AIM:To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus(T2DM) patients who have inadequate control with m...AIM:To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus(T2DM) patients who have inadequate control with metformin monotherapy.METHODS:Eligible patients were randomized to receive vildagliptin 100 mg qd or metformin(500 mg qd for 2 wk and then 500 mg bid) added to open label me tformin 500 mg bid for the 24 wk.The primary endpoi nt was baseline to endpoint hemoglobin A1c(HbA1c) change.RESULTS:The adjusted mean change from baseline in HbA1c at the 24th wk was-0.51% in the vildagliptin/metformin group(mean baseline HbA1c:7.4%) and-0.37% in the metformin monothera py group(mean baseline HbA1c:7.3%).The mean diffe rence was-0.14% with 95% Confidence Interval(-0.24%,-0.05%).As non-inf e riority(margin of 0.4%) was achieved,a test for superiority was performed.This test showed statistically significant superiority of the combination over monotherapy group(P = 0.002).Gastrointestinal(GI) adverse events were signif icantly more frequent in the metformin group than the combin ation group(21.0% vs 15.4%,P = 0.032).CONCLUSION:In patients with T2DM inadequately controlled with metformin up to 1000 mg daily,the addition of vildagliptin 100 mg daily achieved larger HbA1c reduction with fewer GI events than with increa sing the metformin dose.展开更多
AIM: To assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in Asian patients with type 2 diabetes mellitus(T2DM).METHODS: This was a post hoc analysis of a subgroup of Asian patients...AIM: To assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in Asian patients with type 2 diabetes mellitus(T2DM).METHODS: This was a post hoc analysis of a subgroup of Asian patients from a multicenter,randomized,double-blind,placebo-controlled,parallel-group study in T2DM patients inadequately controlled by stable insulin therapy,with or without metformin.A total of 173 patients were randomized 1:1 to receive treatment with vildagliptin 50 mg bid(n = 87) or placebo(n = 86) for 24 wk.Changes in HbA1c and fasting plasma glucose(FPG),from baseline to study endpoint,were analyzed using an analysis of covariance model.Change from baseline to endpoint in body weight was summarized by treatment.Safety and tolerability of vildagliptin was also evaluated.RESULTS: After 24 wk,the difference in adjusted mean change in HbA1c between vildagliptin and placebo was 0.82%(8.96 mmol/mol;P < 0.001) in Asian subgroup,0.85%(9.29 mmol/mol;P < 0.001) in patients also receiving metformin,and 0.73%(7.98 mmol/mol;P < 0.001) in patients without metformin,all in favor of vildagliptin.There was no significant difference in the change in FPG between treatments.Weight was stable in both treatment groups(+0.3 kg and-0.2 kg,for vildagliptin and placebo,respectively).Overall,vildagliptin was safe and well tolerated with similarly low incidences of hypoglycemia(8.0% vs 8.1%) and no severe hypoglycemic events were experienced in either group.CONCLUSION: In Asian patients inadequately controlled with insulin(with or without concomitant metformin),insulin-vildagliptin combination treatment significantly reduced HbA1c compared with placebo,without an increase in risk of hypoglycemia or weight gain.展开更多
AIM:To assess the efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with type 2 diabetes mellitus(T2DM).METHODS:This was a post hoc analysis in Korean patients,from a 24-wk,random...AIM:To assess the efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with type 2 diabetes mellitus(T2DM).METHODS:This was a post hoc analysis in Korean patients,from a 24-wk,randomized,active-controlled,double-blind,parallel-group,multicenter study.Eligible patients were aged between 18 and 80 years,drug naive,and had been diagnosed with T2DM [hemoglobin A1c(HbA1c):7.5-11.0 and fasting plasma glucose(FPG):【 270 mg/dL(【 15 mmol/L)].Patients were randomized(1:1:1:1) to receive the vildagliptin/pioglitazone comb ination at 100/30 mg q.d.(high-dose) or 50/15 mg q.d.(low-dose),vildagliptin 100 mg q.d.,or pioglitazone 30 mg q.d.monotherapies.The primary outcome measure was change in HbA1c from baseline to endpoint.RESULTS:The distribution of baseline demographic and clinical parameters was well balanced between treatment groups.The overall mean age,body mass index,HbA1c,FPG,and duration of disease were 50.8 years,24.6 kg/m2,8.6,10.1 mmol/L,and 2.2 years,respectively.Adjusted mean changes(± standard error) in HbA1c from baseline(~8.7) to week 24 endpoint were-2.03 ± 0.16(high-dose,N = 34),-1.88 ± 0.15(low-dose,N = 34),-1.31 ± 0.21(vildagliptin,N = 36),and-1.52 ± 0.16(pioglitazone,N = 36).The high-dose combination therapy demonstrated greater efficacy than monotherapies [vildagliptin(P = 0.029) and pioglitazone(P = 0.027)].Percentage of patients achieving HbA1c 【 7 and ≤ 6.5 was the highest in the high-dose group(76 and 68) followed by low-dose(58 and 47),vildagliptin(59 and 37),and pioglitazone(53 and 28) groups.The overall incidence of adverse events was comparable.CONCLUSION:In Korean patients,first-line treatment with high-dose combination therapy improved glycemic control compared to pioglitazone and vildagliptin monotherapies,consistent with results published for the overall study population.展开更多
