Main Study Period Research Articles

Characteristics of Bleed-Free Patients on Every-5-Day Dosing in the Protect VIII (BAY 94-9027) Study

Background: BAY 94‐9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 x 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial, in which patients could receive prophylaxis every 7 days (E7D), every 5 days (E5D), or twice-weekly (2×W). Patients in the E5D arm had a low median annualized bleeding rate (ABR) of 1.9. This post hoc analysis was conducted to identify clinical predictors for ‘best responders’ (patients with ABR = 0) during E5D prophylaxis with BAY 94-9027 in PROTECT VIII.Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days. Prophylaxis patients received BAY 94-9027 25 IU/kg 2×W for a 10-week run-in period. Patients with ≤ 1 spontaneous joint or muscle bleed during this period were randomized to 45‒60 IU/kg E5D or 60 IU/kg E7D for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg 2×W. All patients randomized to the E5D arm (n = 43) remained on this dose-frequency throughout the main study. This post hoc analysis presents a description of baseline characteristics of best responders to E5D dosing, defined as patients with ABR = 0 during the main study period; the study was not powered to support a formal statistical comparison.Results: Of 43 patients randomized to E5D dosing, 24 (55.8%) had ABR ≥ 1 and 19 (44.2%) had ABR = 0, meeting the criterion for best responders. The median (95% CI) age was slightly higher for best responders, 38 years [30.0; 47.0] versus 31.5 [24.0; 41.0]), than patients with ABR ≥ 1. In the 12 months prior to the study, best responders had lower median (95% CI) bleeds (2.0 [0.0; 5.0] versus 10.0 [3.0; 21.0]) and joint bleeds (0.0 [0.0; 2.0] versus 8.0 [2.0; 12.0]) compared with patients with ABR ≥ 1. Most patients in both groups had previously received prophylaxis prior to study (84.2% and 70.8%, respectively). Fewer best responders had target joints (57.9%, versus 70.8% of patients with ABR ≥ 1); and those who did have target joints only 36.4% had ≥ 1 target joint, versus 47.1% of patients with ABR ≥ 1.Conclusions: Overall, the 43 patients receiving BAY 94-9027 E5D prophylaxis had a low median ABR of 1.9. The 19 of these patients who had an ABR of 0 (best responders) had numerically fewer bleeds in the 12 months prior to treatment initiation, particularly joint bleeds, and numerically fewer target joints, vs patients with ABR ≥ 1. Though requiring validation in a powered study, taken together, these results suggest the applicability of E5D BAY 94-9027 dosing across patient profiles, and that patients with a similar bleed and joint profile to those analyzed here may be able to achieve ABR of 0 with E5D BAY 94-9027. DisclosuresSantagostino:Bayer, Shire, CSL Behring, Pfizer, Novo Nordisk, Grifols, Kedrion, Sobi, Bioverativ, Octapharma, Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tian:Bayer: Employment. Ducore:CSL Behring: Other: investigator; HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Bayer Healthcare: Consultancy, Other: travel support, investigator; Shire: Consultancy, Other: travel support, investigator; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator.

Extended Interval Prophylaxis with Bay 94-9027 for > 4 Years Leads to Median Spontaneous Annualized Bleeding Rates < 1 in the Protect VIII Extension

