PITCH HF (DCC)

描述（由申请方提供）：PITCH-HF将是评估选择性肺血管扩张剂（5型磷酸二酯酶（PDE 5）抑制剂他达拉非）对伴有左心室（LV）收缩功能障碍（LVSD）和继发性肺动脉高压（PH）的心力衰竭（HF）患者长期临床结局影响的首项试验。伴有继发性PH和右心室（RV）功能障碍的LVSD患者构成HF的高危亚群，发病率和死亡率增加。然而，目前基于指南的治疗集中在LV功能障碍的治疗上。在该人群中进行的PDE 5抑制的安慰剂对照研究已证明了运动能力和生活质量的预后标志物的改善，并为他达拉非对HF发病率和死亡率影响的多中心试验提供了基础。 三个目标地址：（1）至主要终点的时间（心血管（CV）死亡率或HF住院）和次要终点（至CV死亡、HF住院、全因死亡的时间; CV/HF住院的频率）;（2）功能能力的变化（步行6分钟）和生活质量（明尼苏达HF生活问卷），从基线至3个月和18个月;（3）建立血浆样本库（基线，3，18个月），用于可能预测对PDE 5抑制的有益反应的潜在生物标志物的辅助研究。CCC（马萨诸塞州总医院，PI：Marc Semigran MD）和DCC（新英格兰研究所，PI：Rebecca Li PhD; Susan Assmann PhD）提供了广泛的互补专业知识和经验，以确保试验成功。研究药物价值[5400万美元]，以及对药物配送中心的支持，将由[Eli Lilly Inc.]作为儿童礼物提供。 PITCH-HF在第1年招募了100个认证的研究中心（美国和加拿大），将在第2-4年招募2，102名受试者，并对他们进行平均2.5年的治疗随访。[在选定地点进行的试点研究证明了可行性。迄今已获得82个场地承诺。试验将有85%的把握度检测到主要结局的2.5年发生率相对降低20%（从30%降至24%），a = 0.05，受试者脱落率高达15%。主要分析将采用意向治疗，使用考克斯回归模型和协方差分析（如适用）。提出了三项中期分析。患者人群包括：成人e21岁; NYHA II-IV级HF伴LVSD（LVEF < 40%）;并且：12个月内发生失代偿性HF，或3个月内测量的血浆BNP水平e300 pg/ml或NT-proBNP e1800 pg/ml。所有患者必须在6个月内记录继发性PH，并接受稳定的基于指南的药物治疗。对硝酸异山梨酯/肼苯哒嗪联合治疗不耐受的非洲裔美国人可以入组。 这项开创性试验的结果，如果是积极的，将提供一个新的，有效的治疗的实质部分HF患者，具有较高的发病率和死亡率。如果结果为阴性，则将阻止PDE 5抑制剂在收缩期HF中的使用，并将促使进一步研究HF患者RV功能障碍的其他潜在治疗方法。

DESCRIPTION (provided by applicant): PITCH-HF will be the first trial to assess the effect of a selective pulmonary vasodilator, the type 5 phosphodiesterase (PDE5) inhibitor tadalafil, on long-term clinical outcomes in heart failure (HF) patients with left ventricular (LV) systolic dysfunction (LVSD) and secondary pulmonary hypertension (PH). LVSD patients with secondary PH and right ventricular (RV) dysfunction constitute a high-risk subpopulation of HF with increased morbidity and mortality. However, current guideline-based therapy focuses on the treatment of LV dysfunction. Placebo-controlled studies of PDE5 inhibition in this population have demonstrated improvements in the prognostic markers of exercise capacity and quality of life and provide the basis for a multicenter trial of the effect of tadalafil on HF morbidity and mortality. Three Aims address: (1) Time to the primary endpoint (cardiovascular (CV) mortality or HF hospitalization) and secondary endpoints (time to CV mortality, HF hospitalization, all-cause mortality; and frequency of CV/HF hospitalizations); (2) Changes in functional capacity (6-minute walk distance) and quality of life (Minnesota Living with HF questionnaire), from baseline to 3 and 18 months; and (3) Establishment of a plasma samples repository (baseline, 3, 18 months) for ancillary studies of potential biomarkers that may predict beneficial responses to PDE5 inhibition. The CCC (Massachusetts General Hospital, PI: Marc Semigran MD) and the DCC (New England Research Institutes, PIs: Rebecca Li PhD; Susan Assmann PhD) provide extensive complementary expertise and experience to ensure trial success. Study drug, valued at [$54 million], as well as support for the Drug Distribution Center, will be provided as an in-kid gift by [Eli Lilly Inc.] Recruiting 100 certified sites (US and Canada) in year 1, PITCH-HF will enroll 2,102 subjects in years 2-4 and follow them for an average of 2.5 years of treatment. [Feasibility has been demonstrated in a pilot study conducted at selected sites. 82 site commitments have been obtained to-date.] The trial will have 85% power to detect a 20% relative reduction in the 2.5-year rate for the primary outcome (from 30% to 24%) with a = 0.05 and subject attrition rates of up to 15%. Primary analyses will be intention-to-treat, using Cox regression models and analysis of covariance as appropriate. Three interim analyses are proposed. The patient population includes: Adults e21 years; NYHA Class II-IV HF with LVSD (LVEF < 40%); and either: an episode of decompensated HF within 12 months, or plasma BNP level e300 pg/ml or NT-proBNP e1800pg/ml measured within 3 months. All patients must have documented secondary PH within 6 months, and be on stable guideline-based medical therapy. African-Americans intolerant of combined isosorbide dinitrate/hydralazine therapy may be enrolled. The results of this seminal trial, if positive, will provide a new, effective therapy fo a substantive segment of HF patients that has a high morbidity and mortality. If negative, it will deter the use of PDE5 inhibitors in systolic HF and will motivate further investigation into other potential therapies for RV dysfunction in HF patients.