Olaparib for Pulmonary Arterial Hypertension: a Pilot Clinical Study
试验速览
- 阶段
- 早期 1 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Change in pulmonary vascular resistance (PVR) at week 16
研究概览
简要总结
The main OBJECTIVE of this proposal is to extend our preclinical findings on the role of DNA damage and poly(ADP-ribose) polymerases (PARP) inhibition as a therapy for a devastating disease, pulmonary arterial hypertension (PAH), to early-phase clinical trials. We, and others, have published strong evidence that DNA damage accounts for disease progression in PAH and showed that PARP1 inhibition can reverse PAH in several animal models1. Interestingly, PARP1 inhibition is also cardioprotective. Olaparib, an orally available PARP1 inhibitor, can reverse cancer growth in animals and humans with a good safety profile, and is now approved for the treatment of ovarian cancer in Canada, Europe and the USA. The time is thus right to translate our findings in human PAH. The industry-sponsored clinical research on PARP1 inhibitor is currently entirely cancer-oriented. Nonetheless, AstraZeneca Canada accepted to support an early phase clinical trial through in-kind contribution, but the support from foundations and federal agencies is critical to catalyze early-stage development of PARP1 inhibitors for other indications, especially for orphan diseases. A CIHR Project Scheme grant will thus be submitted on September 15 2017, proposing a Phase 1, followed by a Phase 2 trial that will be conducted in recognized PAH programs throughout Canada. At this stage, however, we propose a pilot study to assess the feasibility of the proposed trials in the PAH population. The overall HYPOTHESIS is that PARP1 inhibition with olaparib is a safe and effective therapy for PAH.
The primary objective of the study is to confirm feasibility, to support the safety of using olaparib in PAH patients, and precise the sample size of the coming Phase 1B trial. The feasibility of the comprehensive patient phenotyping that will be proposed within the phase 1B trial will thus be assessed, in addition to adverse events and efficacy signals.
***OPTION pilot trial was merged with the new OPTION multicenter trial (NCT03782818)***
详细描述
BACKGROUND PAH is a progressive and multifactorial condition characterized by the chronic elevation of pulmonary artery (PA) pressure leading to RV failure. In spite of currently approved therapies, patients with PAH have poor quality of life and the 3-year survival of idiopathic PAH remains ~55%. The identification and characterization of new therapeutic targets is thus an urgent need.
In recent years, it has become increasingly appreciated that, as in cancer cells, PAH-PA smooth muscle cells (PASMCs) are exposed to stressful conditions, jeopardizing their survival. To deal with these insults, these cells have developed complementary pathways, allowing them to survive and proliferate and leading to intense remodelling of distal PA. Central to these strategies are the activation of the DNA repair machinery. Survival of these cells is associated with an over-efficient activation of PAPR1, a predominant mechanism involved in DNA repair, and pharmacological inhibition of PARP1 reverses PAH in human cells and clinically relevant animal models.
Recently, Olaparib, an orally available PARP1 inhibitor, was shown to be safe, well tolerated and effective in treating cancers and was approved for the treatment of ovarian cancer.
OLAPARIB IN PAH: A PILOT STUDY The study population will include 6 well-characterized PAH patients that have been stable for >4 months on standard PAH-therapies, as per guidelines.
The primary objective of the study is to confirm the feasibility for a future early stage clinical trial and provide early evidence that Olaparib may be effective in PAH.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •adults (18-75 yrs) with PAH of idiopathic/ hereditary/drug or toxin-induced origin or associated with connective tissue diseases; 2) mean PA pressure ≥25mmHg, PA wedge pressure ≤15mmHg, PVR >480 dyn.s.cm-5 and absence of acute vasoreactivity (we expect PARP1 inhibition will be most effective in patients with significant PA remodelling); 3) WHO functional class II or III; 4) clinically stable with unchanged vasoactive therapy for ≥4 months; 5) two 6MWD of 150-550m and within ±15% of each other (the latter being used as baseline value); 6) a negative serum pregnancy test prior to receiving the first dose of study treatment and willing to use adequate contraception from enrolment through 3 months after the last dose of study treatment for patients of childbearing potential
排除标准
- •other types of pulmonary hypertension; 2) significant restrictive (total lung capacity <60% predicted) or obstructive (FEV1/FVC<60% after a bronchodilator) lung disease; 3) systolic blood pressure <90 mmHg; 4) acute RV failure within the last 3 months; 5) received any investigational drug within 30 days; 6) BMI <18 or >40 kg/m2; 7) cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day 1; 8) presence of ≥3 risk factors for heart failure with preserved ejection fraction (BMI >30 kg/m2, diabetes mellitus, hypertension or coronary artery disease); 9) organ dysfunction other than RV failure; 10) anticipated survival <1 year due to concomitant disease
研究组 & 干预措施
Drug: Olaparib
Olaparib up to 400 mg BID (100 to 400 mg) for 16 weeks
干预措施: Olaparib (Drug)
结局指标
主要结局
Change in pulmonary vascular resistance (PVR) at week 16
时间窗: 16 weeks
At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function
次要结局
未报告次要终点
研究者
Steeve Provencher
Professor
Laval University