It has become increasingly apparent that the looming epidemic of heart failure calls for systematic treatment approaches tailored to the needs of individual patient phenotypes. Although chronic heart failure (CHF) the...It has become increasingly apparent that the looming epidemic of heart failure calls for systematic treatment approaches tailored to the needs of individual patient phenotypes. Although chronic heart failure (CHF) therapies are continuously evolving based on the increasing understanding of the involved etiology, acute heart failure (AHF) therapies are still based on hemodynamic improvements and symptom alleviation. Guidelines on AHF management have highlighted that the currently administered AHF therapies lack evidence and have raised concerns on the safety and efficacy of some of the hitherto accepted treatment modalities. Additionally, the high mortality and morbidity rates associated with the current AHF therapies also add to the imperative need to revisit AHF management. The last decade has witnessed a paradigm shift in the way we define and diagnose AHF. Apart from it being recognized as a distinct clinical entity, research has also led to new data on the pathophysiological changes associated with AHF. These developments along with the limited short- and long-term effects of currently used therapies may herald a paradigm shift in the way we plan and deliver management strategies to treat the pathological progression of heart failure.展开更多
AIM:To compare the use of vildagliptin and sulfonylurea with or without metformin in Indian Muslim patients with type 2 diabetes mellitus,fasting during Ramadan.METHODS:This was a 4-wk,multicenter,non-interventional,o...AIM:To compare the use of vildagliptin and sulfonylurea with or without metformin in Indian Muslim patients with type 2 diabetes mellitus,fasting during Ramadan.METHODS:This was a 4-wk,multicenter,non-interventional,open-label,observational study.Incidence of hypoglycemic events(HEs),adverse events,and changes in glycosylated hemoglobin A1c(HbA1c),fasting plasma glucose,postprandial plasma glucose and body weight were measured pre-and post-Ramadan.RESULTS:Totally,97 patients were recruited and all completed the study(vildagliptin group,n=55;sulfonylurea group,n=42).HEs were reported in low frequencies in both the vildagliptin and the sulfonylurea groups[0 vs 2(4.8%)patients,respectively].Interestingly,HbA1c reduced by-0.43%(-4.71 mmol/mol)in the vildagliptin group[8.75%(72.10 mmol/mol)to8.32%(67.38 mmol/mol),P=0.009]while in the sulfonylurea group there was a small increase by 0.01%[0.08 mmol/mol;8.64%(70.92 mmol/mol)to 8.65%(71.00 mmol/mol),P=0.958].Higher percentage of vildagliptin-treated patients achieved HbA1c<7.0%(<53 mmol/mol)compared with sulfonylurea(16.4%vs4.8%).Mean decrease in the body weight was 1.2 kg and 0.03 kg,respectively(P<0.001).Both treatment groups were well tolerated during Ramadan.CONCLUSION:Vildagliptin is an attractive treatment option for Indian patients with type 2 diabetes mellitus who are fasting during Ramadan.展开更多
AIM:To achieve an evidence-based conclusion regarding the safety and efficacy of telbivudine during pregnancy.METHODS:A pooled analysis of data from a literature search reported 1739 pregnancy outcomes(1673 live birth...AIM:To achieve an evidence-based conclusion regarding the safety and efficacy of telbivudine during pregnancy.METHODS:A pooled analysis of data from a literature search reported 1739 pregnancy outcomes(1673 live births)from 1725 non-overlapping pregnant women treated with telbivudine.The prevalence of live birth defects(3.6/1000)was similar to that of the nonantiviral controls(3.0/1000)and not increased as compared with overall prevalence(14.5 to 60/1000).No target organ toxicity was identified.The prevalence of spontaneous abortion in pregnant women treated with telbivudine(4.2/1000)was not increased compared with the overall prevalence(16/1000).The mother-to-child transmission rate was significantly reduced in pregnant women treated with telbivudine(0.70%)compared to those treated with the non-antiviral controls(11.9%;P<0.0001)or compared to the historical rates of hepatitis B virus(HBV)-infected population without antiviral treatment(10%-15%).RESULTS:Cumulatively 489 pregnancy cases have been reported in the telbivudine pharmacovigilance database(with a cut-off date 31 August 2014),of those,308 had known pregnancy outcomes with 249 cases of live births(239 cases of live birth without congenital anomaly and 10 cases of live birth with congenital anomaly).In the latest antiretroviral pregnancy registry report(1 January 1989 through 31 January 2015)of27 patients exposed to telbivudine during pregnancy(18,6 and 3 during first,second and third trimester,respectively)19 live births were reported and there were no cases of birth defects reported.CONCLUSION:Telbivudine treatment during pregnancy presents a favorable safety profile without increased rates of live birth defects,spontaneous abortion or elective termination,or fetal/neonatal toxicity.Exposure to telbivudine in the first,second and third trimester of pregnancy has been shown to significantly reduce the risk of HBV transmission from mother to child on the basis of standard immune prophylaxis procedure.展开更多
