密固达临床试验介绍课件PPT文档.ppt

MA-1,目 录,密固达作用机制分子结构决定独特的效果体外研究最强的抗骨吸收作用药理结构特点强大吸附力与抗骨吸收作用密固达与Paget骨病密固达与绝经后骨质疏松,MA-2,密固达简介,通用名称：唑来膦酸注射液商品名称：密固达（Aclasta）规格:100ml：5mg（以唑来膦酸无水物计）性状:本品为无色的澄明液体,MA-3,双膦酸药物不同的 R2 侧链结构,利塞膦酸,唑来膦酸,伊班膦酸,阿伦膦酸,MA-4,唑来膦酸是作用最强的双膦酸盐,Green JR,et al.J Bone Miner Res.1994;9:745-751.,动物研究证实：唑来膦酸的骨吸收抑制强度是帕米膦酸盐的100-850倍,MA-5,高吸附力的双膦酸药物在骨组织中很少弥散，停留在骨表面附近,G Russell 2005,注射后几个月内组织液中仍可检测到双膦酸类药物,唑来膦酸与骨矿盐的强大结合力:,唑来膦酸在骨组织循环的可能机制,MA-6,近端胫骨干骺端pQCT,Gasser JA,Green J.Bone.2002;30(3):41S.,松质骨 BMD(%),周,60,40,20,0,0,4,8,12,16,20,24,28,32,唑来膦酸单次静脉给药对于去卵巢大鼠的长期抗骨吸收作用,MA-7,去卵巢大鼠治疗32周后近端胫骨干骺端Micro-CT图像,Gasser JA,Green JR.Bone.2002;30(3):41S.,成人唑来膦酸5mg的等效剂量,OVX,4 g/kg,20 g/kg,100 g/kg,SHAM,单次静脉注射人类的等效剂量对于骨组织微结构具有保护作用,MA-8,唑来膦酸防止去卵巢大鼠骨组织结构恶化以及生物力学的降低,防止去卵巢导致的以下参数降低:骨体积分数 1 骨小梁厚度1 骨小梁数量 1 连接的密度 1 承受最大应力(椎体)1 承受最大压力(股骨:3点弯曲试验)2能量吸收2防止去卵巢导致的以下参数增加:骨小梁间隙 1 结构模型参数 1,1.Glatt M,et al.Osteoporos Int.2004;15:707-715.2.Hornby SB,et al.Calcif Tissue Int.2003;72:519-527.,MA-9,1.Green JR,et al.J Bone Miner Res.1994;9:745-751.2.Data on file,Novartis.,体外颅骨测量：抑制重吸收 vs 矿化作用,治疗比,抑制矿化,抑制骨吸收,化合物,400,20,0.05,阿伦膦酸,IC50(M)2,IC50(M)1,0.4,氯屈膦酸,50,125,0.02,伊班膦酸,400,8,唑来膦酸抑制骨吸收与矿化作用具有更高的治疗比,唑来膦酸在Pagets骨病的应用,MA-11,*HORIZON(Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly).Reid IR,et al.N Engl J Med.2005;353:898-908.,HORIZON*-Pagets骨病临床研究:疗效终点,患者总数:N=357主要终点:治疗反应 过高的SAP水平降低 75%或治疗6个月SAP水平达到正常的百分比 次要终点：治疗28天SAP水平达到正常的百分比产生治疗反应的时间骨吸收指标的变化血浆 CTX尿 CTX,MA-12,2 个月1,Zoledronic Acid(n=176),%产生治疗反应的患者百分比*,6 个月2,90,63,96,89,%,P.001,%,P.001,反应患者,碱性磷酸酶正常患者,%产生治疗反应的患者百分比*,*产生治疗反应:过高的SAP水平降低75%.Dosage:RIS:60 days:1 x 30 mg/day;Zoledronic Acid:single infusion of 5 mg.1.Lyles K,et al.Poster presented at ECCEO5;March 16-19,2005;Rome,Italy.2.Reid IR,et al.N Engl J Med.2005;353:898-908.,治疗2个月和6个月时唑来膦酸具有比利塞膦酸更好的临床疗效,Risedronate(n=171),47,26,74,58,Zoledronic Acid(n=176),Risedronate(n=171),MA-13,天数,10,28,63,91,182,*7%,碱性磷酸酶水平正常患者百分比(%),*P.001.,唑来膦酸与利塞膦酸治疗：碱性磷酸酶正常化疗效比较,Zoledronic Acid(n=176),Risedronate(n=171),Reid IR,et al.N Engl J Med.2005;353:898-908.,1%,*63%,*76%,*89%,26%,49%,58%,MA-14,*P.001,0,10,28,63,91,182,天数,0,100,200,300,400,500,全血碱性磷酸酶水平(U/L),*,*,*,*,*,随访时平均血浆碱性磷酸酶水平(SE),唑来膦酸(n=176),利塞膦酸(n=171),正常范围,Reid IR,et al.N Engl J