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Lee D.O.,East Carolina Neurology Inc. | Ziman R.B.,Northridge | Perkins A.T.,NC Associates | Poceta J.S.,Scripps Research Institute | And 25 more authors.
Journal of Clinical Sleep Medicine | Year: 2011

Study Objective: To evaluate the efficacy and tolerability of gabapentin enacarbil (GEn) 1200 mg or 600 mg compared with placebo in subjects with moderate-to-severe primary restless legs syndrome (RLS). Methods: This 12-week, multicenter, double-blind, placebo-controlled study randomized subjects (1:1:1) to GEn 1200 mg, 600 mg, or placebo. Co-primary endpoints: mean change from baseline in International Restless Legs Scale (IRLS) total score and proportion of responders (rated as "very much" or "much" improved) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 LOCF for GEn 1200 mg compared with placebo. Secondary endpoints included GEn 600 mg compared with placebo on the IRLS and CGI-I at Week 12 LOCF and subjective measures for sleep. Safety and tolerability assessments included adverse events. Results: 325 subjects were randomized (GEn 1200 mg = 113; 600 mg = 115; placebo = 97). GEn 1200 mg significantly improved mean [SD] IRLS total score at Week 12 LOCF (baseline: 23.2 [5.32]; Week 12: 10.2 [8.03]) compared with placebo (baseline: 23.8 [4.58]; Week 12: 14.0 [7.87]; adjusted mean treatment difference [AMTD]: -3.5; p = 0.0015), and significantly more GEn 1200 mg-treated (77.5%) than placebo-treated (44.8%) subjects were CGI-I responders (p < 0.0001). Similar significant results were observed with GEn 600 mg for IRLS (AMTD: -4.3; p < 0.0001) and CGI-I (72.8% compared with 44.8%; p < 0.0001). GEn also significantly improved sleep outcomes (Post-Sleep Questionnaire, Pittsburgh Sleep Diary and Medical Outcomes Sleep Scale) compared with placebo. The most commonly reported adverse events were somnolence (GEn 1200 mg = 18.0%; 600 mg = 21.7%; placebo = 2.1%) and dizziness (GEn 1200 mg = 24.3%; 600 mg = 10.4%; placebo = 5.2%). Dizziness increased with increased dose and led to discontinuation in 2 subjects (GEn 1200 mg, n = 1; GEn 600 mg, n = 1). Somnolence led to discontinuation in 3 subjects (GEn 600 mg). Conclusions: GEn 1200 mg and 600 mg significantly improve RLS symptoms and sleep disturbance compared with placebo and are generally well tolerated.


Dodick D.W.,Mayo Medical School | Goadsby P.J.,King's College London | Goadsby P.J.,University of California at San Francisco | Silberstein S.D.,Thomas Jefferson University | And 31 more authors.
The Lancet Neurology | Year: 2014

Background: Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered humanised anti-CGRP antibody, for migraine prevention. Methods: In this randomised, double-blind, placebo-controlled, exploratory, proof-of-concept phase 2 trial, patients aged 18-55 years with five to 14 migraine days per 28-day period were randomly assigned (1:1) via an interactive web response system to receive an intravenous dose of ALD403 1000 mg or placebo. Site investigators, patients, and the sponsor were masked to treatment allocation during the study. The primary objective was to assess safety at 12 weeks after infusion. The primary efficacy endpoint was the change from baseline to weeks 5-8 in the frequency of migraine days, as recorded in patient electronic diaries. Patients were followed up until 24 weeks for exploratory safety and efficacy analyses. Safety and efficacy analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, NCT01772524. Findings: Between Jan 28, 2013, and Dec 23, 2013, of 174 patients randomly assigned at 26 centres in the USA, 163 received either ALD403 (n=81) or placebo (n=82). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. The most frequent adverse events were upper respiratory tract infection (placebo 6 [7%] patients vs ALD403 7 [9%] patients), urinary tract infection (4 [5%] vs 1 [1%]), fatigue (3 [4%] vs 3 [4%]), back pain (4 [5%] vs 3 [4%]), arthralgia (4 [5%] vs 1 [1%]), and nausea and vomiting (2 [2%] vs 3 [4%]). Six serious adverse events were reported by three patients and were judged to be unrelated to study drug: in the ALD403 group, one patient had four serious adverse events and one had one serious adverse event, and in the placebo group, one patient had one serious adverse event. There were no differences in vital signs or laboratory safety data between the two treatment groups. The mean change in migraine days between baseline and weeks 5-8 was -5·6 (SD 3·0) for the ALD403 group compared with -4·6 (3·6) for the placebo group (difference -1·0, 95% CI -2·0 to 0·1; one-sided p=0·0306). Interpretation: No safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days. Funding: Alder Biopharmaceuticals. © 2014 Elsevier Ltd.