Introduction: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial. This analysis provides an updated assessment of the frequency of spontaneous bleeds with BAY 94-9027 prophylaxis during the PROTECT FVIII trial and its extension of more than 4 years.Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days (ED). Prophylaxis patients received BAY 94-9027 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous or joint bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice weekly (2×W). Following completion of the main PROTECT VIII trial, patients could enter an extension, continuing BAY 94-9027 prophylaxis on either their regimen or switch regimens at the beginning or at any time during the extension. Prophylaxis patients who switched regimen at any time later than 7 days after the beginning of the extension period, were analyzed together in a variable frequency group. Annualized bleeding rates (ABRs) of spontaneous and trauma bleeds were calculated.Results: The intent-to-treat population in the PROTECT VIII study extension included 121 subjects (prophylaxis, n = 107; on demand, n = 14) of the 134 previously treated with BAY 94-9027 in the main study. At data cut-off (31 January 2018), patients in the prophylaxis arms had spent a median (range) of 3.9 (0.8; 5.4) years on-study (main and extension studies combined; a median of 3.2 years were in the extension), with 223 (23; 563) ED. Median dose of BAY 94-9027 prophylaxis during the extension study was 47.8 IU/kg/infusion, with total FVIII consumption of 3488 IU/kg/year. The overall adherence was 100%. At data cut-off or last visit, 34, 45 and 28 patients were in the 2xW, E5D and E7D treatment arms, respectively. During the extension period, median spontaneous ABR (Q1; Q3) was 0.7 (0.0; 2.9) in patients receiving BAY 94-9027 prophylaxis; 2×W (n = 23, 0.8 [0.0; 3.1]), E5D (n = 33, 0.7 [0.0; 2.9]), E7D (n = 23, 0.2 [0.0; 0.8]), or at a variable frequency (n = 28, 1.8 [0.7; 4.3]). This was consistent with median spontaneous ABRs (Q1; Q3) in the main study of 0.0 (0.0; 4.0), 0.0 (0.0; 4.0) and 1.9 (0.0; 6.3) for patients receiving BAY 94-9027 infusions 2×W (n = 24), E5D (n = 43), or E7D (n = 43), respectively; and with spontaneous ABRs for the last 12 months of the extension study of 1.5 (0.0; 2.0), 1.0 (0.0; 3.0) and 0.0 (0.0; 0.0) for these treatment groups (1.0 [1.0; 2.12] in the variable group). Rates of trauma bleeding were consistent across the study periods, with a median ABR of 0.0 in each prophylaxis group in the main study (0.0 [0.0; 2.0] for all prophylaxis patients), 0.3 (0.0; 1.3) for all prophylaxis patients in the extension and 0.0 (0.0; 1.0) for all prophylaxis patients in the last 12 months of the extension.Conclusions: Most patients were treated every 5 or 7 days with BAY 94-9027. Median spontaneous ABR remained < 1 with prophylaxis for > 4 years in all treatment groups (2×W, E5D and E7D). DisclosuresAhuja:Bayer: Honoraria; Bioverativ: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Tseneklidou-Stoeter:Bayer: Employment.

Decrease in Overall and Joint Bleeding Rates with Extended-Interval Dosing: > 4 Years of Bay 94-9027 Prophylaxis in the Protect VIII Extension

Introduction: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial. This analysis provides an updated assessment of the frequency of bleeds and joint bleeds with BAY 94-9027 prophylaxis during the PROTECT VIII trial and its extension of more than 4 years.Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 previous exposure days (ED). Prophylaxis patients received 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice weekly (2×W). Following completion of the main PROTECT VIII trial, patients could enter an extension, continuing BAY 94-9027 prophylaxis on any regimen used in the main study. Prophylaxis patients who switched regimen after 7 days of the extension were analyzed together in a variable frequency group. Overall and joint annualized bleeding rates (ABRs) were calculated based on documentation in electronic patient diaries. Here, we present data for patients receiving prophylaxis.Results: The intent-to-treat population in the PROTECT VIII extension study included 121 subjects (prophylaxis, n = 107; on demand, n = 14) of the 134 patients previously included in the main study (13 did not continue into the extension). At data cut-off (31 January 2018), patients had spent a median time of 3.9 years in the study since enrolment. Patients in the prophylaxis arms had spent a median (range) of 1163 (449; 1579) days in the extension study (approx. 3.2 years), with a median of 211 (96; 318) ED. Most (71) patients had completed 3 years of treatment, 53 had completed 4 years and 33 had completed 5 years of treatment with BAY 94-9027. During the extension, most patients in the 2×W, E5D, or E7D groups did not change regimen (96%, 78% and 65%, respectively). Eleven patients (E5D, 7; E7D, 4) switched to 2×W treatment. Median ABR was 1.6 in prophylaxis patients in the extension, while median joint ABR was 0.9. These values were lower than ABRs during the 6-month main study, of 2.1 and 1.9 for ABR and joint ABR, respectively. In the extension, ABR remained low across all prophylaxis regimens (Table). These values were lower than ABRs for the corresponding treatment groups in the main study (Table). Joint ABR also remained low across extension study patient groups receiving different BAY 94-9027 prophylaxis regimens, and again this was lower than joint ABR in the main study for each group (Table).Conclusions: In the PROTECT VIII extension study, the majority (79/107, 74%) of prophylaxis patients remained on the same dose-frequency of BAY 94-9027during total time in the extension study. Median ABR and joint ABR were lower over the 3-5 years of extension study than in the main study for prophylaxis patients; this was true for the combined prophylaxis cohort and for the 2×W, E5D and E7D BAY 94-9027 prophylaxis groups. Bleed rates were lowest for patients who stayed in the E7D group. Taken together, these results demonstrate that the 2×W, E5D and E7D dose-frequency options for BAY 94-9027 prophylaxis allow patients a decreasingly low rate of bleeds and joint bleeds once treated with a suitable individual regimen. [Display omitted] DisclosuresReding:Genentech: Other: Advisory Board. Pabinger:Bayer, Baxalta/Shire, Novo, Pfizer, Biotest, CSL Behring: Honoraria; CSL Behring and Novo.: Research Funding. Maas Enriquez:Bayer: Employment. Ducore:HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; CSL Behring: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator; Shire: Consultancy, Other: travel support, investigator; Bayer Healthcare: Consultancy, Other: travel support, investigator.