AIM: To evaluate the efficacy and safety of tegaserod, 6 mg twice daily (b.i.d.), in men and women with chronic constipation (CC) from China. METHODS: This was a multicenter, double-blind, placebo-controlled study. Fo...AIM: To evaluate the efficacy and safety of tegaserod, 6 mg twice daily (b.i.d.), in men and women with chronic constipation (CC) from China. METHODS: This was a multicenter, double-blind, placebo-controlled study. Following a 2-wk treatment-free baseline period, patients were randomized to receive either tegaserod (6 mg b.i.d.) or placebo (b.i.d.) for 4 wk. An analysis of covariance with repeated measures was used to determine the overall effect of treatment for the primary efficacy variable; the change from baseline in the number of complete spontaneous bowel movements (CSBMs) during the 4-wk treatment period. Secondary efficacy endpoints included other measures of response in terms of CSBMs, and patients’ daily and weekly assessment of bowel habits. Safety was also assessed, based on the incidence and severity of adverse events (AEs).RESULTS: A total of 607 patients were randomized to receive either tegaserod (n = 304) or placebo (n = 303). Tegaserod treatment resulted in a rapid and significant increase from baseline in the adjusted mean number of CSBMs per week over wk 1-4 compared with placebo (1.39 vs 0.91, P = 0.0002). A statistically significant difference in favor of tegaserod was also observed for a mean increase ≥ 1 CSBM/wk over wk 1-4 (47.7% vs 35.0%, tegaserod vs placebo, respectively, P = 0.0018) and for the absolute number of ≥ 3 CSBMs/wk over wk 1-4 (25.0% vs 14.5%, tegaserod vs placebo, respectively, P = 0.0021). Improvements in other symptoms of CC were also seen in the tegaserod group, including improved stool form and reduced straining. In addition, more patients in the tegaserod group reported satisfactory relief from their constipation symptoms. The frequency and severity of AEs was comparable between tegaserod and placebo groups, with the exception of a greater incidence of diarrhea in patients receiving tegaserod (3.6%) compared with placebo (1.7%).CONCLUSION: Tegaserod treatment improved multiple symptoms of CC and was associated with a favorable safety profile.展开更多
Kinetic parameters of the decomposition of hazardous chemicals can be applied for the estimation of their thermal behavior under any temperature profile.Presented paper describes the application of the advanced kineti...Kinetic parameters of the decomposition of hazardous chemicals can be applied for the estimation of their thermal behavior under any temperature profile.Presented paper describes the application of the advanced kinetic approach for the determination of the thermal behavior also under adiabatic conditions occurring e.g.in batch reactors in case of cooling failure.The kinetics of the decomposition of different samples(different manufacturers and batches) of 3-methyl-4-nitrophenol were investigated by conventional DSC in non-isothermal(few heating rates varying from 0.25 to 8.0K/min) and isothermal(range of 200~260℃) modes.The kinetic parameters obtained with AKTS-Thermokinetics Software were applied for calculating reaction rate and progress under different heating rates and temperatures and verified by comparing simulated and experimental signals.After application of the heat balance to compare the amount of heat generated during reaction and its removal from the system,the knowledge of reaction rate at any temperature profiles allowed the determination of the temperature increase due to the self-heating in adiabatic and pseudo-adiabatic conditions.Applied advanced kinetic approach allowed simulation the course of the Heat-Wait-Search(HWS) mode of operation of adiabatic calorimeters.The thermal safety diagram depicting dependence of Time to Maximum Rate(TMR) on the initial temperature was calculated and compared with the results of HWS experiments carried out in the system with Ф-factor amounting to 3.2.The influence of the Ф-factor and reaction progress reached at the end of the HWS monitoring on the TMR is discussed.Presented calculations clearly indicate that even very minor reaction progress reduces the TMRad of 24h characteristic for a sample with initial reaction progress amounting to zero.Described estimation method can be verified by just one HWS-ARC,or by one correctly chosen ISO-ARC run of reasonable duration by knowing in advance the dependence of the TMR on the initial temperature for any Ф-factor.Proposed procedure results in significant shortening of the measuring time compared to a safety hazard approach based on series of ARC experiments carried out at the beginning of a process safety evaluation.展开更多
Background: Many clinical trials include multiple patient-reported outcomes (PROs) to measure fatigue as secondary or exploratory endpoints of treatment effectiveness. Often, these instruments have overlapping content...Background: Many clinical trials include multiple patient-reported outcomes (PROs) to measure fatigue as secondary or exploratory endpoints of treatment effectiveness. Often, these instruments have overlapping content. The objective of this study was to compare the combined measurement properties of two fatigue scales, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and SF-36 vitality (VT) scale using item response theory (IRT). Methods: The FACIT-Fatigue and SF-36v2 were administered at baseline and weeks 2, 4, 7, 12, and 16 to rheumatoid arthritis (RA) patients (n = 237) enrolled in a 52-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose finding study to evaluate the efficacy and safety of subcutaneous secukinumab administered to pa- tients with active RA. Confirmatory factor analysis (CFA) was used to investigate unidimensionality among FACIT- Fatigue and VT