A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-Controlled, Adaptive Design Study to Evaluate the Efficacy and Safety of MK-5475 in Adults With Pulmonary Arterial Hypertension
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 168
- 试验地点
- 91
- 主要终点
- Phase 2 Cohort: Mean Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks
研究概览
简要总结
This is a two-part (Phase 2/Phase 3) study of frespaciguat, an inhaled soluble guanylate cyclase stimulator, in participants with pulmonary arterial hypertension (PAH).
The first part (Phase 2) will assess three different doses of frespaciguat compared to placebo in a base period of 12 weeks, followed by comparison of three different doses of frespaciguat during an optional 40 month extension period. The treatment dose with the best efficacy and safety profile in the phase 2 cohort base period will be selected for use in the second part (Phase 3) of the study. The primary hypothesis of Phase 2 is that at least one frespaciguat dose is superior to placebo in reducing pulmonary vascular resistance (PVR) from baseline at week 12.
The purpose of the second part (Phase 3) of the study is to confirm the efficacy, safety, and tolerability of frespaciguat at the selected dose compared to placebo during a 12 week base period followed by an extension period of up to 5 years. The primary hypothesis of Phase 3 is that frespaciguat is superior to placebo in increasing 6-minute walk distance (6MWD) from baseline at week 12. Due to sponsor's decision this phase/part was not conducted.
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
- Triple (Participant, Investigator, Outcomes Assessor)
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
- •Pulmonary arterial hypertension (PAH) in one of the following groups:
- •Idiopathic PAH
- •Heritable PAH
- •Drug and toxin-induced PAH
- •PAH associated with connective tissue disease, HIV infection, or congenital heart disease.
- •Diagnosis of PAH documented by right heart catheterization (RHC).
- •Eligibility RHC meeting all of the following criteria:
- •Mean pulmonary artery pressure (mPAP) ≥25 mmHg
- •Pulmonary vascular resistance (PVR) of ≥3 Wood units
- •Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤15 mmHg.
- •World Health Organization functional class (WHO-FC) symptoms between Class II and IV.
- •Two 6-Minute walk distance (6MWD) measurements between 150 and 500 meters, one at screening and one at randomization.
- •Stable concomitant background PAH-specific therapy.
- •Body Mass Index (BMI) between 18.5 kg/m² and 40 kg/m² .
- •Agree to be abstinent from heterosexual intercourse or use contraception during the intervention period and for at least 14 days after the last dose of study intervention.
- •Female participants may not be pregnant or breastfeeding.
排除标准
- •Group 2 to 5 pulmonary hypertension.
- •PAH in one of the following groups:
- •Long term responders to calcium channel blockers
- •Overt features of venous/capillary involvement
- •Evidence of more-than-mild obstructive lung disease.
- •Evidence of more-than-mild parenchymal lung disease.
- •Evidence of more-than-mild obstructive sleep apnea (OSA) that is untreated.
- •Evidence or history of left heart disease, including any of the following:
- •Left ventricular ejection fraction (LVEF) ≤45%
- •Moderate or severe left-sided valvular disease (aortic or mitral valve stenosis or regurgitation)
- •Significant left ventricular diastolic dysfunction on echocardiographic evaluation
- •Presence of 3 or more of the following risk factors for heart failure with preserved ejection fraction: BMI>30 kg/m², essential systemic hypertension, diabetes mellitus of any type, or coronary artery disease.
- •Oxygen saturation measured by pulse oximetry (SpO₂) <90%, despite supplemental oxygen therapy.
- •Chronic renal insufficiency (eGFR <30 mL/min)
- •Chronic liver disease (i.e., Child-Pugh B or C), portal hypertension, cirrhosis, or significant hepatic laboratory abnormalities.
- •Current smoker or currently uses electronic cigarettes (vapes).
- •History of cancer, except: nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated, with appropriate follow up, and unlikely to recur for the duration of the study.
研究组 & 干预措施
Phase 2 Cohort Frespaciguat 380 µg
Participants receive frespaciguat 380 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period.
干预措施: Frespaciguat (Drug)
Phase 2 Cohort Frespaciguat 100 µg
Participants receive frespaciguat 100 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period.
干预措施: Frespaciguat (Drug)
Phase 2 Cohort Frespaciguat 32 µg
Participants receive frespaciguat 32 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period.
干预措施: Frespaciguat (Drug)
Phase 2 Cohort Placebo
Participants receive placebo via oral inhalation once daily for 12 week base period, and one of the MK-5475 doses (380, 100, or 32 µg) for the optional 40 month extension period.
干预措施: Placebo to Frespaciguat (Drug)
Phase 3 Cohort Frespaciguat
Participants receive one of 3 frespaciguat doses (380, 100 or 32 µg) to be selected at end of the Phase 2 Cohort, administered via oral inhalation once daily for 12-week base period and up to 40 months in the extension period
干预措施: Frespaciguat (Drug)
Phase 3 Cohort Placebo
Participants receive placebo via oral inhalation once daily for 12 week base period and up to 40 months in the extension period.
干预措施: Placebo to Frespaciguat (Drug)
结局指标
主要结局
Phase 2 Cohort: Mean Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks
时间窗: At baseline and 12 weeks
PVR was calculated in participants after MK-5475 dosing at baseline and Week 12. PVR is assessed by right heart catheterization (RHC). Based on the variables obtained by right heart catheterization (RHC), the percentage change from baseline PVR was calculated. Per protocol, this outcome measure was assessed only for base period and was not assessed during extension period.
Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
时间窗: At baseline and 12 weeks
6MWD is measured by an exercise test known as 6-Minute Walk Test (6MWT) that assesses functional capacity. It measures the distance covered over a time of 6 minutes and is intended to be used as an outcome measure by which to compare changes in excercise capacity. Each participant's 6MWD is to be measured at baseline and at 12 weeks. An increase in the distance walked during the 6MWT indicates improvement in functional exercise capacity.
次要结局
- Phase 2 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks(At baseline and 12 weeks)
- Phase 2 Cohort: Mean Change From Baseline in Mean Right Atrial Pressure (mRAP) at 12 Weeks(At baseline and 12 weeks)
- Phase 2 Cohort: Mean Change From Baseline in Cardiac Index (CI) at 12 Weeks(At baseline and 12 weeks)
- Phase 2 Cohort: Mean Change From Baseline in Stroke Volume Index (SVI) at 12 Weeks(At baseline and 12 weeks)
- Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks(At baseline and 24 weeks)
- Phase 3 Cohort: Proportion of Participants Whose World Health Organization Functional Class (WHO-FC) is Not Worse at 12 Week Relative to Baseline(At baseline and 12 weeks)
- Phase 2 Cohort: Number of Participants Who Experienced an Adverse Event(Up to approximately 2.25 years)
- Phase 2 Cohort: Number of Participants Who Discontinued Study Drug Due to an Adverse Event(Up to approximately 2.25 years)
- Phase 3 Cohort: Number of Participants Who Experienced an Adverse Event(Up to approximately 2.25 years)
- Phase 3 Cohort: Number of Participants Who Discontinued Study Drug Due to an AE(Up to approximately 2.25 years)