20 results on '"Setze C"'
Search Results
2. Safety results from a pooled analysis of randomized, controlled phase II and III clinical trials and interim data from an open-label extension trial of the interleukin-12/23 monoclonal antibody, briakinumab, in moderate to severe psoriasis
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Langley, R. G., Papp, K., Gottlieb, A. B., Krueger, G. G., Gordon, K. B., Williams, D., Valdes, J., Setze, C., and Strober, B.
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- 2013
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3. G13 : Ombitasvir/paritaprevir/ritonavir for treatment of HCV genotype 1b in Japanese patients with or without cirrhosis: Results from gift-I
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Chayama, K., primary, Suzuki, F., additional, Ikeda, K., additional, Toyoda, H., additional, Sato, K., additional, Karino, Y., additional, Matsuzaki, Y., additional, Kioka, K., additional, Pilot-Matias, T., additional, Setze, C., additional, Zhang, X., additional, Badri, P., additional, Yanke, T., additional, Matsuda, T., additional, Vilchez, R.A., additional, Rodrigues-Jr, L., additional, and Kumada, H., additional
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- 2015
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4. M12-999:ABT-450/r/ABT-267+ABT-333+Ribavirin in Liver Transplant Recipients With Recurrent HCV Genotype 1 Infection.
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Mantry, P., primary, Kwo, P., additional, Coakley, E., additional, Te, H., additional, Vargas, H., additional, Brown, R., additional, Gordon, F., additional, Levitsky, J., additional, Terrault, N., additional, Burton, J., additional, Xie, W., additional, Setze, C., additional, Badri, P., additional, Vilchez, R., additional, and Forns, X., additional
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- 2014
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5. O114 RESULTS OF THE PHASE 2 STUDY M12-999: INTERFERON-FREE REGIMEN OF ABT-450/R/ABT-267 + ABT-333 + RIBAVIRIN IN LIVER TRANSPLANT RECIPIENTS WITH RECURRENT HCV GENOTYPE 1 INFECTION
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Kwo, P., primary, Mantry, P., additional, Coakley, E., additional, Te, H., additional, Vargas, H., additional, Brown, R., additional, Gordon, F., additional, Levitsky, J., additional, Terrault, N., additional, Burton, J., additional, Xie, W., additional, Setze, C., additional, Badri, P., additional, Vilchez, R.A., additional, and Forns, X., additional
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- 2014
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6. Safety results from a pooled analysis of randomized, controlled phase II and III clinical trials and interim data from an open-label extension trial of the interleukin-12/23 monoclonal antibody, briakinumab, in moderate to severe psoriasis
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Langley, R.G., primary, Papp, K., additional, Gottlieb, A.B., additional, Krueger, G.G., additional, Gordon, K. B., additional, Williams, D., additional, Valdes, J., additional, Setze, C., additional, and Strober, B., additional
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- 2012
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7. 1186 SAFETY AND ANTIVIRAL ACTIVITY OF ABT-267, A NOVEL NS5A INHIBITOR, DURING 3-DAY MONOTHERAPY: FIRST STUDY IN HCV GENOTYPE-1 (GT1)-INFECTED TREATMENT-NAIVE SUBJECTS
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Lawitz, E., primary, Marbury, T., additional, Campbell, A., additional, Dumas, E., additional, Kapoor, M., additional, Pilot-Matias, T., additional, Krishnan, P., additional, Setze, C., additional, Xie, W., additional, Podsadecki, T., additional, Bernstein, B., additional, and Williams, L., additional
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- 2012
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8. 1210 ABT-267 COMBINED WITH PEGYLATED INTERFERON ALPHA-2A/RIBAVIRIN IN GENOTYPE 1 (GT1) HCV-INFECTED TREATMENT-NAIVE SUBJECTS: 12 WEEK ANTIVIRAL AND SAFETY ANALYSIS
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Sullivan, G.J., primary, Rodriques-Torres, M., additional, Lawitz, E., additional, Poordad, F., additional, Kapoor, M., additional, Campbell, A., additional, Setze, C., additional, Xie, W., additional, Khatri, A., additional, Dumas, E., additional, Krishnan, P., additional, Pilot-Matias, T., additional, Williams, L., additional, and Bernstein, B., additional
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- 2012