items. A generalized partial credit IRT model was used to cross-calibrate the FACIT-Fatigue and VT items and weighted maximum-likelihood estimation was used to score a composite fatigue index. Analysis of variance was used to compare the composite fatigue index with the original scales in responding to ACR improvement and treatment effects. Results: CFA found less than adequate fit to a unidimensional model. However, specifications of alternative multidimensional models were insufficient in explaining the common variance among items. An IRT model was successfully fitted and the composite fatigue index score was found to be more responsive than the original scales to ACR improvement and treatment effects. Effect sizes and significance tests for changes in scores on the composite index were generally larger than those observed with the original scales. Conclusion: IRT methods offer a promising approach to combining items from different scales measuring the same concept that could improve the detection of treatment effects in clinical studies of RA.展开更多
Background:Psoriasis is a chronic inflammatory skin disease,affecting about 0.6%of the Chinese population.Many patients are not well controlled by conventional treatments,thus there is need for new treatment regimens....Background:Psoriasis is a chronic inflammatory skin disease,affecting about 0.6%of the Chinese population.Many patients are not well controlled by conventional treatments,thus there is need for new treatment regimens.In this study,we assessed the efficacy and safety of secukinumab in Chinese patients with moderate to severe plaque psoriasis.Methods:This study was a 52-week,multicentre,randomized,double-blind,placebo-controlled,parallel-group,Phase 3 trial.A sub-population of study participants(≥18 years)of Chinese ethnicity were randomized to receive subcutaneous injections of 300 or 150 mg secukinumab,or placebo.The co-primary endpoints were psoriasis area severity index(PASI)75 and Investigator’s Global Assessment(IGA)0/1 at Week 12.Results:A total of 441 Chinese patients were enrolled in this study.Co-primary outcomes were achieved;300 and 150 mg secukinumab were superior to placebo as shown in the proportion of patients that achieved PASI 75(97.7%and 87.2%vs.3.7%,respectively;P<0.001),and IGA 0/1(82.3%and 69.7%vs.2.7%;P<0.001)at Week 12.Treatment efficacy was maintained until Week 52.There was no increase in overall adverse events with secukinumab relative to placebo throughout the 52-week period.Conclusion:Secukinumab is highly effective and well tolerated in Chinese patients with moderate to severe plaque psoriasis.展开更多
Psoriasis is a chronic,systemic inflammatory disease characterized by demarcated,scaly,erythematous skin plaques.Psoriatic arthritis(PsA)is the most common comorbidity.
Background:Secukinumab demonstrated sustained efficacy in patients with ankylosing spondylitis(AS)through 5 years in pivotal Phase III studies.Here,we present efficacy and safety results(52-week)of secukinumab in pati...Background:Secukinumab demonstrated sustained efficacy in patients with ankylosing spondylitis(AS)through 5 years in pivotal Phase III studies.Here,we present efficacy and safety results(52-week)of secukinumab in patients with AS from the MEASURE 5 study.Methods:MEASURE 5 was a 52-week,Phase III,China-centric study.Eligible patients were randomly assigned(2:1)to receive subcutaneous secukinumab 150 mg or placebo weekly for the first five doses and then once every 4 weeks(q4w).All placebo patients switched to secukinumab 150 mg q4w starting at Week 16.Primary endpoint was Assessments of SpondyloArthritis international Society(ASAS)20 at Week 16.Randomization was stratified by region(China vs.non-China).Results:Of 458 patients(secukinumab 150 mg,N=305;placebo,N=153)randomized,327(71.4%)were from China and 131(28.6%)were not from China.Of these,97.7%and 97.4%patients completed Week 16 and 91.1%and 95.3%(placebo-secukinumab)patients completed Week 52 of treatment.The primary endpoint was met;secukinumab significantly improved ASAS20 response at Week 16 vs.placebo(58.4%vs.36.6%;P<0.0001);corresponding rate in the Chinese population was 56.0%vs.38.5%(P<0.01).All secondary efficacy endpoints significantly improved with secukinumab 150 mg in the overall population at Week 16;responses were maintained with a trend toward increased efficacy from Week 16 to 52.No new or unexpected safety signals were reported up to Week 52.Conclusions:Secukinumab 150 mg demonstrated rapid and significant improvement in signs and symptoms of AS.Secukinumab was well tolerated and the safety profile was consistent with previous reports.Efficacy and safety results were comparable between the overall and Chinese populations.展开更多
The clinical efficacy of therapeutic antibodies is recognized in many indications,explaining their rapid rise in the worldwide drug market.However,therapeutic antibodies can be immunogenic by inducing a specific immun...The clinical efficacy of therapeutic antibodies is recognized in many indications,explaining their rapid rise in the worldwide drug market.However,therapeutic antibodies can be immunogenic by inducing a specific immune response characterized by the production of anti-drug antibodies(ADAs).ADAs can potentially increase the clearance of therapeutic antibodies,decrease their therapeutic effects1 and induce hypersensitivity reactions.Because humans are thought to be tolerant to their own proteins,sequences of the therapeutic antibodies have been humanized or human antibodies have been directly generated by technologies using human sequences.However,human(ized)antibodies exhibit highly variable levels of immunogenicity,1,2 illustrating the poor understanding of the role of sequence humanization in mitigating the immunogenicity of therapeutic antibodies.Multiple lines of evidence highlight the role of CD4 T lymphocytes during the initiation of an ADA response,3 but few T-cell epitopes of marketed therapeutic antibodies have been described to date.展开更多
