NCT01884675终止3 期
A Randomised, Multicentre, Double-Blind, Placebo-Controlled Study Of Ambrisentan In Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH).
适应症
干预措施
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16
研究概览
简要总结
It is hypothesised that ambrisentan may provide benefit to subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), where currently no proven or licensed treatment options exist. This Phase III, randomized, double-blind placebo controlled parallel group, 16 week study will compare the safety and efficacy of ambrisentan 5 milligrams (mg) versus placebo in subjects with inoperable CTEPH. The study will enrol 160 subjects, to assure at least 72 evaluable subjects per treatment arm, based on 10% drop-out rate.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed written informed consent prior to beginning study-related procedures.
- •Subject must be between 18-80 years of age, inclusive, at the Screening Visit.
- •Subjects must have a diagnosis of CTEPH at an expert centre with a positive V/Q and CT angiogram and a pulmonary angiogram if available within 6 months prior to screening.
- •Subject must meet all of the following haemodynamic criteria by means of a RHC within 3 months prior to screening: Mean pulmonary artery pressure (mPAP) of >25 millimeters of mercury (mmHg), Pulmonary vascular resistance (PVR) >400 dynes.sec/centimetre (cm)^5, Pulmonary capillary wedge pressure (PCWP) or Left ventricle end diastolic pressure (LVEDP) of <15 mmHg.
- •Subjects must have previously been judged inoperable due to the obstruction being surgically inaccessible (i.e. distal disease) by an expert multidisciplinary team which must include at least one cardiology or respiratory consultant, and one consultant PEA surgeon. For countries with CTEPH expert centers [including at least a surgeon with sound experience performing Pulmonary Endarterectomy (PEAs)] the expert team will be the local expert centre. For countries without a CTEPH surgical expert center a central adjudication committee will assess the operability of the subjects during the screening period.
- •Subject must walk a distance of >150 Meters (m) and < 475 m at the screening visit.
- •Subject must have a current diagnosis of being in WHO Functional Class II or III.
- •Subject, with or without supplemental oxygen, must have a resting arterial oxygen saturation (SaO2) > 92% as measured by pulse oximetry at the Screening Visit.
- •Subjects must have received anticoagulation for a minimum of 3 months prior to Screening
- •Female subject of childbearing potential must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of Investigational Product
- •Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study.
- •Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form (ICF) and must sign the form prior to the initiation of any study procedures.
排除标准
- •Subject received previous Pulmonary arterial hypertension (PAH) therapy (Phosphodiesterase type 5 [PDE5i], Endothelin receptor antagonist [ERA], chronic prostanoid use)
- •Subject has previously discontinued other ERA in either another clinical study or commercial product for safety or tolerability reasons other than for liver function abnormalities.
- •Subject has a known hypersensitivity to the Investigational Products, the metabolites, or formulation excipients
- •Subject has previously undergone a pulmonary endarterectomy or a balloon pulmonary angioplasty
- •Subject receiving intravenous inotropes within 2 weeks prior to the Screening Visit (e.g. dopamine, dobutamine)
- •Subjects receiving Calcium Channel Blockers or 5-hydroxy-3-methylglutaryl-coenzyme A 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) on an unstable dose 4 weeks prior to the Screening Visit (to be eligible subjects must not have changed their dose <4 weeks prior to the screening visit)
- •Subject has not enrolled in an exercise training program for cardiopulmonary rehabilitation within 12 weeks prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 16 weeks of the study. Subjects enrolled in an exercise program for pulmonary rehabilitation 12 weeks prior to screening may enter the study if they agree to maintain their current level of rehabilitation for the first 16 weeks of the study.