Efficacy and Safety of Bay 94-9027 Is Sustained for 5 Years: Outcomes in 33 Patients in the Protect VIII Extension Study

IntroductionBAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial and its extension. We present an analysis of efficacy and safety outcomes in patients from PROTECT VIII who had completed at least 5 years of treatment as of 31 January 2018.MethodsPROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days (ED). Prophylaxis patients received BAY 94-9027 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous, joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice-weekly (2×W). Twenty patients received BAY 94-9027 on demand as they had been prior to study. Following completion of the main PROTECT VIII study, patients could enter an extension, continuing BAY 94-9027 on any regimen used in the main study; 121 patients entered the extension, of whom 107 were on the prophylactic arm. Prophylaxis patients who switched regimen after the first 7 days of being in the extension were analyzed in a combined variable frequency (VAR) group. Annualized bleeding rate (ABR) and joint ABR were analyzed, along with safety outcomes.ResultsAt the cut-off date, 33 patients had completed 5 years of treatment with BAY 94-9027 (2×W, n = 3; E5D, n = 10; E7D, n = 6; VAR, n = 14). Median number of infusions (range) was 363 (272-546), and median (range) annual factor consumption was 3385 (2732-5053) IU/kg. Median (range) ABR was 2 (0-15) in the full 5-year period, and 1 (0-12) for the final year. Corresponding joint ABRs were 1 (0-7) and 0 (0-7). Over the 5-year period, study drug-related adverse events (AE)s occurred in 6 patients (18.2%); no patients had a study drug-related serious AE. There were no discontinuations for AEs. No patients had confirmed FVIII inhibitors (titre ≥0.6 Bethesda units).ConclusionsThirty-three patients have received BAY 94-9027 prophylaxis for 5 years. The previously demonstrated efficacy of BAY 94-9027 was maintained across this period; in the last year of the extension median ABR was 1 and a third of patients were entirely free from bleeds. Consistent with the established safety profile of FVIII and with prior analyses of PROTECT VIII, there were few study drug-related AE and no evidence of any long-term toxicity of PEGylated product exposure. Taken together, these data support the use of BAY 94-9027 as a long-term treatment option for patients with hemophilia A. DisclosuresReding:Genentech: Other: Advisory Board. Hvitfeldt Poulsen:Primary investigator and national coordinator on clinical trials from Bayer Health Care: Other: Primary Investigator and national coordinator; Chaired an educational haemophilia symposium for nurses: Other: Chair; Nordic advisory boards (Bayer Health Care, Roche): Membership on an entity's Board of Directors or advisory committees; Lecturer on Nordic meeting on EHL FVIII (SOBI): Other: Lecturer . Tian:Bayer: Employment. Holme:Bayer, Biogen Idec, CSL Behring, Novo Nordisk, Pfizer, Shire and Sobi: Consultancy; Bayer, Octapharma, Pfizer and Shire: Research Funding.