基金Supported by Novartis Pharmaceuticals Corporation, NC-T00396357
文摘AIM:To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus(T2DM) patients who have inadequate control with metformin monotherapy.METHODS:Eligible patients were randomized to receive vildagliptin 100 mg qd or metformin(500 mg qd for 2 wk and then 500 mg bid) added to open label me tformin 500 mg bid for the 24 wk.The primary endpoi nt was baseline to endpoint hemoglobin A1c(HbA1c) change.RESULTS:The adjusted mean change from baseline in HbA1c at the 24th wk was-0.51% in the vildagliptin/metformin group(mean baseline HbA1c:7.4%) and-0.37% in the metformin monothera py group(mean baseline HbA1c:7.3%).The mean diffe rence was-0.14% with 95% Confidence Interval(-0.24%,-0.05%).As non-inf e riority(margin of 0.4%) was achieved,a test for superiority was performed.This test showed statistically significant superiority of the combination over monotherapy group(P = 0.002).Gastrointestinal(GI) adverse events were signif icantly more frequent in the metformin group than the combin ation group(21.0% vs 15.4%,P = 0.032).CONCLUSION:In patients with T2DM inadequately controlled with metformin up to 1000 mg daily,the addition of vildagliptin 100 mg daily achieved larger HbA1c reduction with fewer GI events than with increa sing the metformin dose.
文摘AIM: To assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in Asian patients with type 2 diabetes mellitus(T2DM).METHODS: This was a post hoc analysis of a subgroup of Asian patients from a multicenter,randomized,double-blind,placebo-controlled,parallel-group study in T2DM patients inadequately controlled by stable insulin therapy,with or without metformin.A total of 173 patients were randomized 1:1 to receive treatment with vildagliptin 50 mg bid(n = 87) or placebo(n = 86) for 24 wk.Changes in HbA1c and fasting plasma glucose(FPG),from baseline to study endpoint,were analyzed using an analysis of covariance model.Change from baseline to endpoint in body weight was summarized by treatment.Safety and tolerability of vildagliptin was also evaluated.RESULTS: After 24 wk,the difference in adjusted mean change in HbA1c between vildagliptin and placebo was 0.82%(8.96 mmol/mol;P < 0.001) in Asian subgroup,0.85%(9.29 mmol/mol;P < 0.001) in patients also receiving metformin,and 0.73%(7.98 mmol/mol;P < 0.001) in patients without metformin,all in favor of vildagliptin.There was no significant difference in the change in FPG between treatments.Weight was stable in both treatment groups(+0.3 kg and-0.2 kg,for vildagliptin and placebo,respectively).Overall,vildagliptin was safe and well tolerated with similarly low incidences of hypoglycemia(8.0% vs 8.1%) and no severe hypoglycemic events were experienced in either group.CONCLUSION: In Asian patients inadequately controlled with insulin(with or without concomitant metformin),insulin-vildagliptin combination treatment significantly reduced HbA1c compared with placebo,without an increase in risk of hypoglycemia or weight gain.
基金Supported by the Novartis Pharmaceuticals Corporation
文摘AIM:To assess the efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with type 2 diabetes mellitus(T2DM).METHODS:This was a post hoc analysis in Korean patients,from a 24-wk,randomized,active-controlled,double-blind,parallel-group,multicenter study.Eligible patients were aged between 18 and 80 years,drug naive,and had been diagnosed with T2DM [hemoglobin A1c(HbA1c):7.5-11.0 and fasting plasma glucose(FPG):【 270 mg/dL(【 15 mmol/L)].Patients were randomized(1:1:1:1) to receive the vildagliptin/pioglitazone comb ination at 100/30 mg q.d.(high-dose) or 50/15 mg q.d.(low-dose),vildagliptin 100 mg q.d.,or pioglitazone 30 mg q.d.monotherapies.The primary outcome measure was change in HbA1c from baseline to endpoint.RESULTS:The distribution of baseline demographic and clinical parameters was well balanced between treatment groups.The overall mean age,body mass index,HbA1c,FPG,and duration of disease were 50.8 years,24.6 kg/m2,8.6,10.1 mmol/L,and 2.2 years,respectively.Adjusted mean changes(± standard error) in HbA1c from baseline(~8.7) to week 24 endpoint were-2.03 ± 0.16(high-dose,N = 34),-1.88 ± 0.15(low-dose,N = 34),-1.31 ± 0.21(vildagliptin,N = 36),and-1.52 ± 0.16(pioglitazone,N = 36).The high-dose combination therapy demonstrated greater efficacy than monotherapies [vildagliptin(P = 0.029) and pioglitazone(P = 0.027)].Percentage of patients achieving HbA1c 【 7 and ≤ 6.5 was the highest in the high-dose group(76 and 68) followed by low-dose(58 and 47),vildagliptin(59 and 37),and pioglitazone(53 and 28) groups.The overall incidence of adverse events was comparable.CONCLUSION:In Korean patients,first-line treatment with high-dose combination therapy improved glycemic control compared to pioglitazone and vildagliptin monotherapies,consistent with results published for the overall study population.
