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- Benatar, Michael, et al.
(författare)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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- Frey, Sharon, et al.
(författare)
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Interference of antibody production to hepatitis B surface antigen in a combination hepatitis A/hepatitis B vaccine
- 1999
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 180:6, s. 2018-2022
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Tidskriftsartikel (refereegranskat)abstract
- A randomized trial comparing 3 manufacturing consistency lots of a combination hepatitis A/hepatitis B vaccine to each other and to hepatitis A vaccine and hepatitis B vaccine given separately and concurrently was done to evaluate safety, tolerability, and immunogenicity. Healthy volunteers >/=11 years of age were divided into 4 groups. Each of 3 groups received a separate consistency lot of the combination vaccine, and 1 group received separate but concurrent injections of hepatitis A and hepatitis B vaccines. Injections were given at weeks 0 and 24. The combination vaccine was generally well tolerated. The hepatitis A portion of the combination vaccine produced clinically acceptable high seropositivity rates 4 and 52 weeks after the first injection. The hepatitis B portion of the vaccine did not produce clinically acceptable seropositivity rates 4 weeks after the second injection. Lack of antibody production may be attributed, at least in part, to immunologic interference.
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- Giaquinto, Carlo, et al.
(författare)
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Costs of community-acquired pediatric rotavirus gastroenteritis in 7 European countries : the REVEAL Study.
- 2007
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Ingår i: J Infect Dis. - 0022-1899. ; 195 Suppl 1, s. S36-S44
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Morbidity and resource use due to rotavirus gastroenteritis (RVGE) are substantial in Europe, although comprehensive data on the economic impact of the disease are lacking. METHODS: A cost study was conducted to assess health care resource use data collected during a prospective epidemiologic study of acute gastroenteritis in children <5 years of age in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom. We calculated the average cost (direct and indirect) per episode of confirmed RVGE in primary care, emergency department, and hospital settings. RESULTS: The total societal cost (including direct medical, direct nonmedical, and indirect costs) per episode of RVGE ranged from 166 euros to 473 euros in the primary care setting, from 334 euros to 770 euros in the emergency department setting, and from 1525 euros to 2101 euros in the hospital setting. The majority of hospital-related costs were reimbursed by national health care payers, but the percentage of reimbursed costs declined progressively in the emergency department and primary care settings. The mean number of workdays lost by parents and other relatives varied between study areas and settings, ranging from 2.3 to 7.5 days, and this represented the major cost not reimbursed by national health care payers. CONCLUSIONS: RVGE incurs considerable resource utilization in all health care settings and substantial costs for national health care payers, families of patients, and employers. Routine rotavirus vaccination in infants could significantly reduce the health and economic burden of pediatric RVGE.
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- Van Damme, Pierre, et al.
(författare)
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Multicenter prospective study of the burden of rotavirus acute gastroenteritis in Europe, 2004-2005 : the REVEAL study.
- 2007
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Ingår i: J Infect Dis. - 0022-1899. ; 195 Suppl 1, s. S4-S16
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rotavirus is recognized as a significant cause of pediatric gastroenteritis worldwide. Comprehensive data on the burden of rotavirus disease in Europe were lacking. METHODS: A prospective, multicenter, observational study was conducted during the 2004-2005 season in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom, to estimate the incidence of acute gastroenteritis (AGE) and rotavirus gastroenteritis (RVGE) in children <5 years of age who require medical care in primary care, emergency department, and hospital settings. RESULTS: A total of 2846 children with AGE were included in the study, and, of the 2712 children for whom ELISA results were available, 1102 (40.6%) were found to be rotavirus positive. The estimated annual incidence of RVGE was 2.07-4.97 cases/100 children <5 years of age, and it was highest among children 6-23 months of age, with 56.7%-74.2% of all RVGE cases occurring in children in this age group. Overall, RVGE was estimated to account for 27.8%-52.0% of AGE cases, and it was responsible for up to two-thirds of hospitalizations and emergency department consultations, as well as one-third of primary care consultations for AGE. CONCLUSIONS: Rotavirus infections account for a significant proportion of AGE cases in children <5 years of age in Europe, many of whom require frequent primary care consultations or care in emergency department and/or hospital settings. The results of the present study suggest that routine rotavirus vaccination for infants <6 months of age could significantly reduce the substantial burden of this potentially serious childhood disease.
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- Van der Wielen, Marie, et al.
(författare)
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Impact of community-acquired paediatric rotavirus gastroenteritis on family life : data from the REVEAL study.