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9. Abstract: 517 EFFICACY AND SAFETY OF FENOFIBRIC ACID IN COMBINATION WITH ATORVASTATIN AND EZETIMIBE IN PATIENTS WITH MIXED DYSLIPIDEMIA: A PHASE 3 STUDY
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Jones, P, primary, Goldberg, A, additional, Knapp, H, additional, Kelly, M, additional, Setze, C, additional, Stolzenbach, J, additional, and Sleep, D, additional
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- 2009
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10. Abstract: 1014 LONG-TERM EFFECT OF ADDING FENOFIBRIC ACID TO MODERATEDOSE STATIN ON C-REACTIVE PROTEIN LEVELS IN PATIENTS WITH MIXED DYSLIPIDEMIA
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Davidson, M, primary, Guthrie, R, additional, Kelly, M, additional, Setze, C, additional, and Sleep, D, additional
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- 2009
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11. Efficacy of fenofibric acid in combination with simvastatin in patients with type 2 diabetes mellitus and mixed dyslipidemia
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Mohiuddin, S., primary, Kelly, M., additional, Setze, C., additional, Ansquer, J., additional, and Sleep, D., additional
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- 2009
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12. Safety and Pharmacokinetics of Glecaprevir/Pibrentasvir in Adults With Chronic Genotype 1-6 Hepatitis C Virus Infections and Compensated Liver Disease.
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Gane E, Poordad F, Zadeikis N, Valdes J, Lin CW, Liu W, Asatryan A, Wang S, Stedman C, Greenbloom S, Nguyen T, Elkhashab M, Wörns MA, Tran A, Mulkay JP, Setze C, Yu Y, Pilot-Matias T, Porcalla A, and Mensa FJ
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- Aged, Aminoisobutyric Acids, Antiviral Agents adverse effects, Benzimidazoles adverse effects, Cyclopropanes, Data Interpretation, Statistical, Drug Therapy, Combination, Female, Genotype, Hepacivirus drug effects, Hepacivirus genetics, Hepatitis C, Chronic virology, Humans, Lactams, Macrocyclic, Leucine analogs & derivatives, Liver Cirrhosis drug therapy, Liver Diseases virology, Male, Proline analogs & derivatives, Pyrrolidines, Quinoxalines adverse effects, Sulfonamides adverse effects, Sustained Virologic Response, Antiviral Agents pharmacokinetics, Benzimidazoles pharmacokinetics, Hepatitis C, Chronic drug therapy, Liver Diseases drug therapy, Quinoxalines pharmacokinetics, Sulfonamides pharmacokinetics
- Abstract
Background: Untreated, chronic hepatitis C virus (HCV) infection may lead to progressive liver damage, which can be mitigated by successful treatment. This integrated analysis reports the safety, efficacy, and pharmacokinetics (PK) of the ribavirin-free, direct-acting, antiviral, fixed-dose combination of glecaprevir/pibrentasvir (G/P) in patients with chronic HCV genotype 1-6 infections and compensated liver disease, including patients with chronic kidney disease stages 4 or 5 (CKD 4/5)., Methods: Data from 9 Phase II and III clinical trials, assessing the efficacy and safety of G/P treatment for 8-16 weeks, were included. The presence of cirrhosis was determined at screening using a liver biopsy, transient elastography, or serum biomarkers. The objectives were to evaluate safety, the rate of sustained virologic response at post-treatment week 12 (SVR12), and steady-state PK by cirrhosis status., Results: Among 2369 patients, 308 (13%) were Child-Pugh Class A, including 20 with CKD 4/5. Overall, <1% of patients experienced an adverse event (AE) that led to G/P discontinuation or G/P-related serious AEs (SAEs). The most common AEs were headache and fatigue, occurring at similar frequencies with and without cirrhosis. SAEs were more common in patients with CKD 4/5, but all were unrelated to G/P. There were no cases of drug-induced liver injury or clinically relevant hepatic decompensation. SVR12 rates were 96.4% (297/308) with compensated cirrhosis and 97.5% (2010/2061) without cirrhosis. PK analysis demonstrated a 2.2-fold increase in glecaprevir exposure, but not pibrentasvir exposure, in patients with compensated cirrhosis., Conclusions: G/P was safe and efficacious in patients with compensated liver disease, including those with CKD 4/5., Clinical Trials Registration: NCT02243280, NCT02243293, NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, and NCT02446717., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2019
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13. Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir.