Tsang P.,Sanofi S.A. | Gorse G.J.,Saint Louis University | Strout C.B.,Coastal Carolina Research Center | Sperling M.,Fountain | And 4 more authors.
Vaccine | Year: 2014

We conducted a randomized, controlled, multicenter, phase II study to evaluate the immunogenicity and safety of an investigational intradermal (ID) trivalent influenza vaccine (TIV) and a high-dose (HD) intramuscular (IM) TIV in older adults (≥65 years of age). Older adult subjects were immunized with ID vaccine containing either 15μg hemagglutinin (HA)/strain (n=636) or 21μg HA/strain (n=634), with HD IM vaccine containing 60μg HA/strain (n=320), or with standard-dose (SD) IM vaccine (Fluzone®; 15μg HA/strain; n=319). For comparison, younger adults (18-49 years of age) were immunized with SD IM vaccine. In older adults, post-vaccination geometric mean titers induced by the ID vaccines were superior to those induced by the SD IM vaccine for the A/H1N1 and A/H3N2 strains and non-inferior for the B strain. Seroconversion rates induced by the ID vaccines were superior to those induced by the SD IM vaccine in older adults for the A/H1N1 and B strains and non-inferior for the A/H3N2 strain. Results did not differ significantly for the two ID vaccine dosages. Post-vaccination geometric mean titers, seroconversion rates, and most seroprotection rates were significantly higher in HD vaccine recipients than in older adult recipients of the SD IM or ID vaccines and, for most measures, were comparable to those of younger adult SD IM vaccine recipients. Injection-site reactions, but not systemic reactions or unsolicited adverse events, were more common with the ID vaccines than with the IM vaccines. No treatment-related serious adverse events were reported. This study demonstrated that: (1) the ID and HD vaccines were well-tolerated and more immunogenic than the SD IM vaccine in older adults; (2) the HD vaccine was more immunogenic than the ID vaccines in older adults; and (3) the HD vaccine in older adults and the SD IM vaccine in younger adults elicited comparable antibody responses (ClinicalTrials.gov identifier no.: NCT00551031). © 2014 The Authors.


Greenberg R.N.,University of Kentucky | Gurtman A.,Pfizer | Frenck R.W.,Cincinnati Childrens Hospital Medical Center | Strout C.,Coastal Carolina Research Center | And 6 more authors.
Vaccine | Year: 2014

Background: Unlike free pneumococcal polysaccharide vaccines (PPSVs), pneumococcal conjugate vaccines (PCVs) induce a T-cell-dependent immune response. The study assessed potential influence of initial 13-valent PCV (PCV13) or 23-valent PPSV (PPSV23) on subsequent vaccine administrations. Methods: We conducted a randomized, modified double-blind study in 720 pneumococcal vaccine-naïve adults 60-64 years of age. Subjects received either PCV13 at year 0 and PCV13 at year 1; PCV13 at year 0 and PPSV23 at year 1; or PPSV23 at year 0 and PCV13 at year 1. Antipneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after each vaccination. Results: OPA titers following PPSV23 given 1 year after PCV13 (PCV13/PPSV23) (a) were noninferior for the 12 common serotypes and significantly higher for 6 of 12 common serotypes than those following only an initial PPSV23; and (b) were significantly higher for 11 of 12 common serotypes compared with PPSV23 followed by PCV13 (PPSV23/PCV13). In addition, PPSV23 followed 1 year later by PCV13 (PPSV23/PCV13) elicited significantly lower OPA titers than after only an initial dose of PCV13 for all 13 serotypes. Responses after a second vaccination with either PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for 9 of 13 and 8 of 12 common serotypes compared with the initial PCV13 dose. Conclusion: In pneumococcal vaccine-naïve adults 60-64 years of age, an initial PCV13 augmented the antipneumococcal response to subsequent administration of PPSV23 for many of the serotypes in common to both vaccines. In contrast, an initial PPSV23 resulted in a diminished response to subsequent administration of PCV13 for all serotypes. With a relatively short 1-year interval between doses, responses after a second vaccination with PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for a majority of serotypes compared with the initial PCV13 dose, probably reflecting the need for a longer interval between vaccine administrations.ClinicalTrials.gov Identifier: NCT00574548. © 2014 Elsevier Ltd.


