The Safety, Tolerability, and Pharmacokinetics of TPN171H Tablets in Patients With Pulmonary Arterial Hypertension

Phase Ib Clinical Study on the Safety, Tolerability, and Pharmacokinetics of TPN171H Tablets in the Treatment of Pulmonary Arterial Hypertension (PAH) Patients

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: TPN171H

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai, China
    • Fu Zhu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients who are able to signed the informed consent form ,understand and follow study plans and instructions;
2. Patients aged 18 to 75;
3. 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 ;
4. Patients have a current diagnosis of being in WHO functional class II or III;
5. 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.

Exclusion Criteria:

1. All types of PH except subtypes of Group1 specified in the inclusion criteria;
2. Patients who concomitant severe obstructive pulmonary disease(FEV1/FVC<0.5) ;
3. Total lung volume<60% predicted;
4. Systolic blood pressure below 90/60mmHg at screening;
5. Left ventricular ejection fraction less than 45%, left ventricular short axis shortening rate less than 0.2;
6. Lower limb diseases that affect the completion of 6-MWD testing;
7. Subjects who received PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil, and avanafil) within 4 weeks before baseline
8. 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)
9. Subjects with a clear history of allergic diseases or who have previously stopped taking either aniracetam or tadalafil due to safety or tolerable reasons;
10. 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;
11. 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);
12. Have a history of ophthalmic diseases, such as color vision abnormalities, retinitis pigmentosa, and macular degeneration;
13. Malignant tumor patients;
14. 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;
15. Pathogenic test for HIV positive; Positive test for hepatitis B or hepatitis C; Subjects suffering from acute infectious diseases;
16. Suffered from infectious diseases recently (within 1 month);
17. The subject has ischemic heart disease (defined as symptomatic, requiring anti angina treatment, or having experienced myocardial infarction within the past 3 years);
18. Those who have experienced cerebrovascular events (such as transient ischemic attacks or strokes) within the past 3 months;
19. Participated in any clinical trial within 3 months prior to taking the investigational drug;
20. Pregnant or lactating women;
21. The researchers believe that subjects who are not suitable to participate in this experiment due to other reasons.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: TPN171H; TPN171H 2.5mg TPN171H 5mg TPN171H 10mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of Treatment-Emergent Adverse Events	through study completion, an average of 2 years
Q-T interval	through study completion, an average of 2 years
Tmax	From time zero up to 24 hours post-dose following oral administration of TPN171H
Cmax	From time zero up to 24 hours post-dose following oral administration of TPN171H
AUC0~t	From time zero up to 24 hours post-dose following oral administration of TPN171H
AUC0-∞	From time zero up to 24 hours post-dose following oral administration of TPN171H
Terminal half-life (t 1/2)	From time zero up to 24 hours post-dose following oral administration of TPN171H
Apparent distribution volume (Vd/F)	From time zero up to 24 hours post-dose following oral administration of TPN171H
Clearance rate (CL/F)	From time zero up to 24 hours post-dose following oral administration of TPN171H
Mean Residence Time(MRT)	From time zero up to 24 hours post-dose following oral administration of TPN171H

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6- Minute Walk Distance（6-MWD）	Cardiopulmonary function indicators reflecting the patient's physiological state	through study completion, an average of 2 years
NT-proBNP	Heart failure evaluation indicators to evaluate the severity of heart failure;	through study completion, an average of 2 years
The World Health Organization (WHO) functional class	Evaluate the severity of Pulmonary Arterial Hypertension symptoms at each time point before and after taking TPN171H	through study completion, an average of 2 years
Borg dyspnea index	to evaluate the degree of difficulty breathing in subjects after a 6-minute walk test	through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: Vigonvita Life Sciences
• Collaborators: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
• Investigators: Principal Investigator: Fu Zhu, Shanghai Xuhui Central Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2019
• Primary Completion (Actual): October 14, 2020
• Study Completion (Actual): October 14, 2020

Study Registration Dates

• First Submitted: June 21, 2023
• First Submitted That Met QC Criteria: July 6, 2023
• First Posted (Actual): July 17, 2023

Study Record Updates

• Last Update Posted (Actual): October 13, 2023
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: TPN171H-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No