. Faridi ◽  
Hector Tamez ◽  
Neel M. Butala ◽  
Yang Song ◽  
Changyu Shen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trials ◽  
Positive Predictive Value ◽  
Negative Predictive Value ◽  
Predictive Value ◽  
Claims Data ◽  
High Specificity ◽  
Kappa Statistics ◽  
Administrative Claims ◽  
Medicare Claims

Background: Data from administrative claims may provide an efficient alternative for end point ascertainment in clinical trials. However, it is uncertain how well claims data compare to adjudication by a clinical events committee in trials of patients with cardiovascular disease. Methods: We matched 1336 patients ≥65 years old who received percutaneous coronary intervention in the DAPT (Dual Antiplatelet Therapy) Study with the National Cardiovascular Data Registry CathPCI Registry linked to Medicare claims as part of the EXTEND (Extending Trial-Based Evaluations of Medical Therapies Using Novel Sources of Data) Study. Adjudicated trial end points were compared with Medicare claims data with International Classification of Diseases, Ninth Revision codes from inpatient hospitalizations using time-to-event analyses, sensitivity, specificity, positive predictive value, negative predictive value, and kappa statistics. Results: At 21-month follow-up, the cumulative incidence of major adverse cardiovascular and cerebrovascular events (combined mortality, myocardial infarction, and stroke) was similar between trial-adjudicated events and claims data (7.9% versus 7.2%, respectively; P =0.50). Bleeding rates were lower using adjudicated events compared with claims (5.0% versus 8.6%, respectively; P <0.001). The sensitivity and positive predictive value of comprehensive billing codes for identifying adjudicated events were 65.6% and 85.7% for myocardial infarction, 61.5% and 47.1% for stroke, and 76.8% and 39.3% for bleeding, respectively. Specificity and negative predictive value for all outcomes ranged from 93.7% to 99.5%. All 39 adjudicated deaths were identified using Medicare data. Kappa statistics assessing agreement between events for myocardial infarction, stroke, and bleeding were 0.73, 0.52, and 0.49, respectively. Conclusions: Claims data had moderate agreement with adjudication for myocardial infarction and poor agreement but high specificity for bleeding and stroke in the DAPT Study. Deaths were identified equivalently. Using claims data in clinical trials could be an efficient way to assess mortality among Medicare patients and may help detect other outcomes, although additional monitoring is likely needed to ensure accurate assessment of events.

scholarly journals A highly predictive signature of cognition and brain atrophy for progression to Alzheimer’s dementia

2018 ◽  
Author(s):  
Angela Tam ◽  
Christian Dansereau ◽  
Yasser Itturia-Medina ◽  
Sebastian Urchs ◽  
Pierre Orban ◽  
...  
Keyword(s):  
Machine Learning ◽  
Clinical Trials ◽  
High Risk ◽  
Positive Predictive Value ◽  
Predictive Value ◽  
High Specificity ◽  
Alzheimer’S Dementia ◽  
Learning Tools ◽  
Operating Characteristics ◽  
Alzheimer's Dementia

AbstractClinical trials in Alzheimer’s disease need to enroll patients whose cognition will decline over time, if left untreated, in order to demonstrate the efficacy of an intervention. Machine learning models used to screen for patients at risk of progression to dementia should therefore favor specificity (detecting only progressors) over sensitivity (detecting all progressors), especially when the prevalence of progressors is low. Here, we explore whether such high-risk patients can be identified using cognitive assessments and structural neuroimaging, by training machine learning tools in a high specificity regime. A multimodal signature of Alzheimer’s dementia was first extracted from ADNI1. We then validated the predictive value of this signature on ADNI1 patients with mild cognitive impairment (N=235). The signature was optimized to predict progression to dementia over three years with low sensitivity (55.1%) but high specificity (95.6%), resulting in only moderate accuracy (69.3%) but high positive predictive value (80.4%, adjusted for a “typical” 33% prevalence rate of true progressors). These results were replicated in ADNI2 (N=235), with 87.8% adjusted positive predictive value (96.7% specificity, 47.3% sensitivity, 85.1% accuracy). We found that cognitive measures alone could identify high-risk individuals, with structural measurements providing a slight improvement. The signature had comparable receiver operating characteristics to standard machine learning tools, yet a marked improvement in positive predictive value was achieved over the literature by selecting a high specificity operating point. The multimodal signature can be readily applied for the enrichment of clinical trials.

scholarly journals Hepatitis C Virus (HCV) diagnosis, epidemiology and access to treatment in a UK cohort

2017 ◽  
Author(s):  
Emily Adland ◽  
Gerald Jesuthasan ◽  
Louise Downs ◽  
Victoria Wharton ◽  
Gemma Wilde ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Viral Load ◽  
Hepatitis C ◽  
Positive Predictive Value ◽  
Predictive Value ◽  
Clinical Care ◽  
Virologic Response ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Direct Acting Antiviral

