PITCH HF (DCC)

描述（由申请人提供）：PITCH-HF将是第一个评估选择性肺血管扩张剂，5型磷酸二酯酶（PDE5）抑制剂他达拉非对心力衰竭（HF）合并左室（LV）收缩功能障碍（LVSD）和继发性肺动脉高压（PH）患者长期临床结果影响的试验。伴有继发性PH和右心室功能障碍的LVSD患者是HF的高危亚群，其发病率和死亡率都较高。然而，目前基于指南的治疗侧重于左室功能障碍的治疗。在该人群中，PDE5抑制的安慰剂对照研究表明，运动能力和生活质量的预后指标有所改善，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。三个目标涉及：(1)到达主要终点的时间（心血管（CV）死亡率或HF住院）和次要终点的时间（到达CV死亡率、HF住院、全因死亡率的时间，以及CV/HF住院的频率）；(2)从基线到3个月和18个月的功能能力（6分钟步行距离）和生活质量（明尼苏达州HF生活问卷）的变化；(3)建立血浆样本库（基线3,18个月），用于潜在生物标志物的辅助研究，这些生物标志物可能预测PDE5抑制的有益反应。CCC（马萨诸塞州总医院，PI: Marc Semigran医学博士）和DCC（新英格兰研究所，PI: Rebecca Li博士；Susan Assmann博士）提供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[礼来公司]作为儿童礼物提供。在第一年招募100个认证站点（美国和加拿大），PITCH-HF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。[在选定地点进行的试点研究已证明可行性。迄今已获得82个场址承诺。该试验将有85%的能力检测2.5年主要结果的相对降低20%（从30%降至24%），a = 0.05，受试者损耗率高达15%。初步分析将是意向治疗，适当时使用Cox回归模型和协方差分析。提出了三个中期分析。患者人群包括：21岁的成年人；NYHA II-IV级HF伴LVSD (LVEF < 40%)；12个月内发生失代偿性HF，或3个月内血浆BNP水平为e300 pg/ml或NT-proBNP水平为e1800pg/ml。所有患者必须在6个月内有继发性PH记录，并接受稳定的基于指南的药物治疗。对硝酸异山梨酯/肼嗪联合治疗不耐受的非裔美国人可以入组。如果这项开创性试验的结果是阳性的，将为大量高发病率和死亡率的心衰患者提供一种新的、有效的治疗方法。如果结果为阴性，将阻止PDE5抑制剂在收缩期心衰中的应用，并将推动对心衰患者RV功能障碍的其他潜在治疗方法的进一步研究。

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.