文摘It has become increasingly apparent that the looming epidemic of heart failure calls for systematic treatment approaches tailored to the needs of individual patient phenotypes. Although chronic heart failure (CHF) therapies are continuously evolving based on the increasing understanding of the involved etiology, acute heart failure (AHF) therapies are still based on hemodynamic improvements and symptom alleviation. Guidelines on AHF management have highlighted that the currently administered AHF therapies lack evidence and have raised concerns on the safety and efficacy of some of the hitherto accepted treatment modalities. Additionally, the high mortality and morbidity rates associated with the current AHF therapies also add to the imperative need to revisit AHF management. The last decade has witnessed a paradigm shift in the way we define and diagnose AHF. Apart from it being recognized as a distinct clinical entity, research has also led to new data on the pathophysiological changes associated with AHF. These developments along with the limited short- and long-term effects of currently used therapies may herald a paradigm shift in the way we plan and deliver management strategies to treat the pathological progression of heart failure.
基金Supported by Novartis Healthcare Private Limited,India
文摘AIM:To compare the use of vildagliptin and sulfonylurea with or without metformin in Indian Muslim patients with type 2 diabetes mellitus,fasting during Ramadan.METHODS:This was a 4-wk,multicenter,non-interventional,open-label,observational study.Incidence of hypoglycemic events(HEs),adverse events,and changes in glycosylated hemoglobin A1c(HbA1c),fasting plasma glucose,postprandial plasma glucose and body weight were measured pre-and post-Ramadan.RESULTS:Totally,97 patients were recruited and all completed the study(vildagliptin group,n=55;sulfonylurea group,n=42).HEs were reported in low frequencies in both the vildagliptin and the sulfonylurea groups[0 vs 2(4.8%)patients,respectively].Interestingly,HbA1c reduced by-0.43%(-4.71 mmol/mol)in the vildagliptin group[8.75%(72.10 mmol/mol)to8.32%(67.38 mmol/mol),P=0.009]while in the sulfonylurea group there was a small increase by 0.01%[0.08 mmol/mol;8.64%(70.92 mmol/mol)to 8.65%(71.00 mmol/mol),P=0.958].Higher percentage of vildagliptin-treated patients achieved HbA1c<7.0%(<53 mmol/mol)compared with sulfonylurea(16.4%vs4.8%).Mean decrease in the body weight was 1.2 kg and 0.03 kg,respectively(P<0.001).Both treatment groups were well tolerated during Ramadan.CONCLUSION:Vildagliptin is an attractive treatment option for Indian patients with type 2 diabetes mellitus who are fasting during Ramadan.
文摘AIM:To achieve an evidence-based conclusion regarding the safety and efficacy of telbivudine during pregnancy.METHODS:A pooled analysis of data from a literature search reported 1739 pregnancy outcomes(1673 live births)from 1725 non-overlapping pregnant women treated with telbivudine.The prevalence of live birth defects(3.6/1000)was similar to that of the nonantiviral controls(3.0/1000)and not increased as compared with overall prevalence(14.5 to 60/1000).No target organ toxicity was identified.The prevalence of spontaneous abortion in pregnant women treated with telbivudine(4.2/1000)was not increased compared with the overall prevalence(16/1000).The mother-to-child transmission rate was significantly reduced in pregnant women treated with telbivudine(0.70%)compared to those treated with the non-antiviral controls(11.9%;P<0.0001)or compared to the historical rates of hepatitis B virus(HBV)-infected population without antiviral treatment(10%-15%).RESULTS:Cumulatively 489 pregnancy cases have been reported in the telbivudine pharmacovigilance database(with a cut-off date 31 August 2014),of those,308 had known pregnancy outcomes with 249 cases of live births(239 cases of live birth without congenital anomaly and 10 cases of live birth with congenital anomaly).In the latest antiretroviral pregnancy registry report(1 January 1989 through 31 January 2015)of27 patients exposed to telbivudine during pregnancy(18,6 and 3 during first,second and third trimester,respectively)19 live births were reported and there were no cases of birth defects reported.CONCLUSION:Telbivudine treatment during pregnancy presents a favorable safety profile without increased rates of live birth defects,spontaneous abortion or elective termination,or fetal/neonatal toxicity.Exposure to telbivudine in the first,second and third trimester of pregnancy has been shown to significantly reduce the risk of HBV transmission from mother to child on the basis of standard immune prophylaxis procedure.