IncobotulinumtoxinA Is an Effective and Well-Tolerated Treatment for Upper Facial Lines: Results From an Open-Label Extension Period of a Phase III Study.

In clinical practice, different upper facial areas are commonly treated together. To evaluate the efficacy and safety of repeated incobotulinumtoxinA injections for the treatment of upper facial lines (UFL) in a 3-month open-label extension (OLEX) period. In the main study period (randomized, double blind, placebo controlled; n = 156), subjects with moderate-to-severe UFL (glabellar frown lines [GFL], horizontal forehead lines [HFL], and lateral periorbital lines [LPL]) on the 5-point Merz Aesthetics Scales (MAS) received 54 to 64 U incobotulinumtoxinA or placebo. In the OLEX, all subjects (n = 139) received 1 treatment with 54 to 64 U incobotulinumtoxinA. Investigator- and subject-assessed MAS scores were evaluated at rest and maximum contraction. Response was defined either as a MAS score of "none" or "mild" or a ≥1-point improvement in MAS scores. A clear, rapid treatment response was seen in each individual treated area and for all areas combined. At Day 30, a response of none or mild at maximum contraction (investigator's rating) was reported for 80.1%, 77.2%, and 66.9% of subjects for GFL, HFL, and LPL, respectively. IncobotulinumtoxinA was well tolerated, with no evidence of an increase in adverse events with repeat injection. IncobotulinumtoxinA is highly effective for the simultaneous treatment of UFL with a good safety profile (EudraCT Number: 2011-005887-20).

Impact of temperature variation between adjacent days on childhood hand, foot and mouth disease during April and July in urban and rural Hefei, China.

Previous studies have found that both high temperature and low temperature increase the risk of childhood hand, foot and mouth disease (HFMD). However, little is known about whether temperature variation between neighboring days has any effects on childhood HFMD. A Poisson generalized linear regression model, combined with a distributed lag non-linear model, was applied to examine the relationship between temperature change and childhood HFMD in Hefei, China, from 1st January 2010 to 31st December 2012. Temperature change was defined as the difference of current day's mean temperature and previous day's mean temperature. Late spring and early summer (April-July) were chosen as the main study period due to it having the highest childhood HFMD incidence. There was a statistical association between temperature change between neighboring days and childhood HFMD. The effects of temperature change on childhood HFMD increased below a temperature change of 0°C (temperature drop). The temperature change has the greatest adverse effect on childhood HFMD at 7days lag, with 4% (95% confidence interval 2-7%) increase per 3°C drop of temperature. Male children and urban children appeared to be more vulnerable to the effects of temperature change. Temperature change between adjacent days might be an alternative temperature indictor for exploring the temperature-HFMD relationship.

EPS04.6 Aspergillus fumigatus chronic colonization and lung function decline in CF may have a two-way relationship

Objectives Aspergillus fumigatus is commonly found in CF airways. Our aim was to assess the relationship between A. fumigatus chronic colonization and lung function in CF patients. Methods A retrospective case-control study of CF patients born from 1989 to 2002 was performed. Medical records were reviewed from the time of initial diagnosis until December 2013. Chronic colonization was defined as two or more positive sputum cultures in a given year. Each patient chronically colonized with A. fumigatus was matched with three control patients (never colonized by A. fumigatus ) for age, sex and year of birth (±3 years). A large number of parameters including patients' characteristics and pharmacological treatments were recorded. The primary outcome measure was the difference in forced expiratory volume in 1 second (FEV 1 ) in percent predicted between groups. Linear mixed models were used for longitudinal analyses to evaluate the relationship between A. fumigatus chronic colonization and lung function during a 7-year study period and study the lung function 4 years before the main study period. Results Twenty patients had chronic colonization and were matched with 60 controls. A significant difference in lung function between groups was detected throughout the 7-year study period after adjustment for confounders (est = –8.66, p=0.020). Four years before, FEV 1 baseline was the only factor associated with the course of lung function (est = 0.66, p Conclusion A decreased FEV 1 baseline appears to be a risk factor for chronic colonization by A. fumigatus which, in turn, may cause a faster deterioration of lung function.