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Schnell G, Tripathi R, Krishnan P, Beyer J, Reisch T, Irvin M, Dekhtyar T, Setze C, Rodrigues L Jr, Alves K, Burroughs M, Redman R, Chayama K, Kumada H, Collins C, and Pilot-Matias T
- Subjects
- Anilides administration & dosage, Anilides adverse effects, Antiviral Agents administration & dosage, Antiviral Agents adverse effects, Carbamates administration & dosage, Carbamates adverse effects, Cyclopropanes, Drug Therapy, Combination adverse effects, Female, Genotype, Hepacivirus genetics, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic epidemiology, Hepatitis C, Chronic ethnology, Humans, Japan epidemiology, Lactams, Macrocyclic, Macrocyclic Compounds administration & dosage, Macrocyclic Compounds adverse effects, Male, Middle Aged, Polymorphism, Genetic, Proline analogs & derivatives, Ribavirin administration & dosage, Ribavirin adverse effects, Ribavirin therapeutic use, Ritonavir administration & dosage, Ritonavir adverse effects, Sulfonamides, Treatment Failure, Treatment Outcome, Valine, Anilides therapeutic use, Antiviral Agents therapeutic use, Carbamates therapeutic use, Drug Resistance, Viral genetics, Hepacivirus drug effects, Hepatitis C, Chronic virology, Macrocyclic Compounds therapeutic use, Ritonavir therapeutic use
- Abstract
Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks., (© 2017 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.)
- Published
- 2018
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14. Randomized Phase 3 Trial of Ombitasvir/Paritaprevir/Ritonavir and Ribavirin for Hepatitis C Virus Genotype 2-Infected Japanese Patients.
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Sato K, Chayama K, Alves K, Toyoda H, Suzuki F, Kato K, Rodrigues L Jr, Zhang X, Setze C, Pilot-Matias T, Burroughs M, Redman R, and Kumada H
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- Aged, Anilides administration & dosage, Anilides adverse effects, Antiviral Agents administration & dosage, Antiviral Agents adverse effects, Carbamates administration & dosage, Carbamates adverse effects, Cyclopropanes, Drug Combinations, Drug Therapy, Combination, Female, Genotype, Hepacivirus genetics, Humans, Japan, Lactams, Macrocyclic, Macrocyclic Compounds administration & dosage, Macrocyclic Compounds adverse effects, Male, Middle Aged, Proline analogs & derivatives, Ribavirin administration & dosage, Ribavirin adverse effects, Ritonavir administration & dosage, Ritonavir adverse effects, Sulfonamides, Sustained Virologic Response, Valine, Anilides therapeutic use, Antiviral Agents therapeutic use, Carbamates therapeutic use, Hepatitis C drug therapy, Macrocyclic Compounds therapeutic use, Ribavirin therapeutic use, Ritonavir therapeutic use
- Abstract
Introduction: In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection., Methods: Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients., Results: A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5-99.5%) and 75.0% (36/48; 95% confidence interval 62.8-87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis., Conclusions: OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile., Trial Registration: ClinicalTrials.gov identifier, NCT02023112., Funding: AbbVie.
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- 2017
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15. Analysis of Hepatitis C Virus Genotype 1b Resistance Variants in Japanese Patients Treated with Paritaprevir-Ritonavir and Ombitasvir.