文摘AIM: To evaluate the efficacy and safety of tegaserod, 6 mg twice daily (b.i.d.), in men and women with chronic constipation (CC) from China. METHODS: This was a multicenter, double-blind, placebo-controlled study. Following a 2-wk treatment-free baseline period, patients were randomized to receive either tegaserod (6 mg b.i.d.) or placebo (b.i.d.) for 4 wk. An analysis of covariance with repeated measures was used to determine the overall effect of treatment for the primary efficacy variable; the change from baseline in the number of complete spontaneous bowel movements (CSBMs) during the 4-wk treatment period. Secondary efficacy endpoints included other measures of response in terms of CSBMs, and patients’ daily and weekly assessment of bowel habits. Safety was also assessed, based on the incidence and severity of adverse events (AEs).RESULTS: A total of 607 patients were randomized to receive either tegaserod (n = 304) or placebo (n = 303). Tegaserod treatment resulted in a rapid and significant increase from baseline in the adjusted mean number of CSBMs per week over wk 1-4 compared with placebo (1.39 vs 0.91, P = 0.0002). A statistically significant difference in favor of tegaserod was also observed for a mean increase ≥ 1 CSBM/wk over wk 1-4 (47.7% vs 35.0%, tegaserod vs placebo, respectively, P = 0.0018) and for the absolute number of ≥ 3 CSBMs/wk over wk 1-4 (25.0% vs 14.5%, tegaserod vs placebo, respectively, P = 0.0021). Improvements in other symptoms of CC were also seen in the tegaserod group, including improved stool form and reduced straining. In addition, more patients in the tegaserod group reported satisfactory relief from their constipation symptoms. The frequency and severity of AEs was comparable between tegaserod and placebo groups, with the exception of a greater incidence of diarrhea in patients receiving tegaserod (3.6%) compared with placebo (1.7%).CONCLUSION: Tegaserod treatment improved multiple symptoms of CC and was associated with a favorable safety profile.
文摘Kinetic parameters of the decomposition of hazardous chemicals can be applied for the estimation of their thermal behavior under any temperature profile.Presented paper describes the application of the advanced kinetic approach for the determination of the thermal behavior also under adiabatic conditions occurring e.g.in batch reactors in case of cooling failure.The kinetics of the decomposition of different samples(different manufacturers and batches) of 3-methyl-4-nitrophenol were investigated by conventional DSC in non-isothermal(few heating rates varying from 0.25 to 8.0K/min) and isothermal(range of 200~260℃) modes.The kinetic parameters obtained with AKTS-Thermokinetics Software were applied for calculating reaction rate and progress under different heating rates and temperatures and verified by comparing simulated and experimental signals.After application of the heat balance to compare the amount of heat generated during reaction and its removal from the system,the knowledge of reaction rate at any temperature profiles allowed the determination of the temperature increase due to the self-heating in adiabatic and pseudo-adiabatic conditions.Applied advanced kinetic approach allowed simulation the course of the Heat-Wait-Search(HWS) mode of operation of adiabatic calorimeters.The thermal safety diagram depicting dependence of Time to Maximum Rate(TMR) on the initial temperature was calculated and compared with the results of HWS experiments carried out in the system with Ф-factor amounting to 3.2.The influence of the Ф-factor and reaction progress reached at the end of the HWS monitoring on the TMR is discussed.Presented calculations clearly indicate that even very minor reaction progress reduces the TMRad of 24h characteristic for a sample with initial reaction progress amounting to zero.Described estimation method can be verified by just one HWS-ARC,or by one correctly chosen ISO-ARC run of reasonable duration by knowing in advance the dependence of the TMR on the initial temperature for any Ф-factor.Proposed procedure results in significant shortening of the measuring time compared to a safety hazard approach based on series of ARC experiments carried out at the beginning of a process safety evaluation.
文摘Background: Many clinical trials include multiple patient-reported outcomes (PROs) to measure fatigue as secondary or exploratory endpoints of treatment effectiveness. Often, these instruments have overlapping content. The objective of this study was to compare the combined measurement properties of two fatigue scales, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and SF-36 vitality (VT) scale using item response theory (IRT). Methods: The FACIT-Fatigue and SF-36v2 were administered at baseline and weeks 2, 4, 7, 12, and 16 to rheumatoid arthritis (RA) patients (n = 237) enrolled in a 52-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose finding study to evaluate the efficacy and safety of subcutaneous secukinumab administered to pa- tients with active RA. Confirmatory factor analysis (CFA) was used to investigate unidimensionality among FACIT- Fatigue and VT items. A generalized partial credit IRT model was used to cross-calibrate the FACIT-Fatigue and VT items and weighted maximum-likelihood estimation was used to score a composite fatigue index. Analysis of variance was used to compare the composite fatigue index with the original scales in responding to ACR improvement and treatment effects. Results: CFA found less than adequate fit to a unidimensional model. However, specifications of alternative multidimensional models were insufficient in explaining the common variance among items. An IRT model was successfully fitted and the composite fatigue index score was found to be more responsive than the original scales to ACR improvement and treatment effects. Effect sizes and significance tests for changes in scores on the composite index were generally larger than those observed with the original scales. Conclusion: IRT methods offer a promising approach to combining items from different scales measuring the same concept that could improve the detection of treatment effects in clinical studies of RA.