Spatial and temporal variability of winter snow and precipitation days in the western and central Spanish Pyrenees

ABSTRACTIn this study we analysed the spatial distribution of the long‐term average and interannual variability of the number of snow days (NSD) and the number of precipitation days (NPD) in winter (DJFM) in the Spanish Pyrenees, using data from 38 meteorological stations for the period 1981–2010. The interannual variability of the NSD and the NPD in winter was related to the frequency of weather types over the Iberian Peninsula. Data from six stations were also used to analyse a longer time period (1961–2013) to confirm the consistency of the results obtained during the main study period (1981–2010).The results indicated that the NPD is only influenced by the distance to sea whereas the NSD is determined by elevation and distance to the sea. A high frequency of west (W), northwest (NW) and cyclonic (C) weather systems led to a high NPD in winter across the entire study area, whereas the frequency of north (N) weather types was only correlated with the NPD at the most westerly stations. For the NSD there was a gradient from the Western Pyrenees to eastern areas, mainly explained by the frequency of N weather types in the former area, and high frequencies of NW and W weather types associated with the latter. For most stations there was no significant trend found in the NPD or the NSD for the 1981–2010 period. However, a slight decrease was found for stations strongly correlated with NW weather types, and a slight increase was found for stations strongly correlated with the C weather type, which was related to a decreasing (increasing) frequency of NW (C) weather types during the same period. Analysis of the 1961–2013 and 1971–2000 time slices using a smaller subset of stations revealed a similar relationship between weather types and the NSD. This indicates that the 1981–2010 period is sufficiently representative to describe the relationship of the NSD and the NPD to weather type frequency. However, the study period chosen can markedly influence the trends observed, as the results showed a statistically significant decrease in the NSD for the 1971–2000 period, but no significant trends for the 1961–2013 and 1980–2010 periods.

Effectiveness of neuraminidase inhibitors in preventing hospitalization during the H1N1 influenza pandemic in British Columbia, Canada

ObjectivesIn British Columbia (BC), Canada, neuraminidase inhibitors (NIs) were publicly funded during the 2009 A(H1N1)pdm09 pandemic for treatment of high-risk patients and/or anyone with moderate-to-severe illness. We assessed antiviral effectiveness (AVE) against hospitalization in that context.MethodsA population-based cohort study was conducted using linked administrative data. The cohort included all individuals living in BC during the study period (1 September to 31 December 2009) with a diagnostic code consistent with influenza or pandemic H1N1. The main study period pertained to the second-wave A(H1N1)pdm09 circulation (1 October to 31 December 2009), with sensitivity analyses around the more specific pandemic peak (18 October to 7 November). Exposure was defined by same-day NI prescription. The main outcome was all-cause hospitalization within 14 days of the outpatient influenza diagnosis. Cox proportional hazards models assessed AVE with 1 : 1 propensity-score matching and covariate adjustment.ResultsAfter matching, there were 304/58 061 NI-exposed and 345/58 061 unexposed patients hospitalized during the main study period. The very young [<6 months (35.0; 95% CI 16.7–73.4)], the old [65–79 years (13.7; 95% CI 10.1–18.6)] and the very old [≥80 years (38.7; 95% CI 26.6–56.5)] had the highest hospitalization rate per 1000 patients overall. Fully adjusted AVE against all-cause hospitalization during the main study period was 16% (95% CI 2%–28%), similar to the pandemic peak (15%; 95% CI −4%–30%).ConclusionsThe use of NIs was associated with modest protection against hospitalization during the 2009 pandemic, but appeared underutilized in affected age groups with the highest hospitalization risk.

