Phase Ib Clinical Study on the Safety, Tolerability, and Pharmacokinetics of TPN171H Tablets in the Treatment of Pulmonary Arterial Hypertension (PAH) Patients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Cmax
研究概览
简要总结
Exploring the safety, tolerability, and pharmacokinetic (PK) characteristics of oral TPN171H tablets in patients with Pulmonary Arterial Hypertension under continuous multiple administration conditions, providing a basis for determining the administration plan and recommended dosage in phase II clinical study.
详细描述
This study was divided into screening period, treatment period and medication follow-up period, and the treatment period included 3 cycles.
First cycle: subjects receiving the test drug 2.5mg QD for 2 consecutive weeks, PK blood collection on Day 1 and Day 7, and the subjects discharged and returned to the hospital on Day 14 for medication monitoring blood collection, safety examination and efficacy assessment.
Second cycle: up to 14 weeks; the second cycle is divided into monitoring and observation cycles; subjects who complete the first cycle and examinations enter the second cycle, with a 14 day monitoring period and 12 week observation period, with the second cycle dose of 5 mg QD, subjects received PK sampling on Day 7.
Third cycle:The third cycle lasts for 8 days, subjects receive 10mg QD for 8 days; subjects received PK sampling on Day 7; subjects who completed an 8-day safety observation period on Day 8 without abnormal safety tests may be discharged. After discharge into the medication follow-up period.
Medication follow-up period: up to 2 years; subjects entering the follow-up period will continue to take the dose of the last treatment period, return to hospital once every 12 weeks for safety examination and efficacy assessment until the subject intolerance or withdrawal from the study or expiration of 2 years (whichever occurs first).
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
- •Patients who are able to signed the informed consent form ,understand and follow study plans and instructions;
- •Patients aged 18 to 75;
- •Patients with symptomatic PAH (Group1) with right heart catheterization results within the past 36 months (first category), a pulmonary vascular resistance (PVR) > 3 Wood, a mean pulmonary artery pressure (mPVP) ≥25 mmHg and a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg ;
- •Patients have a current diagnosis of being in WHO functional class II or III;
- •Targeted therapeutic drugs were not added, discontinued, or dosed within 4 weeks prior to baseline; 6.6-MWD between 100m &450m;
- •7.Patients who are willing to take proper contraceptive during the study and within 3 months after the study completed.
排除标准
- •All types of PH except subtypes of Group1 specified in the inclusion criteria;
- •Patients who concomitant severe obstructive pulmonary disease(FEV1/FVC<0.5) ;
- •Total lung volume<60% predicted;
- •Systolic blood pressure below 90/60mmHg at screening;
- •Left ventricular ejection fraction less than 45%, left ventricular short axis shortening rate less than 0.2;
- •Lower limb diseases that affect the completion of 6-MWD testing;
- •Subjects who received PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil, and avanafil) within 4 weeks before baseline
- •CYP3A4 enzyme inducers (such as bosentan, aprepitant, barbiturates, carbamazepine, rifampicin, pioglitazone) or inhibitors (such as cimetidine, ciprofloxacin, boceprevir-d9，telaprevir, clarithromycin, nefazodone, and ritonavir) were taken within 2 months before the start of the trial, Regular or intermittent administration of nitrates (such as nitroglycerin, isosorbide nitrate,pentaerithrityl tetranitrate ) or any form of nitric oxide donor (including nicorandil, L-arginine) and α- Receptor blocking (such as phenoxybenzamine, prazosin, terazosin,tamsulosin)
- •Subjects with a clear history of allergic diseases or who have previously stopped taking either aniracetam or tadalafil due to safety or tolerable reasons;
- •Previous or current drug dependence, clear history of neurological or mental disorders, such as epilepsy, dementia, psychological or other emotional issues, may invalidate informed consent or limit the subject's ability to comply with the protocol;
- •Acute or chronic organic diseases (excluding breathing difficulties) prevent subjects from completing the necessary testing items required in the study (especially the 6-minute walking distance test);
- •Have a history of ophthalmic diseases, such as color vision abnormalities, retinitis pigmentosa, and macular degeneration;
- •Malignant tumor patients;
- •Moderate or severe liver function injury and/or blood ALT and AST exceeding 1.5 times the upper limit of normal values, and blood creatinine exceeding 1.5 times the upper limit of normal values;
- •Pathogenic test for HIV positive; Positive test for hepatitis B or hepatitis C; Subjects suffering from acute infectious diseases;
- •Suffered from infectious diseases recently (within 1 month);
- •The subject has ischemic heart disease (defined as symptomatic, requiring anti angina treatment, or having experienced myocardial infarction within the past 3 years);
- •Those who have experienced cerebrovascular events (such as transient ischemic attacks or strokes) within the past 3 months;
- •Participated in any clinical trial within 3 months prior to taking the investigational drug;
- •Pregnant or lactating women;
- •The researchers believe that subjects who are not suitable to participate in this experiment due to other reasons.
研究组 & 干预措施
TPN171H
TPN171H is received 2.5mg QD for 2 consecutive weeks, then 5 mg QD for 14 consecutive weeks. If the dose is well-tolerated,TPN171H is up-titrated to 10mg QD , which will last for up to 2 years.
干预措施: TPN171H (Drug)
结局指标
主要结局
Cmax
时间窗: From time zero up to 24 hours post-dose following oral administration of TPN171H
Clearance rate (CL/F)
时间窗: From time zero up to 24 hours post-dose following oral administration of TPN171H
Tmax
时间窗: From time zero up to 24 hours post-dose following oral administration of TPN171H
AUC0~t
时间窗: From time zero up to 24 hours post-dose following oral administration of TPN171H
AUC0-∞
时间窗: From time zero up to 24 hours post-dose following oral administration of TPN171H
Apparent distribution volume (Vd/F)
时间窗: From time zero up to 24 hours post-dose following oral administration of TPN171H
Q-T interval
时间窗: through study completion, an average of 2 years
Terminal half-life (t 1/2)
时间窗: From time zero up to 24 hours post-dose following oral administration of TPN171H
Incidence of Treatment-Emergent Adverse Events
时间窗: through study completion, an average of 2 years
Mean Residence Time(MRT)
时间窗: From time zero up to 24 hours post-dose following oral administration of TPN171H
次要结局
- 6- Minute Walk Distance（6-MWD）(through study completion, an average of 2 years)
- NT-proBNP(through study completion, an average of 2 years)
- The World Health Organization (WHO) functional class(through study completion, an average of 2 years)
- Borg dyspnea index(through study completion, an average of 2 years)