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Krishnan P, Schnell G, Tripathi R, Beyer J, Reisch T, Zhang X, Setze C, Rodrigues L Jr, Burroughs M, Redman R, Chayama K, Kumada H, Collins C, and Pilot-Matias T
- Subjects
- Antiviral Agents therapeutic use, Cyclopropanes, Drug Resistance, Viral genetics, Drug Therapy, Combination, Genetics, Population, Hepacivirus drug effects, Hepacivirus pathogenicity, Hepatitis C virology, Humans, Japan, Lactams, Macrocyclic, Polymorphism, Genetic, Proline analogs & derivatives, Sulfonamides, Treatment Failure, Valine, Viral Nonstructural Proteins genetics, Anilides therapeutic use, Carbamates therapeutic use, Hepacivirus genetics, Hepatitis C drug therapy, Macrocyclic Compounds therapeutic use, Ritonavir therapeutic use
- Abstract
Treatment of HCV genotype 1b (GT1b)-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) in studies M12-536 and GIFT-I demonstrated high sustained virologic response (SVR) rates. The virologic failure rate was 3% (13/436) across the two studies. Analyses were conducted to evaluate the impact of baseline resistance-associated variants (RAVs) on treatment outcome and the emergence and persistence of RAVs in patients experiencing virologic failure. Baseline paritaprevir resistance-conferring variants in NS3 were infrequent, while Y93H in NS5A was the most prevalent ombitasvir resistance-conferring variant at baseline. A comparison of baseline prevalence of polymorphisms in Japanese and western patients showed that Q80L and S122G in NS3 and L28M, R30Q, and Y93H in NS5A were significantly more prevalent in Japanese patients. In the GIFT-I study, the prevalence of Y93H in NS5A varied between 13% and 21% depending on the deep-sequencing detection threshold. Among patients with Y93H comprising <1%, 1 to 40%, or >40% of their preexisting viral population, the 24-week SVR (SVR24) rates were >99% (276/277), 93% (38/41), and 76% (25/33), respectively, indicating that the prevalence of Y93H within a patient's viral population is a good predictor of treatment response. The predominant RAVs at the time of virologic failure were D168A/V in NS3 and Y93H alone or in combination with other variants in NS5A. While levels of NS3 RAVs declined over time, NS5A RAVs persisted through posttreatment week 48. Results from these analyses are informative in understanding the resistance profile of an ombitasvir- plus paritaprevir/ritonavir-based regimen in Japanese GT1b-infected patients., (Copyright © 2016 Krishnan et al.)
- Published
- 2015
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16. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis.
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Kumada H, Chayama K, Rodrigues L Jr, Suzuki F, Ikeda K, Toyoda H, Sato K, Karino Y, Matsuzaki Y, Kioka K, Setze C, Pilot-Matias T, Patwardhan M, Vilchez RA, Burroughs M, and Redman R
- Subjects
- Aged, Asian People, Cyclopropanes, Double-Blind Method, Drug Combinations, Female, Genotype, Hepacivirus classification, Hepacivirus genetics, Hepatitis C, Chronic complications, Humans, Lactams, Macrocyclic, Liver Cirrhosis complications, Male, Middle Aged, Proline analogs & derivatives, Sulfonamides, Valine, Anilides administration & dosage, Antiviral Agents administration & dosage, Carbamates administration & dosage, Hepatitis C, Chronic drug therapy, Macrocyclic Compounds administration & dosage, Ritonavir administration & dosage
- Abstract
Unlabelled: GIFT-I is a phase 3 trial evaluating the efficacy and safety of a 12-week regimen of coformulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) for treatment of Japanese hepatitis C virus genotype 1b-infected patients. It consists of a double-blind, placebo-controlled substudy of patients without cirrhosis and an open-label substudy of patients with compensated cirrhosis. Patients without cirrhosis were randomized 2:1 to once-daily OBV/PTV/r (25 mg/150 mg/100 mg; group A) or placebo (group B). Patients with cirrhosis received open-label OBV/PTV/r (group C). The primary efficacy endpoint was the rate of sustained virological response 12 weeks posttreatment in interferon-eligible, treatment-naive patients without cirrhosis and hepatitis C virus RNA ≥100,000 IU/mL in group A. A total of 321 patients without cirrhosis were randomized and dosed with double-blind study drug (106 received double-blind placebo and later received open-label OBV/PTV/r), and 42 patients with cirrhosis were enrolled and dosed with open-label OBV/PTV/r. In the primary efficacy population, the rate of sustained virological response 12 weeks posttreatment was 94.6% (106/112, 95% confidence interval 90.5-98.8). Sustained virological response 12 weeks posttreatment rates were 94.9% (204/215) in group A, 98.1% (104/106) in group B (open-label), and 90.5% (38/42) in group C. Overall, virological failure occurred in 3.0% (11/363) of patients who received OBV/PTV/r. The rate of discontinuation due to adverse events was 0%-2.4% in the three patient groups receiving OBV/PTV/r. The most frequent adverse event in patients in any group was nasopharyngitis., Conclusion: In this broad hepatitis C virus genotype 1b-infected Japanese patient population with or without cirrhosis, treatment with OBV/PTV/r for 12 weeks was highly effective and demonstrated a favorable safety profile., (© 2015 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)
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- 2015
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17. Randomized trial of interferon- and ribavirin-free ombitasvir/paritaprevir/ritonavir in treatment-experienced hepatitis C virus-infected patients.
