Patient-Level Meta-analysis: Effect of age of initiation, intensity and duration

描述（由申请方提供）：标题：患者水平荟萃分析：使用关节评分（通过灵敏度和特异性磁共振成像（MRI）和灵敏度体格关节检查评估关节结局）进行的凝血因子VIII预防治疗的起始年龄、治疗持续时间和治疗强度（给药方案）对血友病性关节病预防的影响。摘要：本提案将讨论重度血友病A沿着结构性和功能性关节疾病的发展以及预防或改善关节损伤的益处。严重血友病患者的慢性关节病是一种重要的疾病，由关节内的微小或大的赘生物引起，并导致疼痛，限制了就业和社会参与。预防性治疗或常规输注凝血因子VIII以预防出血，是预防关节和危及生命的出血事件的标准治疗。然而，虽然在两岁之前开始的高剂量、频繁的输注（称为初级预防）在预防慢性关节病方面是有效的，但关于延迟或较低强度的预防是否以及在多大程度上预防、限制或逆转关节损伤仍存在许多问题。此外，目前还不清楚预防是否以及在多大程度上可以帮助患有关节疾病的青少年和成人（二级预防）。本提案的目的是使用三项研究的现有数据，包括关节成像与敏感和特异性磁共振成像（MRI），以确定血友病关节疾病的自然史，一级预防的长期结局和二级预防的影响。三项研究中有两项包括随时间推移的连续测量，所有研究均包括接受预防治疗的患者与未接受预防治疗的患者。其中两项研究包括在两岁时开始预防的患者，所有三项研究都包括在两岁后开始预防的患者。在本提案中，个体患者数据将作为一项研究进行汇总和分析。提出了分析模型来确定无预防患者关节损伤的时间轨迹，并确定预防对预防、逆转或减轻关节损伤程度的影响。此外，本研究将讨论开始预防性治疗的年龄、FVIII剂量和给药频率对预防性治疗结局的影响。由于这三项研究纳入了大量受试者（至少56例患者接受非预防性治疗，60例患者接受一级预防性治疗，106例患者接受二级预防性治疗），并且每项MRI研究包括4 - 6张关节图像，因此很可能达到拟定研究的目的。

DESCRIPTION (provided by applicant): Title: Patient-Level Meta-analysis: Effects of age of initiation, duration of therapy and intensity of treatment (dosing schedule) with factor VIII prophylaxis on prevention of hemophilic arthropathy using joint scoring via sensitive and specific magnetic resonance imaging (MRI) and sensitive physical joint examination to assess joint outcome. Abstract: This proposal will address the development of structural and functional joint disease in severe hemophilia A along with the benefits of prophylaxis in preventing or ameliorating joint damage. Chronic arthropathy in severe hemophilia is an important morbidity caused by microscopic or large hemorrhages into joints and results in pain that limits employment and social participation. Prophylaxis, or routine infusions of factor VIII to prevent bleeding, is the standard of care therapy to prevent joint and life-threatening bleeding events. However, while high-dose, frequent infusions begun before the age of two years (called primary prophylaxis) is effective in preventing chronic arthropathy, many questions remain regarding whether and to what degree delayed or less intensive prophylaxis prevents, limits or reverses joint damage. In addition, it is unknown whether and to what extent prophylaxis can help teens and adults with established joint disease (secondary prophylaxis). The aim of this proposal is to use existing data from three research studies that include joint imaging with sensitive and specific magnetic resonance imaging (MRI) in order to determine the natural history of hemophilic joint disease, the long-term outcome of primary prophylaxis and the impact of secondary prophylaxis. Two of the three studies include serial measurements over time and all of the studies include patients on prophylaxis in comparison to no prophylaxis. Two of the studies include patients who began prophylaxis by the age of two years, and all three studies include patients who began prophylaxis beyond the age of two years. In this proposal, individual patient data will be aggregated and analyzed as a single study. Analytic models are proposed to determine the time-trajectory of joint damage in patients on no-prophylaxis, and to determine the effects of prophylaxis on preventing, reversing or reducing the degree of joint damage. In addition, the study will address the impact of age of starting prophylaxis, FVIII dose and dose frequency on outcome of prophylaxis. Because the three studies incorporate a large number of subjects (at least 56 patients on no-prophylaxis, 60 patients on primary prophylaxis and 106 patients on secondary prophylaxis, and include four to six joint images for each MRI study, it is likely that the objectives of the proposed study will be met.