Safety and efficacy outcomes of long-term treatment up to 4 years with 5% lidocaine medicated plaster in patients with post-herpetic neuralgia

Objective:Prospective evaluation of the long-term efficacy and safety of the 5% lidocaine medicated plaster in patients with post-herpetic neuralgia (PHN).Research design and methods:Patients with persisting pain for ≥3 months after acute herpes zoster and a baseline pain intensity of at least 4 on an 11-point numerical rating scale (NRS 0–10) were treated with 5% lidocaine medicated plasters for up to 5 years and monitored in regular intervals. Efficacy parameters are presented for the first 4 years and include patients’ recall of pain relief (6-point verbal rating scale (VRS), clinical global impression of change (CGIC), patients’ global impression of change PGIC), and the global evaluations of study medication. Safety parameters (clinical examination, skin evaluation, laboratory) and adverse events (AEs) were assessed at regular visits.Clinical trial registration:KF10004/02.Results:A total of 102 patients continuing from a 1 year main study period were included in an extension phase of up to 3 years. Ten patients (9.8%) dropped out due to lack of efficacy and 9 patients (8.8%) due to treatment-related AEs; 56 patients (54.9%) left the study for non-treatment-related reasons. Twenty-seven patients (26.4%) were still under treatment after a total treatment period of 4 years. On average, a pain relief of at least 4.3 (between moderate and a lot) was achieved throughout the study. At all visits the CGIC and the PGIC were much or very much improved in about 80% of patients. At the final visit, study medication was rated at least to be good by 91% of physicians and 89% of patients. Drug-related adverse events (DRAEs) were reported in 19 of 102 patients, mainly mild to moderate localized skin reactions. There were no hints for a reduced analgesic effect or an increase of DRAEs with long-term treatment.Conclusions:This study demonstrates that long-term treatment of ≥12 months with the 5% lidocaine medicated plaster is effective and well tolerated in PHN patients. These findings support the recommendations to use the 5% lidocaine medicated plaster as baseline therapy for localized neuropathic pain after herpes zoster infection (PHN).

The efficacy and tolerability of MK-0633, a 5-lipoxygenase inhibitor, in chronic asthma

Leukotriene B4 (LTB(4)) is a potent inflammatory mediator in asthma, and is increased in more severe asthma. Targeting LTB(4), in addition to cysteinyl leukotrienes, could be beneficial in asthma. This was a randomized, double-blind trial of once-daily MK-0633, a potent 5-lypoxygenase inhibitor, 10mg, 50mg, and 100mg, and placebo in patients 18-70 years with a history of chronic asthma, and FEV(1) ≥45 and ≤85% predicted. There was a 6-week main period and optional 18-week and 34-week periods (52 weeks total), the latter two comparing only MK-0633 100mg and placebo. The primary endpoint was the change from baseline in FEV(1) over the last 4 weeks of the 6-week primary treatment period. Secondary endpoints included symptom scores, β-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-β-agonist FEV(1), and blood eosinophils. MK-0633 100mg was significantly more effective than placebo for the change from baseline in FEV(1) (0.20L vs. 0.13L; p=0.004). The other MK-0633 doses were not significantly more effective than placebo. MK-0633 (at various doses) was also more effective than placebo for β-agonist use, AQLQ, AM and PM PEFR, ACQ, and post-β-agonist FEV(1) (p<0.05 for all). MK-0633 was associated with a dose-dependent increase in elevated aspartate aminotransferase and alanine aminotransferase. Because of the relative benefit-risk ratio, the optional study periods were terminated after unblinding for the main study period. Overall, the benefit-risk ratio did not support the clinical utility of MK-0633 in asthma.

Developing community pharmacy services wanted by local people: information and advice about prescription medicines

Abstract An extended information service on prescription medicines was evaluated in four community pharmacies over a period of 11 months, including a three-month pilot phase. Written patient information leaflets (PILs) and structured verbal advice designed according to the preferences of local people were provided by the pharmacist to patients prescribed any of three study drugs — amoxycillin, atenolol or ibuprofen. A total of 1,614 PILs were issued. Data were collected from a sample of 311 recipients about their perception and recall of the information service. Altogether, 64 per cent remembered receiving the study leaflet and 56 per cent remembered receiving some verbal information from the pharmacist. More than 80 per cent of service recipients supported the provision of both verbal and written information by the pharmacist. In the main study period (n=203), the types of information respondents could recall receiving most frequently were when to take the medicine (67 per cent), the name of the medicine (53 per cent) and side effects (41 per cent). Sixty seven per cent (40) of those receiving amoxycillin, 61 per cent (43) taking atenolol and 38 per cent (28) taking ibuprofen recognised a side effect of their medicine given in both the leaflet and verbal advice. For all three drugs, side effects were recognised most frequently when included in both the written and verbal information. Support for this aspect of the pharmacist's extended role has been demonstrated in practice and the feasibility of service implementation is discussed.