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Chayama K, Notsumata K, Kurosaki M, Sato K, Rodrigues L Jr, Setze C, Badri P, Pilot-Matias T, Vilchez RA, and Kumada H
- Subjects
- Adult, Aged, Cyclopropanes, Drug Therapy, Combination, Female, Humans, Interferons, Lactams, Macrocyclic, Liver Cirrhosis, Male, Middle Aged, Proline analogs & derivatives, Ribavirin, Sulfonamides, Valine, Young Adult, Anilides administration & dosage, Antiviral Agents administration & dosage, Carbamates administration & dosage, Hepatitis C, Chronic drug therapy, Macrocyclic Compounds administration & dosage, Ritonavir administration & dosage
- Abstract
Unlabelled: Approximately 2 million Japanese individuals are infected with hepatitis C virus and are at risk for cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Patients in whom interferon (IFN)/ribavirin (RBV) therapy has failed remain at risk as effective therapeutic options are limited. This phase 2, randomized, open-label study evaluated an IFN- and RBV-free regimen of once-daily ombitasvir (ABT-267), an NS5A inhibitor, plus paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (paritaprevir/ritonavir), in pegylated IFN/RBV treatment-experienced Japanese patients with hepatitis C virus subtype 1b or genotype 2 infection. Patients without cirrhosis (aged 18-75 years) with subtype 1b infection received ombitasvir 25 mg plus paritaprevir/ritonavir 100/100 mg or 150/100 mg for 12 or 24 weeks; patients with genotype 2 infection received ombitasvir 25 mg plus paritaprevir/ritonavir 100/100 mg or 150/100 mg for 12 weeks. Sustained virologic response (SVR) at posttreatment week 24 (SVR24 ) was the primary endpoint. Adverse events were collected throughout the study. One hundred ten patients received ≥1 dose of study medication. In the subtype 1b cohort, SVR24 rates were high (88.9%-100%) regardless of paritaprevir dose or treatment duration. In the genotype 2 cohort, SVR24 rates were 57.9% and 72.2% with 100 mg and 150 mg of paritaprevir, respectively. The SVR24 rate was higher in patients with subtype 2a (90%) than 2b (27%). Concordance between SVR12 and SVR24 was 100%. The most common adverse events overall were nasopharyngitis (29%) and headache (14%)., Conclusion: In this difficult-to-treat population of patients in whom prior pegylated IFN/RBV had failed, ombitasvir/paritaprevir/ritonavir demonstrated potent antiviral activity with a favorable safety profile among Japanese patients with hepatitis C virus genotype 1b or 2a infection., (© 2015 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)
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- 2015
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18. In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A.
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Krishnan P, Beyer J, Mistry N, Koev G, Reisch T, DeGoey D, Kati W, Campbell A, Williams L, Xie W, Setze C, Molla A, Collins C, and Pilot-Matias T
- Subjects
- Cell Line, Drug Resistance, Viral, Hepacivirus drug effects, Humans, Proline, Valine, Anilides therapeutic use, Antiviral Agents therapeutic use, Carbamates therapeutic use, Hepatitis C drug therapy
- Abstract
Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
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- 2015
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19. An interferon-free antiviral regimen for HCV after liver transplantation.