Med.2005;353:898-908.,*P.001,*P.001,*P.001,*P.001,唑来膦酸使平均血浆碱性磷酸酶水平恢复正常,HORIZON-PFT(Pivotal Fracture Trial关键部位骨折试验)2301 研究核心内容,密固达与绝经后骨质疏松-全面降低各部位骨折风险,提高骨密度,MA-16,Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial,Black DM,et al.N Engl J Med.2007;356:1809-1822.,MA-17,HORIZON Pivotal Fracture TrialHORIZON关键骨折临床研究(PFT)概述,研究目的：观察唑来膦酸5毫克治疗降低绝经后骨质疏松患者骨折风险的疗效为期3年，随机、双盲、安慰剂对照、多中心临床研究27个国家，239各研究中心的7736名女性入组 治疗方法：每年一次静脉输注唑来膦酸5毫克或安慰剂基础补充钙剂 10001500 mg/d;维生素 D 4001200 IU/d主要疗效终点第I层面：降低3年椎体骨折风险第I和II层面：延长3年发生髋部骨折的时间,ZOL=zoledronic acidBlack DM,et al.N Engl J Med.2007;356:1809-1822.,MA-18,新发椎体骨折发生率%,60%*(43%,72%),71%*(62%,78%),0,10,01,02,03,年,5,15,1.5%(42/2822),3.7%(106/2853),2.2%(63/2822),7.7%(220/2853),3.3%(92/2822),10.9%(310/2853),70%*(62%,76%),*P.0001,relative risk reduction vs placebo(95%confidence interval)Adapted from Black DM,et al.N Engl J Med.2007;356:1809-1822.,唑来膦酸治疗3年椎体形态骨折发生率降低达70%,MA-19,唑来膦酸治疗3年多发(2)椎体形态骨折发生率降低达89%,89%*(77%,95%),3年多发(2)椎体骨折,0.2%(7/2822),2.3%(66/2853),多发(2)椎体骨折发生率%,0,2,1,3,*P=.0001,relative risk reduction vs placebo(95%confidence interval)Data from Black DM,et al.N Engl J Med.2007;356:1809-1822.,MA-20,*Relative risk reduction vs placebo(95%confidence interval)Adapted from Black DM,et al.N Engl J Med.2007;356:1809-1822.,P=.0024,1,2,3,0,首次髋部骨折发生的时间(月),0,3,6,9,12,15,18,21,24,27,30,33,36,41%*(17%,58%),唑来膦酸治疗3年髋部骨折累积危险性降低达41%,累积危险性(%),MA-21,P.0001,累积危险性(%),发生第一次临床椎体骨折的时间（月）,0,3,6,9,12,15,18,21,24,27,30,33,36,77%*(63%,86%),1,2,3,0,*Relative risk reduction vs placebo(95%confidence interval)Adapted from Black DM,et al.N Engl J Med.2007;356:1809-1822.,唑来膦酸治疗3年临床椎体骨折累积危险性降低达77%,MA-22,P=.0002,发生第一次非椎体骨折的时间（月）,2,4,6,8,10,12,0,3,6,9,12,15,18,21,24,27,30,33,36,25%*(13%,36%),0,*Relative risk reduction vs placebo(95%confidence interval)Adapted from Black DM,et al.N Engl J Med.2007;356:1809-1822.,唑来膦酸治疗3年非椎体骨折累积危险性降低达25%,累积危险性(%),MA-23,Values above bars are 3-year cumulative event rates based on Kaplan-Meier estimates.