Dodging the vote?

This study investigates the impact of ending the military draft on voter turnout in the U.S. The main study period runs from 1948 through 2006. After controlling for the unemployment rate, the degree of labor force unionization, the U.S.-Iraq War, the impact of voting in presidential elections, the female labor force participation rate, the percent of the adult population with a college degree, income, and a variable to reflect strong approval or disapproval of the U.S. President, compelling empirical evidence is found that ending the military draft in the U.S. acted to significantly reduce the aggregate voter participation rate.

Promethazine Compared With Metoclopramide for Hyperemesis Gravidarum

To compare the effects of promethazine with those of metoclopramide for hyperemesis gravidarum. Women at their first hospitalization for hyperemesis gravidarum were approached when intravenous antiemetic therapy was needed. They were randomly assigned to receive 25 mg promethazine or 10 mg metoclopramide every 8 hours for 24 hours in a double-blind study. Primary outcomes were vomiting episodes by diary and well-being visual numerical rating scale score (10-point scale) in the 24-hour main study period. Participants also filled out an adverse-effects questionnaire at 24 hours and a nausea visual numerical rating scale score at recruitment and at 8, 16, and 24 hours. A total of 73 and 76 women, randomized to metoclopramide and promethazine, respectively, were analyzed. Median vomiting episodes were one (range 0-26) compared with two (range 0-26) (P=.81), and well-being visual numerical rating scale scores were 8 (range 1-10) compared with 7 (range 2-10) (P=.24) for metoclopramide and promethazine, respectively. Repeat-measures analysis of variance of the nausea visual numerical rating scale scores showed no significant difference between study drugs (F score=0.842, P=.47). Reported drowsiness (58.6% compared with 83.6%, P=.001, number needed to treat to benefit [NNTb] 5), dizziness (34.3% compared with 71.2%, P<.001, NNTb 3), dystonia (5.7% compared with 19.2%, P=.02, NNTb 8), and therapy curtailment owing to adverse events (0 of 73 [0%] compared with 7 of 76 [9.2%], P=.014) were encountered less frequently with metoclopramide. Promethazine and metoclopramide have similar therapeutic effects in patients who are hospitalized for hyperemesis gravidarum. The adverse effects profile was better with metoclopramide.

Updated Estimates of Survival and Cost Effectiveness for Imatinib versus Interferon-?? Plus Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukaemia

For trials in which participants are followed beyond the main study period to assess long-term outcomes, economic evaluations conducted using short-term data should be systematically updated to reflect new information. We used 60-month survival data from the IRIS (International Randomized study of Interferon vs STI571) trial to update previously published cost-effectiveness estimates, based on 19 months of follow-up, of imatinib versus interferon (IFN)-alpha plus low-dose cytarabine in patients with chronic-phase chronic myeloid leukaemia. For patients treated with imatinib, we used the 60-month data to calibrate the survival curves generated from the original cost-effectiveness model. We used historical data to model survival for patients randomized to IFNalpha. We updated costs for medical resources using 2006 Medicare reimbursement rates and applied average wholesale prices (AWPs) and wholesale acquisition costs (WACs) to study medications. Five-year survival for patients randomized to imatinib was better than predicted in the original model (89.4% vs 83.2%). We estimated remaining life expectancy with first-line imatinib to be 19.1 life-years (3.8 life-years over the original model) and 15.2 QALYs (3.1 QALYs over the original estimate). Estimates for IFNalpha remained at 9.1 life-years and 6.3 QALYs. When we applied AWPs to study medications, incremental cost-effectiveness ratios (ICERs) were $US 51,800-57,500 per QALY. When we applied WACs, ICERs were $US 42,000-46,200 per QALY. Although the analysis revealed that the original survival estimates were conservative, the updated cost-effectiveness ratios were consistent with, or slightly higher than, the original estimates, depending on the method for assigning costs to study medications.