Hopkins R.J.,Emergent BioSolutions | Howard C.,Emergent BioSolutions | Hunter-Stitt E.,Emergent BioSolutions | Kaptur P.E.,Emergent BioSolutions | And 6 more authors.
Vaccine | Year: 2014

Background: This study was conducted to support licensure of a post-exposure prophylaxis indication for BioThrax® (anthrax vaccine adsorbed) concurrent with antimicrobials for individuals exposed to aerosolized anthrax spores. Methods: The immunogenicity and safety of a three-dose regimen (0, 2, and 4 weeks) of BioThrax administered subcutaneously (SC) were evaluated in 200 healthy adults 18-65 years of age. Toxin-neutralizing antibody (TNA) was expressed as 50% neutralization factor (NF50) at predetermined time points through Day 100. Safety was assessed by physical examinations, vital signs, solicited local and systemic reactions using web-enabled subject diaries, in-clinic solicited reactions, and unsolicited adverse events (AEs). Results: The prospectively defined success criteria for the primary and secondary endpoints were met. This required the lower bound of the 95% confidence interval (CI) for the proportion of subjects with a TNA NF50 value to be greater than 40% at Day 63 (primary), Day 70 (secondary) and Days 63-100 (secondary). At Day 63, 71% of subjects achieved a TNA NF50 threshold value ≥0.56, with a lower bound of the 95% CI ≥40% (64%). The percentage of subjects achieving a TNA NF50 threshold value ≥0.56 at Day 70 was 58% (95% CI: 50%, 65%), and the mean value on Days 63-100 (inclusive) was 53% (95% CI: 41%, 55%). The threshold TNA NF50 value of 0.56 was developed from previous rabbit challenge and human immunogenicity studies. No related serious AEs occurred during the study, and no subjects withdrew from the study because of an AE. Tenderness and pain at the injection site were recorded most often in subject diaries following vaccination. Conclusions: BioThrax, administered as three SC doses at 0, 2, and 4 weeks, was well tolerated. The prospectively defined success criteria for TNA levels on Days 63, 70, and 63-100 were achieved. © 2014 Elsevier Ltd.


Gurwith M.,Paxvax, Inc. | Lock M.,Paxvax, Inc. | Taylor E.M.,Paxvax, Inc. | Ishioka G.,Paxvax, Inc. | And 8 more authors.
The Lancet Infectious Diseases | Year: 2013

Background: Replication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5-Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus. Methods: We did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18-40 years to receive one of five doses of Ad4-H5-Vtn (107 viral particles [VP], 108 VP, 109 VP, 1010 VP, 1011 VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 μg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01006798. Findings: We enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6-17) and three of 41 placebo recipients (7%, 2-20) seroconverted. HAI GMT was 6 (95% CI 5-7) for vaccinees, and 5 (5-6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 1011 VP cohort (100%; 95% CI 82-100) and eight of 22 placebo recipients (36%; 17-59); 17 of 19 participants in the 1011 VP cohort (89%; 67-99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5-40); GMT was 135 (89-205) with 1011 VP, compared with 13 (7-21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16·8%] of 125 vs one [2·4%] of 41, p=0·017; 24 [19·2%] of 125 vs two [4·9%] of 41, p=0·027; 41 [32·8%] of 125 vs six [14·6%] of 41, p=0·028; respectively). No serious treatment-related adverse events occurred. Interpretation: Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1. Funding: Wellcome Trust Foundation, PaxVax. © 2013 Elsevier Ltd.


Taylor D.N.,VaxInnate | Treanor J.J.,University of Rochester | Strout C.,Coastal Carolina Research Center | Johnson C.,Johnson County Clin Trials | And 5 more authors.
Vaccine | Year: 2011

Background: Influenza vaccines perform poorly in the elderly with reduced serological response and vaccine efficacy. We evaluated a novel influenza vaccine consisting of the globular head of the HA1 domain of the A/Solomon Islands/3/2006 (H1N1) influenza virus (VAX125) genetically fused to the TLR5 ligand, flagellin, and produced in Escherichia coli. Methods: 120 subjects ≥65 years old were enrolled at three clinical centers. VAX125 vaccine was administered at doses of 0.5, 1, 2, 3, 5 or 8 μg delivered i.m. as a single dose vaccination on Day 0 using a dose-escalation with 20 subjects in each dose level. Subjects were followed for adverse events and sera were tested by hemagglutination-inhibition (HAI) against egg-grown virus on days 0, 7, 14, and 28. Serum C-reactive protein (CRP) and anti-flagellin antibody were also assessed. Results: The mean age was 71 years. The vaccine was well tolerated at all dose levels, with no more than mild to moderate local or systemic symptoms. The geometric mean titers (GMT) increased in all dose groups. In the 5 μg group the day 14 post-vaccination HAI titer was 1:226 showing a 12-fold increase over baseline. The 8 μg group showed a similar post-vaccination GMT increase (∼8-fold). In the combined 5 and 8 μg groups, the seroconversion rate was 75% and the seroprotection rate was 98%. Conclusions: A 5 μg dose of VAX125 was safe and able to induce a greater than 10-fold increase HAI antibody levels and nearly complete seroprotection in subjects over 65 years old. The use of flagellin to adjuvant influenza vaccines via the TLR5 innate immune pathway appears to be a useful approach to overcome poor immune responses in the elderly. VAX125 is a promising new candidate for prevention of influenza A disease in both young adults and the elderly. © 2011 Elsevier Ltd.


