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Bachmann G.,The New School | Crosby U.,University of Texas Southwestern Medical Center | Feldman R.A.,Miami Research Associates | Ronkin S.,Pfizer | Constantine G.D.,Pfizer
Menopause | Year: 2011

Objective: Phase 3 studies of postmenopausal women with or at risk for osteoporosis reported that, compared with placebo, bazedoxifene increased the incidence of hot flushes. The current study evaluated the vasomotor effects of bazedoxifene in healthy nonflushing postmenopausal women. Methods: In this phase 2 study, nonflushing postmenopausal women (n = 494) were randomized to daily treatment with bazedoxifene 5, 10, or 20 mg; raloxifene 60 mg; or placebo for 12 weeks. The primary endpoint was the percentage of women reporting hot flushes at any time during the study; secondary endpoints included the mean number and severity of hot flushes and the mean number of days with hot flushes. Effects on bone turnover markers and lipid parameters were also evaluated. Results: Over the 12-week study, 25.5% of placebo-treated women reported hot flushes. The incidence of hot flushes with bazedoxifene 5, 10, and 20 mg and raloxifene 60 mg was 26.0%, 33.7%, 27.6%, and 21.4%, respectively, with no significant differences from that with placebo. The active treatment groups showed no significant differences from placebo in the mean number or severity of hot flushes during week 12 or any 4-week period. Bazedoxifene and raloxifene showed beneficial effects on lipid parameters and markers of bone turnover. All doses of bazedoxifene were generally well tolerated and did not increase endometrial thickness, vaginal bleeding, or breast pain compared with placebo over 12 weeks of therapy. Conclusions: Data from this phase 2 clinical trial suggest that bazedoxifene does not increase the incidence of hot flushes relative to placebo in nonflushing postmenopausal women. © 2011 by The North American Menopause Society. Source

Block S.L.,Kentucky Pediatric and Adult Research | Yi T.,Med Immune Ltd. | Sheldon E.,Miami Research Associates | Dubovsky F.,Med Immune Ltd. | Falloon J.,Med Immune Ltd.
Vaccine | Year: 2011

Background: Trivalent seasonal influenza vaccines contain 2 A strains and 1 B strain. B strains of 2 antigenically distinct lineages, Yamagata and Victoria, have been co-circulating annually, and the B strain included in vaccines often has not been a lineage match to the major circulating strain. Thus, a vaccine containing B strains from both lineages could broaden protection against influenza. Quadrivalent live attenuated influenza vaccine (Q/LAIV) is an investigational 4-strain formulation of LAIV that contains 2 A strains, A/H1N1 and A/H3N2, and 2 B strains, 1 from each lineage. Methods: A randomized, double-blind, active-controlled study of Q/LAIV was conducted in 1800 adults aged 18-49 years to compare the immunogenicity and safety of Q/LAIV to trivalent LAIV (T/LAIV). Subjects were randomized 4:1:1 to receive an intranasal dose of Q/LAIV (. n=. 1200) or 1 of 2 matching T/LAIV vaccines, each containing 1 of the B strains included in Q/LAIV (. n=. 600 total). The primary endpoint was the comparison of the post-vaccination strain-specific geometric mean titers (GMT) of hemagglutination inhibition antibody in Q/LAIV recipients to those in T/LAIV recipients, with immunologic noninferiority of Q/LAIV to be demonstrated if the upper bound of the 2-sided 95% confidence interval (CI) for the ratio of the GMTs [T/LAIV divided by Q/LAIV] was ≤1.5 for all strains. Results and Conclusion: Q/LAIV met the criteria for noninferiority: the ratios of the GMTs for the A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.09 (95% CI, 1.01-1.18), 1.05 (95% CI, 0.96-1.14), 1.10 (95% CI, 0.97-1.25), and 0.92 (95% CI, 0.82-1.03), respectively. Solicited symptoms and adverse events were similar in the Q/LAIV and T/LAIV arms. Q/LAIV may confer increased protection against influenza by targeting B strains from both lineages. © 2011 Elsevier Ltd. Source

Everson G.T.,University of Colorado at Denver | Sims K.D.,Bristol Myers Squibb | Rodriguez-Torres M.,Fundacion de Investigacion | Hezode C.,Service dHepato Gastroenterologie | And 17 more authors.
Gastroenterology | Year: 2014

Background & Aims The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection. Methods We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]). Results In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms. Conclusions In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090. © 2014 by the AGA Institute. Source

Taylor D.N.,VaxInnate | Treanor J.J.,University of Rochester | Sheldon E.A.,Miami Research Associates | Umlauf S.,VaxInnate | And 7 more authors.
Vaccine | Year: 2012