ABSTRACTBackgroundAs direct acting antiviral (DAA) therapy is progressively rolled out for patients with hepatitis C virus (HCV) infection, careful scrutiny of HCV epidemiology, diagnostic testing, and access to care is crucial to underpin improvements in delivery of treatment.MethodsWe performed a retrospective study of HCV infection in a UK teaching hospital to evaluate the performance of different diagnostic laboratory tests, to describe the population with active HCV infection, and to determine the proportion of these individuals who access clinical care.ResultsOver a total time period of 33 months between 2013 and 2016, we tested 38,510 individuals for HCV infection and confirmed a new diagnosis of active HCV infection (HCV-Ag+ and/or HCV RNA+) in 359 (positive rate 0.9%). Our in-house HCV-Ab test had a positive predictive value of 87% when compared to repeat HCV-Ab testing in a regional reference laboratory, highlighting the potential for false positives to arise based on a single round of antibody-based screening. Of those confirmed Ab-positive, 70% were HCV RNA positive. HCV-Ag screening performed well, with 100% positive predictive value compared to detection of HCV RNA. There was a strong correlation between quantitative HCV-Ag and HCV RNA viral load (p<0.0001). Among the 359 cases of infection, the median age was 37 years, 85% were male, and 36% were in prison. Among 250 infections for which genotype was available, HCV genotype-1 (n=110) and genotype-3 (n=111) accounted for the majority. 117/359 (33%) attended a clinic appointment and 48 (13%) had curative treatment defined as sustained virologic response at 12 weeks (SVR12).ConclusionsHCV-Ab tests should be interpreted with caution as an indicator of population prevalence of HCV infection, both as a result of the detection of individuals who have cleared infection and due to false positive test results. We demonstrate that active HCV infection is over-represented among men and in the prison population. A minority of patients with a diagnosis of HCV infection access clinical care and therapy; enhanced efforts are required to target diagnosis and providing linkage to clinical care within high risk populations.ABBREVIATIONSDAADirect Acting AntiviralELISAEnzyme linked immunosorbent assayHCVHepatitis C VirusHCV-AbIgG antibody to Hepatitis C virusHCV-AgHepatitis C virus core antigenHCV RNAHepatitis C ribonucleic acid (viral load)MSMmen who have sex with menNATnucleic acid testingPCRpolymerase chain reaction (test for viral load)PPVpositive predictive valuePWIDpeople who inject drugsSDGSustainable Development GoalsSVRsustained virologic responseWHOWorld Health Organisation

The pharmacogenetics of OATP1B1 variants and their impact on the pharmacokinetics and efficacy of elbasvir/grazoprevir

2019 ◽  
Vol 20 (9) ◽  
pp. 631-641
Author(s):  
Zifang Guo ◽  
Luzelena Caro ◽  
Michael N Robertson ◽  
Peggy Hwang ◽  
Patricia Hoover ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Retrospective Analysis ◽  
Genetic Variants ◽  
Sustained Virologic Response ◽  
Area Under Curve ◽  
Risk Allele ◽  
Geometric Mean ◽  
Virologic Response

Aim: To evaluate the effect of SLCO1B1 genetic variants on grazoprevir pharmacokinetics and efficacy. Methods: A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Results: Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of grazoprevir area under curve (AUC)0–24 were: rs4149056 (risk allele C), one copy, 1.13 (1.06–1.21), two copies, 1.43 (1.16–1.77); and rs11045819 (risk allele A), one copy, 0.93 (0.87–1.00); two copies, 0.78 (0.61–1.00). The rs2306283 variant was not associated with grazoprevir exposure. None of the SLCO1B1 variants were associated with sustained virologic response. Conclusion: Genetic variants in SLCO1B1 were associated with modest changes in grazoprevir pharmacokinetics, but not with meaningful differences in efficacy.

scholarly journals Baseline Polymorphisms and Emergence of Drug Resistance in the NS3/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a/Ribavirin in Phase 2 and Phase 3 Studies

2015 ◽  
Vol 59 (10) ◽  
pp. 6017-6025 ◽  
Author(s):  
K. L. Berger ◽  
J. Scherer ◽  
M. Ranga ◽  
N. Sha ◽  
J. O. Stern ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Interferon Alpha ◽  
Sustained Virologic Response ◽  
Pegylated Interferon ◽  
Virologic Response ◽  
Phase 2 ◽  
Genotype 1 ◽  
Phase 3 ◽  
Pegylated Interferon Alpha

ABSTRACTAnalysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease inhibitor faldaprevir plus pegylated interferon alpha/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (n= 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (P< 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (n= 507 GT-1a;n= 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold differencein vitro). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure.

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