Gorse G.J.,Saint Louis University | Falsey A.R.,Rochester General Hospital | Fling J.A.,University of North Texas Health Science Center | Poling T.L.,Heartland Research Associates | And 2 more authors.
Vaccine | Year: 2013

Background: To increase vaccine acceptance, intradermal (ID) influenza vaccine (Fluzone® Intradermal, Sanofi Pasteur Inc.) may be an attractive alternative to intramuscular (IM) vaccination due to smaller needle and volume injected. Methods: A multicenter, randomized (2:1 ID vs IM vaccines) study, blinded for ID vaccine lots, was conducted among 4292 adults 18-64 years of age enrolled in October 2008. Three lots of investigational trivalent influenza vaccine containing 9. μg hemagglutinin (HA) per strain in 0.1 mL administered ID with a 30 gauge, 1.5 mm long needle were compared to standard dose vaccine (0.5 mL containing 15 μg HA/strain) given IM. Results: The post-vaccination antibody geometric mean titers (GMT) for the ID vaccine were similar to the IM vaccine (H1N1: 193.2 vs. 178.3, H3N2: 246.7 vs. 230.7, and B: 102.5 vs. 126.9). Non-inferiority was met for the ID vaccine compared to IM vaccine as assessed by antibody GMT ratios (IM/ID) for all three virus strains (H1N1: 0.92, H3N2: 0.94, and B: 1.24). Seroconversion rates were non-inferior for H1N1 and H3N2, but not for B (ID vs. IM: H1N1: 61.2% vs. 60.5%, H3N2: 75.3% vs. 74.8%, and B: 46.2% vs. 54.2%). Seroprotection (HAI titer ≥1:40) rates were similar between groups (ID vs. IM, H1N1: 91.1% vs. 91.7%, H3N2: 90.7% vs. 91.4%, and B: 87.4% vs. 89.3%). Local injection site reactions overall were more common with ID than IM vaccine (ID vs. IM: 89.2% vs. 60.2%), but were usually grade 1 or 2 and transient. The frequencies of local injection site pain and systemic reactions were similar between vaccine groups, except more myalgia with IM vaccine. Conclusions: The ID vaccine elicited immune responses comparable to IM vaccine except for the seroconversion rate to B virus. With the exception of pain, local injection site reactions were more common with the ID vaccine, but well-tolerated and of short duration. Trial registration: ClinicalTrials.gov identifier: NCT00772109. © 2013 Elsevier Ltd.


PubMed | Saint Louis University, Fountain, Coastal Carolina Research Center and Sanofi S.A.
Type: Clinical Trial, Phase II | Journal: Vaccine | Year: 2014

We conducted a randomized, controlled, multicenter, phase II study to evaluate the immunogenicity and safety of an investigational intradermal (ID) trivalent influenza vaccine (TIV) and a high-dose (HD) intramuscular (IM) TIV in older adults (65 years of age). Older adult subjects were immunized with ID vaccine containing either 15g hemagglutinin (HA)/strain (n=636) or 21g HA/strain (n=634), with HD IM vaccine containing 60g HA/strain (n=320), or with standard-dose (SD) IM vaccine (Fluzone(); 15g HA/strain; n=319). For comparison, younger adults (18-49 years of age) were immunized with SD IM vaccine. In older adults, post-vaccination geometric mean titers induced by the ID vaccines were superior to those induced by the SD IM vaccine for the A/H1N1 and A/H3N2 strains and non-inferior for the B strain. Seroconversion rates induced by the ID vaccines were superior to those induced by the SD IM vaccine in older adults for the A/H1N1 and B strains and non-inferior for the A/H3N2 strain. Results did not differ significantly for the two ID vaccine dosages. Post-vaccination geometric mean titers, seroconversion rates, and most seroprotection rates were significantly higher in HD vaccine recipients than in older adult recipients of the SD IM or ID vaccines and, for most measures, were comparable to those of younger adult SD IM vaccine recipients. Injection-site reactions, but not systemic reactions or unsolicited adverse events, were more common with the ID vaccines than with the IM vaccines. No treatment-related serious adverse events were reported. This study demonstrated that: (1) the ID and HD vaccines were well-tolerated and more immunogenic than the SD IM vaccine in older adults; (2) the HD vaccine was more immunogenic than the ID vaccines in older adults; and (3) the HD vaccine in older adults and the SD IM vaccine in younger adults elicited comparable antibody responses (ClinicalTrials.gov identifier no.: NCT00551031).

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