Efficacy and Safety of Qishen Yiqi Dropping Pills in Patients With Severe Pulmonary Hypertension

A single-center, parallel, randomized, controlled trial will be conducted to evaluate the efficacy and safety of Qishen Yiqi Dropping Pills combined with western medicine therapy compared with western medicine therapy alone in Asian patients with pulmonary hypertension. A total of 120 pulmonary hypertension patients aged 18-75 years will be recruited into the study in Guangdong Provincial People's Hospital. After a screening period of no more than 2 weeks, patients will be randomly assigned to the Qishen Yiqi Dropping Pills 0.5g three times daily plus targeted drug therapy group or the targeted drug therapy alone group in a 1:1 ratio. All patients in both groups will receive treatment for 52 weeks, and participants will be followed for 26 weeks after the end of treatment. The primary outcomes are the changes in patients' quality of life score, 6-minute walk distance, and Borg score.

Inclusion criteria

• 1. Male or female participants aged between 18 and 75 years (inclusive) at the screening visit.

• Diagnosed with pulmonary arterial hypertension (PAH) classified according to the *2021 Chinese Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension*, and belonging to one of the following subgroups:
• Subgroup Ⅰ: Idiopathic pulmonary arterial hypertension (IPAH) under the category of arterial pulmonary hypertension
• Subgroup Ⅱ: Pulmonary hypertension secondary to left heart disease (congenital heart disease) 3. World Health Organization (WHO) Functional Class III or IV symptoms at screening.

• Meet all of the following hemodynamic criteria confirmed by right heart catheterization (RHC) at study screening: mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg.

• Able to walk a minimum of 100 meters and a maximum of 440 meters during the 6-Minute Walk Test (6MWT) at the screening visit; in addition, participants must demonstrate stable baseline 6MWT performance between the screening visit and the randomization visit.

• Participants with pulmonary hypertension who are either treatment-naïve or currently receiving treatment: for participants who have received prior treatment (defined as having used PAH-targeted therapeutic agents within 4 weeks before screening), mPAP ≥ 25 mmHg and PCWP ≤ 15 mmHg must be confirmed at the randomization visit.

• Able to understand study procedures, willing to comply with study restrictions, and willing and able to provide written informed consent prior to the initiation of all study-related procedures.

Exclusion criteria

• 1. Meet any of the following criteria: 2. Diagnosed with Group 3 or Group 5 pulmonary hypertension (PH) according to the *2021 Chinese Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension*.

• Echocardiogram within 6 months before screening indicates left ventricular ejection fraction (LVEF) ≤ 40%, or clinically significant ischemic mitral or aortic valve disease, or constrictive heart disease as judged by the investigator.

• Presence of 3 or more of the following risk factors for left ventricular dysfunction:
• Body mass index (BMI) ≥ 30 kg/m² at screening visit
• History of essential hypertension
• Diabetes mellitus of any type
• History of significant coronary artery disease (CAD) confirmed by any of the following:
• History of myocardial infarction
• History of percutaneous coronary intervention (PCI)
• Angiographic evidence of ≥ 50% stenosis in at least one major coronary artery
• Positive cardiac stress imaging test
• History of coronary artery bypass graft surgery (CABG)
• History of chronic stable angina or unstable angina 5. Uncontrolled systemic arterial hypertension: systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg at randomization visit (Day 1).

• History of long QT syndrome or torsades de pointes ventricular tachycardia. 7. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal (ULN) at screening visit.

• Severe renal impairment: estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² at screening calculated by the CKD-EPI formula.

• Severe hepatic impairment (Child-Pugh Class C) at screening visit, with or without cirrhosis; patients receiving renal dialysis or with a history of renal transplantation.

• Known coagulation defects, including: hereditary or acquired coagulation disorders (factor XII deficiency, factor XIII deficiency), reduced coagulation factor production due to acute or chronic liver disease, impaired coagulation efficiency caused by lupus anticoagulant, disseminated intravascular coagulation (DIC), or anticoagulant factor autoantibodies.

• Evidence or history of major hemorrhage or intracranial hemorrhage. 12. History of increased intracranial pressure. 13. Pregnant or lactating women. 14. Any surgical or medical condition that may significantly alter the absorption, distribution, metabolism, or excretion of any drug, including but not limited to: history of major gastrointestinal surgery deemed clinically significant by the investigator within 12 months before screening (e.g., gastrectomy, gastrointestinal stoma anastomosis, intestinal resection, gastric bypass surgery, gastroenterostomy, or gastric banding), current active inflammatory bowel disease, or history of active inflammatory bowel disease.

• Any surgical or medical condition not specified in the protocol that, in the investigator's opinion, would expose the patient to higher risk due to study participation, or may prevent the patient from complying with study requirements or completing the trial period.

• Patients who are unwilling or unable to safely discontinue current pulmonary arterial hypertension (PAH)-targeted medications during the study as required by the protocol.

• History of any contraindication or hypersensitivity reaction to any study drug or drugs with similar chemical structures.

• History of active substance abuse (including alcohol) within the past 1 year, or patients considered potentially unreliable by the investigator.

• Personnel directly involved in the conduct of this clinical study.