*P=.0024;P.0001;P=.0002;relative risk reduction vs placebo Hip fracture was not excluded from analysis of non-vertebral fracture.Black DM,et al.N Engl J Med.2007;356:1809-1822.,41%*(17%,58%),77%(63%,86%),25%(13%,36%),临床椎体骨折,髋部骨折,非椎体骨折,1.4%(52/3875),0.5%(19/3875),2.5%(88/3861),2.6%(84/3861),8.0%(292/3875),10.7%(388/3861),3年新发临床骨折累积危险性（%）,0,10,5,15,唑来膦酸治疗3年降低临床骨折累积危险性（髋部、椎体、非椎体）,MA-24,0,6,12,18,24,30,36,月,5.90*,3.66*,2.39*,与基线比较变化率%,ZOL 5 mg,Placebo,ZOL n=PBO n=,Bracketed values are least square mean difference,ZOL vs placebo*P.0001,P-value computed from 3-way ANOVA with treatment,stratum and center as explanatory variables.Adapted from Black DM,et al.N Engl J Med.2007;356:1809-1822.,6.71%*,与安慰剂比较唑来膦酸治疗3年显著增加椎体BMD,MA-25,与安慰剂比较唑来膦酸治疗3年显著增加全髋BMD,ZOL n=PBO n=,Bracketed values are least square mean difference,ZOL vs placebo*P.0001,P-value computed from 3-way ANOVA with treatment,stratum and region as explanatory variables.Adapted from Black DM,et al.N Engl J Med.2007;356:1809-1822.,MA-26,与安慰剂比较唑来膦酸治疗3年显著增加股骨颈BMD,0,6,12,18,24,30,36,月,2.17*,1.58*,3.89*,ZOL 5 mg,Placebo,ZOL n=PBO n=,Bracketed values are least square mean difference,ZOL vs placebo*P.0001,P-value computed from 3-way ANOVA with treatment,stratum and region as explanatory variables.Adapted from Black DM,et al.N Engl J Med.2007;356:1809-1822.,5.06%*,与基线比较变化率%,MA-27,Placebo,CT检测骨结构结果显示唑来膦酸治疗后骨小梁结构得到保留,Recker R,et al.Presented at:34th European Symposium on Calcified Tissues;May 5-9,2007;Copenhagen,Denmark.Abstract PO21-M.,ZOL 5 mg,唑来膦酸与安慰剂组间比较骨小梁体积(BV/TV，16.59%vs,13.52%,P0.015)骨小梁数量(1.31/mm vs.1.22/mm,P0.006),骨小梁空间(0.76 mm vs.0.82 mm,P0.008),连接的密度(4.32/mm3 vs.3.57/mm3,P0.052).,MA-28,唑来膦酸静脉给药后3天内出现的常见症状（5%）,0,2,4,6,8,10,12,14,16,给药次数,发热,肌痛,流感样症状,头痛,关节痛,1,2,3,1,2,3,1,2,3,1,2,3,1,2,3,发生率(%),15%,2%,1%,1%,2%,1%,2%,1%,2%,1%,8%,7%,6%,5%,1%,Data from Black DM,et al.N Engl J Med.2007;356:1809-1822.,MA-29,OTC解热镇痛药可以有效降低给用后症状,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,5,10,15,24,29,34,39,48,53,58,63,给药后时间(小时),口表测量平均体温变化(SEM)(C),ZOL&扑热息痛ZOL&布洛芬,ZOL&PLACPLAC&PLAC,Design:2 x 500 mg paracetamol vs 2 x 200 mg ibuprofen vs placebo every 6 hours for 3 days.Oral study medication started 4 hours after infusion,MA-30,唑来膦酸治疗绝经后骨质疏松患者具有广泛疗效,绝经后骨质疏松女性，一年一次静脉给予唑来膦酸5mg，治疗3年可以显著降低1：椎体骨折(变形性骨折70%,临床骨折77%)1髋部骨折(41%)1非椎体骨折(25%)1骨折或疼痛导致的卧床/活动受限时间身高缩短1与安慰剂比较具有显著增加BMD作用136个月内骨形成与骨吸收指标降低至绝经前水平，并维持1 患者对药物的耐受性良好1预防骨折的疗效以及良好的依从性提示唑来膦酸5mg治疗骨质疏松具有显著优势1,1.Black DM,et al.N Engl J Med.2007;356:1809-1822.2.Black DM,et al.Presented at:ASBMR 28th Annual Meeting;September 15-19,2006;Philadelphia,Pa.Abstract 1054.,