Background: We evaluated the safety and immunogenicity profiles of 3 novel influenza vaccine constructs consisting of the globular head of the HA1 domain of the Novel H1N1 genetically fused to the TLR5 ligand, flagellin. HA1 was fused to the C-terminus of flagellin in VAX128A, replaced the D3 domain of flagellin in VAX128B and was fused in both positions in VAX128C. Methods: In a dose escalation trial, 112 healthy subjects 18-49 and 100 adults ≥65 years old were enrolled in a double blind, placebo controlled clinical trial at two centers. Vaccines were administered IM at doses ranging from 0.5 to 20 μg. VAX128C was selected for second study performed in 100 subjects 18-64 years old comparing 1.25 and 2.5 μg doses. All subjects were followed for safety and sera collected pre- and post-vaccination were tested by hemagglutination-inhibition (HAI). Serum C-reactive protein and cytokine levels were also measured. Conclusions: In the first study high HAI titers and high seroconversion and seroprotection rates were observed at doses ≥2.5 μg in adults 18-49. In adults ≥65 years, the vaccines doses of ≥4 μg were required to induce a ≥4-fold rise in HAI titer, 50% seroconversion and 70% seroprotection. Based on safety, VAX128A was tested up to 8 μg, VAX128B to 16 μg and VAX128C to 20 μg. Dose escalation for VAX128A was stopped at 8 μg because one subject had temperature 101.6 °F associated with a high CRP response, VAX128B was stopped at 16 μg because of a severe AE associated with a high CRP and IL-6 response. VAX128C was not stopped before reaching the 20 μg dose. In the second study VAX128C was well tolerated among 100 subjects who received 1.25 or 2.5 μg. The peak GMT was 385 (95%CI 272-546), 79% (71-87%) seroconversion and 92% (84-96%) seroprotection. Discussion: Flagellin adjuvanted vaccines can be designed to minimize reactogenicity and retain immunogenicity, thereby representing a promising next generation vaccine technology. © 2012 Elsevier Ltd. Source

Plennevaux E.,Sanofi S.A. | Sheldon E.,Miami Research Associates | Blatter M.,Primary Physicians Research | Reeves-Hoche M.-K.,Sanofi S.A. | Denis M.,Sanofi S.A.
The Lancet | Year: 2010

Background: Data are needed from large clinical trials of paediatric, adult, and elderly people to find the appropriate antigen dose and vaccination schedule for the 2009 pandemic influenza A H1N1. We therefore report preliminary safety and immunogenicity results after one injection of a licensed monovalent pandemic H1N1 vaccine in the USA. Methods: We randomly assigned healthy children (aged 6-35 months and 3-9 years) and adults (18-64 years and ≥65 years) to vaccine containing per dose 7·5 μg (children and adults), 15 μg (children and adults), or 30 μg (adults only) haemagglutinin in two placebo-controlled, observer-masked, multicentre phase 2 studies done in the USA. Participants were allocated with an interactive voice-response system or computer-generated randomisation lists with opaque scratchable patches. Primary outcome was haemagglutination inhibition antibody response 21 days after the first of two planned vaccinations (interim analysis of studies in progress). Analyses were by full-analysis set. The trials are registered with ClinicalTrials.gov as NCT00953524 and NCT00952419. Findings: 410 of 423 children and 724 of 750 adults given an active vaccine, and 50 of 51 children and 95 of 99 adults given placebo were assessed for immunogenicity on day 21. After active vaccination, 45 of 101 (45%; 95% CI 35-55) to 47 of 94 (50%; 40-61) infants aged 6-35 months, 75 of 109 (69%; 59-77) to 80 of 106 (75%; 66-83) 3-9-year-old children, 134 of 141 (95%; 90-98) to 144 of 144 (100%; 98-100) of 18-64-year-old adults, and 93 of 100 (93%; 86-96) to 93 of 98 (95%; 89-98) elderly adults were seroprotected (proportion with titres ≥1:40). No vaccine-related serious adverse events occurred. Injection-site and systemic reactions were reported by up to about 50% of every age and vaccine group, with no noticeable differences between vaccine and placebo groups. Interpretation: One dose of vaccine was highly immunogenic in adults, suggesting that it afforded sufficient protection against this pandemic influenza A H1N1 virus. Two doses of vaccine will probably be needed in children younger than 9 years. Safety and reactogenicity of the vaccine were acceptable and similar to those of seasonal vaccine. Funding: Office of the Assistant Secretary for Preparedness and Response, and Biomedical Advanced Research and Development Authority. © 2010 Elsevier Ltd. All rights reserved. Source

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