- •Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) > 3x Upper limit of normal (ULN)
- •Bilirubin > 1.5xULN (>35% direct bilirubin)
- •Subject has severe renal impairment [estimated creatinine clearance <30 millilitre/minute (mL/min)] at the Screening Visit
- •Subject has moderate - severe hepatic impairment (Child-Pugh class B-C with or without cirrhosis) at the Screening Visit
- •Subject has clinically significant anaemia: Hemoglobin (Hb) < 10 grams/decilitre (g/dL)
- •Subjects with bleeding disorders or significant active peptic ulceration in the opinion of the investigator
- •Subject has uncontrolled hypertension (>180/110 mmHg) at screening
- •Subject has severe hypotension (<90/50 mmHg) at screening
- •Subject has had an acute myocardial infarction within the last 90 days prior to screening
- •Subject has, in the opinion of the investigator, clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction (ejection fraction <50% of normal); left ventricular outflow obstruction; symptomatic coronary artery disease; autonomic hypotension; fluid depletion.
- •Subject with significant pulmonary disease Forced expiratory volume in 1 second (FEV1) <70% of predicted): Chronic obstructive pulmonary disease (COPD), Emphysema, evidence of fibrotic lung disease on imaging
- •Subject has clinically significant fluid retention in the opinion of the investigator
- •Subject with significant obesity [Body mass index (BMI) ≥35], cardiovascular, musculoskeletal or any other condition that in the opinion of the investigator may involve an impairment of exercise capacity or the performance of the 6MWD test (e.g. previous history of hip/knee surgery, lower limb ulcers associated with autoimmune diseases)
- •Subject with cardiovascular, liver, renal, haematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the investigational product or severely limit the lifespan of the subject other than the condition being studied
- •Subjects with a prior malignancy whose cancer is expected to require additional active treatment in the next 2 years and whose prior malignancy would prevent them from fully participating in the study
- •Female subject who is pregnant or breastfeeding
- •Subject has demonstrated noncompliance with previous medical regimens
- •Subject has a recent (within 1 year) history of abusing alcohol or illicit drugs
- •Subject has participated in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit.
研究组 & 干预措施
Ambrisentan
Experimental
Subjects in this arm will receive ambrisentan 5 mg tablet once daily during the treatment period.
干预措施: Ambrisentan 5 mg (Drug)
Placebo
Placebo Comparator
Subjects in this arm will receive ambrisentan-matching placebo tablet once daily during the treatment period.
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16
时间窗: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal
The 6-minute walk test was conducted according to the American Thoracic Society guidelines in accordance with local standard operating procedures. 6MWD was measured by a 6-minute walk test. This test measures the distance that a participant can walk in a period of 6 minutes. Change from baseline was calculated at Weeks 4, 8, 12 and 16. Change from Baseline was calculated as value at the specified visit minus the Baseline value. Data at Baseline is based on average of two consecutive test results during Screening/Baseline period that differ by \<10%. If only one measurement was available, that measurement was used. In any cases where the protocol-defined criteria for Baseline 6MWD was not met, the Baseline value was based on the last two consecutive measurements for a participant.
次要结局
- Change From Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal(Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal)
- Change From Baseline in Mean Right Atrial Pressure (mRAP) and Mean Pulmonary Artery Pressure (mPAP) at Week 16(Baseline (Week 0) and Week 16)
- Change From Baseline in Cardiac Index at Week 16(Baseline (Week 0) and Week 16)
- Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)(From the start of study treatment and until follow up (Week 16/Follow up))
- Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal(Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal)
- Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16(Baseline (Week 0) and Week 16)
- Change From Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal(Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal)
- Number of Participants With Clinical Worsening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)(From randomization to Week 16/Follow up visit (21 weeks))
- Change From Baseline in Quality of Life as Measured by Short Form 36 Health Survey (SF-36)(Baseline and up to Week 16/Early Withdrawal)
- Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)(Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal)
- Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal(Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal)
- Number of Participants With Significant Liver Events at Weeks 4, 8, 12, and 16/Early Withdrawal(Weeks 4, 8, 12, and 16/Early Withdrawal)
- Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal(Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal)
- Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal(Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal)
- Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline(Baseline (Week 0), Weeks 4, 8, 12 and 16/early withdrawal,)
- Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline(Baseline (Week 0), Weeks 4, 8, 12 and 16/early withdrawal)
- Number of Participants With Testicular Function (Males Only) of Potential Clinical Concern Any Time Post Baseline(Baseline, Weeks 4 and 16/early withdrawal)
研究者
研究点 (1)
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