Acute Haemodynamic Study of TPN171H in Patients With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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This study is a phase IIa proof-of-concept study to evaluate the effect of single-dose TPN171H tablets on acute haemodynamic parameters in patients with pulmonary arterial hypertension.The trial is expected to include 60 patients, divided into 6 groups, according to 1:1:1:1:1:1 into the placebo group and the test drugs 2.5mg, 5mg, 10mg group, tadalafil tablets 20mg, 40mg group, each group 10 cases.

Detailed Description
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This study is a multi-center, randomized, placebo and positive controlled phase IIa proof-of-concept study to evaluate the effect of single-dose TPN171H tablets on acute hemodynamic parameters in patients with pulmonary arterial hypertension.The trial is expected to include 60 patients, divided into 6 groups, according to 1:1:1:1:1:1 into the placebo group and the test drugs 2.5mg, 5mg, 10mg group, tadalafil tablets 20mg, 40mg group, each group 10 cases. During the screening period, the tube placement period, and the observation period, the patients will conduct various inspections and evaluation observations as required. The Swan-Ganz floating catheter and echocardiography were used to evaluate the efficacy of TPN171H; PK parameters: including Tmax, Cmax, AUC0-t , t1/2,CL/F, Vz/F, λz; Safety evaluation indicators include: vital signs, physical examination, laboratory examination (blood routine, blood biochemistry, blood gas analysis), 12-lead ECG, adverse events.

Official Title
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Multi-center, Randomized，Placebo and Positive Controlled Clinical Study of TPN171H Tablets on Acute Haemodynamics in Patients With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: TPN171H
* Drug: Placebo
* Drug: Tadalafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18 to 75; Patients who have voluntarily decided to participate in this study, and signed the informed consent form; Patients who are able to understand and follow study plans and instructions; Patients with symtomatic PAH (Group1), a pulmonary vascular resistance (PVR) > 3 Wood, a mean pulmonary artery pressure (mPVP) ≥25 mmHg and a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg either due to: Idiopathic PAH (IPAH) Familial PAH Associated PAH due to drugs or toxins Associated PAH due to connective tissue disease Associated PAH due to congenital heart disease, if patients underwent surgical correction more than 1 year prior to screening Have a current diagnosis of being in WHO functional class II or III; Patients who are willing to take proper contraceptive during the study and within 3 months after the study completed. Exclusion Criteria: All types of PH except subtypes of Group1 specified in the inclusion criteria; Moderate to severe COPD (FEV1 < 60% predicted); Moderate to severe restrictive lung disease (FVC < 70% predicted); Pre-treatment with PAH therapy within the last 1 months before the screening visit (including endothelin receptor antagonists, PDE5 inhibitors, guanylate cyclase agonist and prostacycline analogues); A positive response to acute vasodilator testing; Coagulation dysfunction (defined as activated partial thromboplastin time and international normalized ratio are both >1.5 times upper limit normal) or patients with potential bleeding risk; Hepatic dysfunction indicated by: serum bilirubin>3 times upper limit normal, ALT and AST>2.5 times upper limit normal; Renal insufficiency (creatinine clearance<30 mL/min)； Systolic blood pressure<90 mmHg at screening; QT prolongation at screening, whose values (QTcF) exceeding 450 msec in males and 470 msec in females; Have enrolled in/or have a plan of an exercise training program for pulmonary rehabilitation before the screening visit/or during the study; Patients who have a recent (within 3 months) history of abusing alcohol or illicit drugs; Body weight<40 kg； Patients who have participated in a clinical study involving another investigational drug within 1 month before the screening visit; For any other reasons that affect compliance with the study protocol, especially the long-term monitoring of floating catheters, according to the decision of investigators; HBV, HCV, HIV or Tp infection; Patients with gastrointestinal, urinary, reproductive, immunologic, endocrine, or central nervous system disease that, in the opinion of the investigator, will affect the study; Have a history of malignancies within 2 years, except for a cured basal cell or skin squamous cell carcinoma; Pregnant women, or breast feeding women; Patients with hypersensitivity to iloprost or any of the excipients.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPN171H 2.5mg group<br>TPN171H 2.5mg tablet + Placebo 10mg tablet | Drug: TPN171H<br>* Tablets; Oral; Single dose<br>* Other names: Simmerafil;|
| Experimental: TPN171H 5mg group<br>TPN171H 5mg tablet + Placebo 10mg tablet | Drug: TPN171H<br>* Tablets; Oral; Single dose<br>* Other names: Simmerafil;|
| Experimental: TPN171H 10mg group<br>TPN171H 10mg tablet + Placebo 5mg tablet | Drug: TPN171H<br>* Tablets; Oral; Single dose<br>* Other names: Simmerafil;|
| Placebo Comparator: Placebo group<br>Placebo 5mg tablet+ Placebo 10mg tablet | Drug: Placebo<br>* Tablets; Oral; Single dose<br>|
| Active Comparator: tadalafil 20mg group<br>tadalafil tablet 20mg | Drug: Tadalafil<br>* Tablets; Oral; Single dose<br>* Other names: ADCIRCA;|
| Active Comparator: tadalafil 40mg group<br>tadalafil tablets 20mg *2 | Drug: Tadalafil<br>* Tablets; Oral; Single dose<br>* Other names: ADCIRCA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of the maximum change in pulmonary vascular resistance(PVR) to the second baseline |  | Within 24 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of maximum change in PVR |  | Within 24 hours after drug administration | 
| The area under the curve for reduction in PVR |  | Within 24 hours after drug administration | 
| Change in arterial oxygenation |  | Within 24 hours after drug administration | 
| Change in right ventricular function |  | Within 24 hours after drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary arterial hypertension, Acute Haemodynamic Study, TPN171H, Simmerafil, PK/PD study