基金This study was sponsored by Novartis Pharma AG,Basel,Switzerland。
文摘Background:Psoriasis is a chronic inflammatory skin disease,affecting about 0.6%of the Chinese population.Many patients are not well controlled by conventional treatments,thus there is need for new treatment regimens.In this study,we assessed the efficacy and safety of secukinumab in Chinese patients with moderate to severe plaque psoriasis.Methods:This study was a 52-week,multicentre,randomized,double-blind,placebo-controlled,parallel-group,Phase 3 trial.A sub-population of study participants(≥18 years)of Chinese ethnicity were randomized to receive subcutaneous injections of 300 or 150 mg secukinumab,or placebo.The co-primary endpoints were psoriasis area severity index(PASI)75 and Investigator’s Global Assessment(IGA)0/1 at Week 12.Results:A total of 441 Chinese patients were enrolled in this study.Co-primary outcomes were achieved;300 and 150 mg secukinumab were superior to placebo as shown in the proportion of patients that achieved PASI 75(97.7%and 87.2%vs.3.7%,respectively;P<0.001),and IGA 0/1(82.3%and 69.7%vs.2.7%;P<0.001)at Week 12.Treatment efficacy was maintained until Week 52.There was no increase in overall adverse events with secukinumab relative to placebo throughout the 52-week period.Conclusion:Secukinumab is highly effective and well tolerated in Chinese patients with moderate to severe plaque psoriasis.
文摘Psoriasis is a chronic,systemic inflammatory disease characterized by demarcated,scaly,erythematous skin plaques.Psoriatic arthritis(PsA)is the most common comorbidity.
基金This study was supported by Novartis Pharma AG,Basel,Switzerland and designed by Novartis personnelMedical writing support was funded by Novartis.
文摘Background:Secukinumab demonstrated sustained efficacy in patients with ankylosing spondylitis(AS)through 5 years in pivotal Phase III studies.Here,we present efficacy and safety results(52-week)of secukinumab in patients with AS from the MEASURE 5 study.Methods:MEASURE 5 was a 52-week,Phase III,China-centric study.Eligible patients were randomly assigned(2:1)to receive subcutaneous secukinumab 150 mg or placebo weekly for the first five doses and then once every 4 weeks(q4w).All placebo patients switched to secukinumab 150 mg q4w starting at Week 16.Primary endpoint was Assessments of SpondyloArthritis international Society(ASAS)20 at Week 16.Randomization was stratified by region(China vs.non-China).Results:Of 458 patients(secukinumab 150 mg,N=305;placebo,N=153)randomized,327(71.4%)were from China and 131(28.6%)were not from China.Of these,97.7%and 97.4%patients completed Week 16 and 91.1%and 95.3%(placebo-secukinumab)patients completed Week 52 of treatment.The primary endpoint was met;secukinumab significantly improved ASAS20 response at Week 16 vs.placebo(58.4%vs.36.6%;P<0.0001);corresponding rate in the Chinese population was 56.0%vs.38.5%(P<0.01).All secondary efficacy endpoints significantly improved with secukinumab 150 mg in the overall population at Week 16;responses were maintained with a trend toward increased efficacy from Week 16 to 52.No new or unexpected safety signals were reported up to Week 52.Conclusions:Secukinumab 150 mg demonstrated rapid and significant improvement in signs and symptoms of AS.Secukinumab was well tolerated and the safety profile was consistent with previous reports.Efficacy and safety results were comparable between the overall and Chinese populations.
基金The research leading to these results was supported by the lInnovative MedicinesInitiative Joint Undertaking ABIRISK project under grant agreement#115303theresources of which comprise financial contribution from the European Union's Seventh Framework Programme(FP7/2007-2013)+1 种基金in-kind contributions from EFPIA companiesThis work was also supported by the Labex in Research on Medication and Therapeutic Innovation(LERMT)(to B.M.)and the CEA(to B.M.).
文摘The clinical efficacy of therapeutic antibodies is recognized in many indications,explaining their rapid rise in the worldwide drug market.However,therapeutic antibodies can be immunogenic by inducing a specific immune response characterized by the production of anti-drug antibodies(ADAs).ADAs can potentially increase the clearance of therapeutic antibodies,decrease their therapeutic effects1 and induce hypersensitivity reactions.Because humans are thought to be tolerant to their own proteins,sequences of the therapeutic antibodies have been humanized or human antibodies have been directly generated by technologies using human sequences.However,human(ized)antibodies exhibit highly variable levels of immunogenicity,1,2 illustrating the poor understanding of the role of sequence humanization in mitigating the immunogenicity of therapeutic antibodies.Multiple lines of evidence highlight the role of CD4 T lymphocytes during the initiation of an ADA response,3 but few T-cell epitopes of marketed therapeutic antibodies have been described to date.