- 2010
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Ingår i: BMC Family Practice. - : Springer Science and Business Media LLC. - 1471-2296. ; 11, s. 22-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rotavirus is the leading cause of acute gastroenteritis (AGE) and the most frequent cause of severe diarrhoea in children aged less than 5 years. Although the epidemiology of rotavirus gastroenteritis (RVGE) is well documented, there are few data on the impact of RVGE on the families of affected children. METHODS: Data associated with the burden of RVGE, including number of working days lost, levels of parental stress, the need for alternative childcare arrangements and additional nappies used, were extracted from questionnaires completed by parents of children participating in a prospective, multicentre, observational study (Rotavirus gastroenteritis Epidemiology and Viral types in Europe Accounting for Losses in public health and society, REVEAL), conducted during 2004-2005 in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom to estimate the incidence of RVGE in children aged less than 5 years seeking medical care as a result of AGE. RESULTS: 1102 children with RVGE were included in the present analysis. The proportion of RVGE cases that required at least one parent or other person to be absent from work was 39%-91% in the hospital setting, 44%-64% in the emergency department, and 20%-64% in primary care. Self-reported levels of parental stress were generally high (mean stress levels, > or = 5 on a 10-point visual analogue scale). Additional childcare arrangements were required in up to 21% of RVGE episodes. The mean number of nappies used per day during RVGE episodes was approximately double that used when the child was not ill. CONCLUSIONS: Paediatric RVGE cases cause disruption to families and parental stress. The burden of RVGE on children and their families could be substantially reduced by routine rotavirus vaccination of infants.
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| 8. |
- Andersen, Peter M., et al.
(författare)
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EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) : revised report of an EFNS task force
- 2012
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 19:3, s. 360-E24
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Tidskriftsartikel (refereegranskat)abstract
- Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel. Methods: All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus. Recommendations: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient's ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient's social and cultural background.
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| 9. |
- Giaquinto, Carlo, et al.
(författare)
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Clinical consequences of rotavirus acute gastroenteritis in Europe, 2004-2005 : the REVEAL study.
- 2007
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Ingår i: J Infect Dis. - 0022-1899. ; 195 Suppl 1, s. S26-35
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The availability of comprehensive, up-to-date epidemiologic data would improve the understanding of the disease burden and clinical consequences of rotavirus gastroenteritis (RVGE) in Europe. METHODS: During the 2004-2005 season, a prospective, multicenter, observational study was conducted in children <5 years of age in primary care, emergency department, and hospital settings in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom. The clinical consequences of acute gastroenteritis (AGE) and RVGE were estimated. RESULTS: The estimated percentage of children with rotavirus-positive AGE admitted to a hospital was 10.4%-36.0%, compared with 2.1%-23.5% of children with rotavirus-negative AGE. In France, Germany, Italy, Spain, and the United Kingdom, the relative risk of hospitalization was statistically significantly higher for children with rotavirus-positive AGE than for those with rotavirus-negative AGE. Children with rotavirus-positive AGE were more likely to have lethargy, fever, vomiting, and dehydration, and, therefore, more severe disease than were children with rotavirus-negative AGE. Dehydration was up to 5.5 times more likely in children with rotavirus-positive AGE than in those with rotavirus-negative AGE. CONCLUSIONS: Rotavirus-positive AGE is more severe, causes more dehydration, and results in more emergency department consultations and hospitalizations than does rotavirus-negative AGE. Variations in the management of RVGE seen across study areas could be explained by differences in health care systems. Routine rotavirus vaccination of infants could significantly reduce the substantial burden of RVGE and would have major benefits for potential patients, their families, and health care providers.
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- Itzler, Robbin, et al.
(författare)
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Robustness of the healthcare utilization results from the Rotavirus Efficacy and Safety Trial (REST) evaluating the human-bovine (WC3) reassortant pentavalent rotavirus vaccine (RV5).
- 2010
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Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 10:1, s. 42-
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The Rotavirus Efficacy and Safety Trial was a placebo-controlled Phase III study that evaluated the safety and efficacy of a three-dose pentavalent rotavirus vaccine (RV5) including its effect on healthcare utilization for rotavirus gastroenteritis (RVGE). The per-protocol (PP) analyses, which counted events occurring 14 days after dose 3 among infants without protocol violations, have already been published. This paper evaluates the consistency of the healthcare utilization results based on the modified intention to treat (MITT) analyses with the PP analyses. The MITT analyses include all infants receiving at least one dose of vaccine or placebo and follow-up begins after dose 1. The paper also explores the consistency of the results for different subgroups of the study population with different types of surveillance. METHODS: Data on healthcare utilization for acute gastroenteritis were collected via telephone interviews after administration of the first dose. Parents were either contacted every 6 weeks or every 2 weeks depending on the substudy in which they were enrolled. Those contacted every 2 weeks were also asked to complete symptom diaries. Poisson regression was used to evaluate the effect of RV5 on the rates of RVGE-associated healthcare encounters in all of the analyses. RESULTS: In the first 2 years after vaccination, RV5 reduced the combined rate of hospitalizations and emergency department (ED) visits 88.9% (95% CI: 84.9, 91.9) for all RVGE regardless of serotype in the MITT analysis compared with a 94.5% (95% CI: 91.2, 96.6) reduction based on the G1-G4 PP analysis. By type of surveillance, the rate reductions for the G1-G4 PP analysis were 91.0 % (95% CI: 81.7, 95.5) and 95.9% (95% CI: 92.2, 97.8) among parents contacted every 2 weeks (number evaluable =4,451) and every 6 weeks (number evaluable =52,683) respectively. CONCLUSIONS: Our analyses demonstrated that the effect of RV5 on reducing the rate of hospitalizations and ED visits based on the MITT analyses were generally consistent with the PP analyses. The rate of events for subgroups with different intensities of surveillance differed but the effect of RV5 on the relative rate reductions were consistent with the results that have already been published. Trial Registration ClinicalTrials.gov number, NCT00090233.
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