Availability and Sales of Alcohol in Four Canadian Provinces: A Time-Series Analysis

The research question addressed in the present study, with ARIMA time-series analyses, was the extent to which changes in economic and physical availability had an effect on sales of alcohol in four Canadian provinces during the second half of the 20th century. The annual sales, by type of beverage (spirits, wine and beer) as well as total sales, measured in pure alcohol per inhabitant age 15 and above in each province, were used as dependent variables in the analyses. The inhabitants' real disposable income, the real price of alcohol, and the number of on- and off-premise outlets per 100,000 inhabitants were used as independent variables. All the time-series were differenced to remove long-term trends. The main study period was 1951–2000. In some of the analyses the study periods were shorter, primarily due to lack of data. Changes in economic availability in general, and in price in particular, had larger effects on sales than physical availability. Among the beverages analyzed in the study, the demand for spirits was most sensitive to changes in availability. Economic availability had a greater effect on sales than the number of outlets. However, one might question to what extent the number of outlets really is a feasible measure of transaction costs associated with purchases of alcohol.

Different types of inflammatory reactions in peri‐implant soft tissues

The aim of the present study was to analyze some features of the peri-implant mucosa at sites in the dog model which had been exposed to plaque accumulation for periods up to 9 months. The experiment was carried out in 5 labrador dogs. The mandibular right and left 2nd, 3rd and 4th premolars (2P2, 3P3, 4P4) and the 1st molars (1M1) were extracted. Following a 3-month healing period, 3 titanium fixtures (Nobelpharma AB, Göteborg, Sweden) were installed in the edentulous premolar/molar regions. Abutment connection was performed 3 months later and a meticulous plaque control period of 3 months was initiated. A clinical examination was performed at the end of this preparatory period and a main study period of 9 months continued. During this period, the plaque control regimen was maintained in the mesial and central (left: L1, 2 and right: R1, 2) implant segments, whereas plaque was allowed to accumulate on the distal implants, i.e.. L3 and R3. At the end of the main study period, i.e., 12 months after abutment connection, the clinical examination was repeated, the animals perfused and biopsies obtained. Semi-thin sections were produced for histometric and morphometric analyses. The peri-implant mucosa at implant sites exposed to daily and comprehensive plaque control at biopsy was clinically noninflamed and the connective tissue lateral to a junctional epithelium was devoid of accumulations of inflammatory cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Subchronic (13-week) toxicity of heptachlorodibenzo- p-dioxin in male Sprague-Dawley rats

A 13-week oral toxicity study with 1,2,3,4,6,7,8-heptachlorodibenzo- p-dioxin (HpCDD) was performed in Sprague-Dawley rats. Rats received HpCDD at five different dose levels or 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) at one dose level. The doses were divided into 4 daily loading doses and 6 biweekly maintenance doses. At the end of the 13-week dosing period half of the rats were scheduled for necropsy and the other half after another 13-week off-dose period. This preliminary report contains only data from male rats during the 13-week main study period. At the two highest doses of HpCDD and in the TCDD dosage group the body weight or body weight gain was reduced. Mortality was 15, 50 and 5%, respectively. Wasting syndrome was the primary cause of death, but some rats died of hemorrhage without wasting, which may be related to the dose-dependent decrease in platelet counts. Phosphoenolpyruvate carboxykinase (PEPCK), the rate limiting enzyme of gluconeogenesis, was decreased only at the two highest dose levels of HpCDD and in the TCDD group, all of which also showed mortality. Ethoxyresorufin O-deetylase (EROD) was induced dose-dependently in all treated groups. Serum total thyroxine (T4) concentrations were decreased beginning at the middle dose of HpCDD. The study demonstrates that the toxicity observed after subchronic exposure to HpCDD is very similar to that of TCDD. Most importantly, most of the effects after subchronic and acute dose exposure are identical, confirming the validity of 0.007 as the toxic equivalency factor for HpCDD.