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Kwo PY, Mantry PS, Coakley E, Te HS, Vargas HE, Brown R Jr, Gordon F, Levitsky J, Terrault NA, Burton JR Jr, Xie W, Setze C, Badri P, Pilot-Matias T, Vilchez RA, and Forns X
- Subjects
- 2-Naphthylamine, Adult, Aged, Anilides adverse effects, Antiviral Agents adverse effects, Calcineurin Inhibitors blood, Calcineurin Inhibitors therapeutic use, Carbamates adverse effects, Cyclopropanes, Drug Therapy, Combination, Female, Hepacivirus genetics, Hepacivirus isolation & purification, Humans, Lactams, Macrocyclic, Macrocyclic Compounds adverse effects, Male, Middle Aged, Proline analogs & derivatives, RNA, Viral blood, Ribavirin administration & dosage, Ritonavir therapeutic use, Sulfonamides therapeutic use, Uracil analogs & derivatives, Uracil therapeutic use, Valine, Viral Nonstructural Proteins antagonists & inhibitors, Young Adult, Anilides therapeutic use, Antiviral Agents therapeutic use, Carbamates therapeutic use, Hepatitis C, Chronic drug therapy, Liver Transplantation, Macrocyclic Compounds therapeutic use
- Abstract
Background: Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection., Methods: We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigator's discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment., Results: Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study., Conclusions: Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).
- Published
- 2014
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20. Study design, rationale, and baseline characteristics: evaluation of fenofibric acid on carotid intima-media thickness in patients with type IIb dyslipidemia with residual risk in addition to atorvastatin therapy (FIRST) trial.
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Davidson M, Rosenson RS, Maki KC, Nicholls SJ, Ballantyne CM, Setze C, Carlson DM, and Stolzenbach J
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- Aged, Aged, 80 and over, Atorvastatin, Carotid Arteries pathology, Carotid Intima-Media Thickness, Cholesterol, HDL blood, Cholesterol, LDL blood, Coronary Artery Disease blood, Coronary Artery Disease pathology, Disease Progression, Double-Blind Method, Dyslipidemias blood, Dyslipidemias pathology, Female, Fenofibrate therapeutic use, Follow-Up Studies, Humans, Male, Middle Aged, Risk Factors, Triglycerides blood, Anticholesteremic Agents therapeutic use, Carotid Arteries drug effects, Coronary Artery Disease drug therapy, Dyslipidemias drug therapy, Fenofibrate analogs & derivatives, Heptanoic Acids therapeutic use, Hypolipidemic Agents therapeutic use, Pyrroles therapeutic use
- Abstract
Purpose: Elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels contribute to cardiovascular disease risk and can be effectively treated with fenofibric acid. A trial is under way to evaluate the effect of once-daily fenofibric acid or placebo on carotid intima-media thickness (CIMT) progression in patients with controlled low-density lipoprotein cholesterol (LDL-C) levels achieved through atorvastatin treatment, but with high TG and low HDL-C levels., Methods: In this multicenter, double-blind study, 682 patients were randomized to once-daily delayed-release capsules of choline fenofibrate 135 mg (fenofibric acid [Trilipix(®); Abbott, North Chicago, IL]) or placebo plus atorvastatin treatment after a 2- to 10-week diet and atorvastatin run-in period. Key inclusion criteria included age ≥45 years; posterior-wall common CIMT ≥0.7 mm on at least one side at baseline; fasting results of TG ≥150 mg/dL, and HDL-C ≤45 mg/dL for men or HDL-C ≤55 mg/dL for women at screening while receiving atorvastatin; controlled LDL-C; and known coronary heart disease (CHD) or a CHD risk equivalent. The primary efficacy variable is the rate of change from baseline through week 104 in the mean posterior-wall intima-media thickness of the common carotid arteries (composite value of left and right sides)., Conclusions: This trial is the first to examine the effect of fenofibric acid on CIMT and the first CIMT trial to select patients with controlled LDL-C and elevated TG and low HDL-C as inclusion criteria. Also, this trial will prospectively evaluate the effect of treatment on LDL particles and address shortcomings of previous CIMT trials.
- Published
- 2012
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