Study of Efficacy and Safety of LTP001 in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to explore the efficacy and safety of LTP001 in participants with pulmonary arterial hypertension (PAH) to determine if LTP001 has an adequate clinical profile to warrant further clinical development in this indication.

Detailed Description
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This is a non-confirmatory, randomized, subject- and investigator-blinded, placebo controlled study of LTP001 in PAH participants. Approximately 44 male and female adults with PAH participants will be randomized in a 3:1 ratio of LTP001 active dose to placebo. Participants will be screened for up to 8 weeks followed by 24 weeks of daily dosing with visits approximately every 4 weeks. One follow up visit will also be the end of study visit and occurs approximately 30 days after the end of treatment. Total study duration is approximately 37 weeks from start of screening to end of study visit. If a participant continues into the open-label extension study, then the follow-up visit may be skipped.

Official Title
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A Randomized, Participant- and Investigator-blinded, Placebo-controlled Study to Investigate Efficacy, Safety, and Tolerability of LTP001 in Participants With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: LTP001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of PAH belonging to one of the following subgroups of the Clinical Classification Group 1 (WHO): participants with idiopathic pulmonary arterial hypertension (IPAH) Hereditary pulmonary arterial hypertension Congenital heart disease (surgically repaired at least 12 months prior to screening) drug or toxin induced (for example, anorexigen, or methamphetamine use). Resting mean pulmonary arterial pressure (mPAP) > 25 mmHg; pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure < 15 mmHg, as determined by right heart catheterization within 20 days of randomization. Pulmonary Vascular Resistance > 6 Wood units (480 dynes s/cm-5), as determined by right heart catheterization within 20 days of randomization. WHO Functional Class II-III 6MWD must be between 150 and 550 m (inclusive). The qualifying test needs to be within 20 days of randomization. To meet the above criterion additional six minute walk test (6MWT) may be performed up to a maximum of 3 tests in total prior to dosing; the minimal time difference between two tests should be at least 4 h. Standard of care therapy which is stable at least 6 weeks prior to RHC and qualifying 6MWT assessment within 20 days of randomization. Standard of care includes one or more of the following treatments: prostacyclin analogues and receptor agonists (if I.V., dose adjustments must be within 20% of initial stable dose) endothelin receptor antagonists (ERAs) phosphodiesterase type 5 inhibitors (PDE5i) soluble guanylate cyclase (sGC) stimulators Exclusion Criteria: Participants with pulmonary hypertension (PH) in the Clinical Classification Groups 2-5 (WHO), and any PAH Group 1 subgroups not covered by Inclusion Criterion #4. Participants with a history of left sided heart disease, chronic left sided heart failure, congenital or acquired valvular disease compromising left ventricular function and/or pulmonary venous hypertension or symptomatic coronary disease (non-symptomatic, revascularized coronary artery disease would be acceptable). Participants with obstructive lung disease defined as: FEV1/FVC < 60% and FEV1 < 60% of predicted value after bronchodilator administration as well as participants with moderate or severe restrictive lung disease: Total Lung Capacity < 70% of predicted value. Testing must have occurred within 24months of screening. If historical testing is not available, then lung function testing must be conducted during the screening period. Acute or chronic impairment (other than dyspnea), which would limit the ability to comply with study requirements, including interference with physical activity and execution of study procedures such as 6MWT (e.g., angina pectoris, claudication, musculoskeletal disorder, multiple sclerosis, need for walking aids). Additional protocol-defined inclusion / exclusion criteria may apply.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LTP001<br>Participants will receive LTP001 orally once daily in the morning for approximately 24 weeks | Drug: LTP001<br>* LTP001 will be administered orally once daily in the morning<br>|
| Placebo Comparator: Placebo<br>Participants will receive LTP001 placebo capsules matching LTP001 orally once daily in the morning for approximately 24 weeks | Drug: Placebo<br>* Placebo to LTP001 will be administered once daily in the morning<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline right heard catheterization Pulmonary vascular resistance (PVR) at week 25 | PVR defined as the resistance against blood flow from the pulmonary artery to the left atrium measured in dyn.s.cm-5 | Baseline, week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Six Minute Walk Distance (6MWD) | 6MWD test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes | Baseline, weeks 13 and 25 | 
| Change from baseline in Right Ventricle (RV) pressures at week 25 | The Right Heart Catheterization (RHC) assessment is performed to assess several hemodynamic variables in pulmonary hypertension, including RV pressures. | Baseline, Week 25 | 
| Change from baseline in pulmonary capillary wedge pressure at week 25 | The Right Heart Catheterization (RHC) assessment is performed to assess several hemodynamic variables in pulmonary hypertension, including pulmonary capillary wedge pressure (PCWP). | Baseline, Week 25 | 
| Change from baseline in pulmonary artery pressures at week 25 | The Right Heart Catheterization (RHC) assessment is performed to assess several hemodynamic variables in pulmonary hypertension, including pulmonary artery pressure. | Baseline, Week 25 | 
| Change from baseline in Cardiac Output (CO) at week 25 | The Right Heart Catheterization (RHC) assessment was performed to assess several hemodynamic variables in pulmonary hypertension, including Cardiac Output (CO). | Week 25 | 
| Change from baseline in tricuspid annular plane systolic excursion (TAPSE) | Key Right Ventricular (RV) function endpoints such as Tricuspid Annular Plane Sys Excursion (TAPSE) are to be assessed with echocardiography. | Baseline, weeks 5, 13 and 25 | 
| Change from baseline in tricuspid annular systolic velocity (TASV) | Key Right Ventricular (RV) function endpoints such as tricuspid annular systolic velocity (TASV) are to be assessed with echocardiography. | Baseline, weeks 5, 13 and 25 | 
| Change from baseline of peak velocity of excursion (RV S') | Key Right Ventricular (RV) function endpoints such as peak velocity of excursion (RV S') are to be assessed with echocardiography. | Baseline, weeks 5, 13 and 25 | 
| Change from baseline in fractional area change (FAC) | Key Right Ventricular (RV) function endpoints such as RV fractional area change (RV FAC) are to be assessed with echocardiography. | Baseline, weeks 5, 13 and 25 | 
| Change from baseline in EmPHasis-10 | emPHasis-10 is a questionnaire with 10 questions and is designed to determine how pulmonary hypertension affects a participant's life. | Baseline, weeks 13 and 25 | 
| Change from baseline in PAH-SYMPACT | PAH-SYMPACT is a questionnaire used to assess pulmonary arterial hypertension symptoms and their impact. | Baseline, weeks 13 and 25 | 
| Maximum Observed Blood Concentrations (Cmax) for LTP001 | The maximum (peak) observed blood drug concentration after single dose administration (ng x mL-1) | Weeks 1 and 25 | 
| Time to Reach Maximum Blood Concentrations (Tmax) of LTP001 | The time to reach maximum (peak) blood drug concentration after single dose administration (h) | Weeks 1 and 25 | 
| Time to Clinical Worsening | Time to any of the following: Death Hospital stay greater than 24 hours due to worsening of pulmonary arterial hypertension Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy Initiation of parenteral prostanoid therapy, initiation of oxygen therapy, initiation of any other pulmonary arterial hypertension-specific therapies or need for increase of diuretics for more than 4 weeks due to worsening of pulmonary arterial hypertension Disease progression Significant drop in six minute walk distance | Baseline to Week 29 | 
| Change from baseline in N-terminal fragment of the prohormone B-type natriuetic peptide (NT-ProBNP) | NT-proBNP is a blood biomarker to assess right ventricular distress. | Baseline to Week 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Hypertension