Extension Study of Efficacy and Safety of LTP001 in Pulmonary Arterial Hypertension Participants

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to measure the long-term safety and efficacy profile of LTP001 in participants with pulmonary arterial hypertension (PAH). The study offers participants who had completed the CLTP001A12201 double-blind parent study in PAH an opportunity to receive LTP001 (whether they were on LTP001 or not). Unblinding of the treatment received in CLTP001A12201 is generally not needed, but can occur on request by the investigator.

Detailed Description
-----------------
This is a non-randomized, open-label extension study of LTP001 for participants with PAH who complete the parent study CLTP001A12201. Eligible participants will be presented with the opportunity to enroll in the extension study at the end of treatment visit of the parent study. Participants in the extension study will receive a once daily dose of LTP001 for 52 weeks regardless of their parent study treatment (i.e. LTP001 or placebo). Visits to assess the safety, tolerability and efficacy of LTP001 will take place at Weeks 5, 13, 26, 39 and 52, including a right heart catheterization at Week 26 and a 6-minute walk test and echocardiography at Weeks 26 and 52. At Week 56, approximately 30 days after the treatment period, participants will have one safety follow-up phone call. The safety and efficacy profile of LTP001 observed in this extension study as well as the parent study will determine the continuation of the extension study.

Official Title
-----------------
An Open-label Extension Study to Investigate Efficacy, Safety and Tolerability of LTP001 in Participants With Pulmonary Arterial Hypertension

Conditions
-----------------
Pulmonary Arterial Hypertension

Intervention / Treatment
-----------------
* Drug: LTP001


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. Participant is currently completing the Novartis-sponsored study CLTP001A12201 in PAH and completed key efficacy and safety procedures up to the end of treatment of the core study, without meeting discontinuation criteria in the core study. Willingness and ability to comply with scheduled visits, treatment plans and any other study procedures. Participant currently has no evidence of treatment failure, as determined by the investigator, following previous treatment. In the opinion of the Investigator would benefit from LTP001 treatment. Exclusion Criteria: History of hypersensitivity to the study treatment. Sexually active males not committing to condom use precautions: sexually active males must use a condom during intercourse while taking drug and for 24 hours after stopping study medication and should not father a child in this period nor donate sperm. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Required or planned transplant or heart/lung surgery. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and until EOT visit (2 weeks post-last treatment). Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant Use of oral, estrogen and progesterone, injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms). Women are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy) or total hysterectomy at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. Acute or chronic impairment (other than dyspnea), which would limit the ability to comply with study requirements, including interference with physical activity or execution of study procedures such as 6MWT (e.g., angina pectoris, claudication, musculoskeletal disorder, need for walking aids). Permanent discontinuation of Novartis drug in the core efficacy study due to toxicity or disease progression despite active treatment, non-compliance to study procedures, withdrawal of consent or any other reason.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LTP001<br>Participants will receive LTP001 orally once daily in the morning for approximately 52 weeks | Drug: LTP001<br>* LTP001 will be administered orally once daily in the morning<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with AEs and SAEs | Long term safety follow up. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline right heart catheterization Pulmonary vascular resistance (PVR) at week 26 | PVR defined as the resistance against blood flow from the pulmonary artery to the left atrium measured in dyn·s/cm-5 | Baseline, week 26 | 
| Change from baseline in Right Atrium (RA) pressures at week 26 | The Right Heart Catheterization (RHC) assessment is performed to assess several hemodynamic variables in pulmonary hypertension, including RA pressures | Baseline, week 26 | 
| Change from baseline in mean PosteroAnterior (PA) pressure at week 26 | The Right Heart Catheterization (RHC) assessment is performed to assess several hemodynamic variables in pulmonary hypertension, including PA pressure | Baseline, week 26 | 
| Change from baseline in Pulmonary Capillary Wedge Pressure (PCWP) at week 26 | The Right Heart Catheterization (RHC) assessment is performed to assess several hemodynamic variables in pulmonary hypertension, including PCWP | Baseline, week 26 | 
| Change from baseline in Cardiac Output (CO) pressures at week 26 | The Right Heart Catheterization (RHC) assessment is performed to assess several hemodynamic variables in pulmonary hypertension, including CO | Baseline, week 26 | 
| Change from baseline in Systemic Vascular Resistance (SVR) at week 26 | The Right Heart Catheterization (RHC) assessment is performed to assess several hemodynamic variables in pulmonary hypertension, including SVR | Baseline, week 26 | 
| Change from baseline in Six Minute Walk Distance (6MWD) | 6MWD test measures the distance that a participant can quickly walk on a flat, hard surface in a period of 6 minutes | Baseline, week 26, week 52 | 
| Change from baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) | Key Right Ventricular endpoints such as TAPSE are to be assessed with electrocardiography | Baseline, week 26, week 52 | 
| Change from baseline in Tricuspid Annular Plane Systolic Velocity (TASV) | Key Right Ventricular (RV) function endpoints such as TASV are to be assessed with electrocardiography | Baseline, week 26, week 52 | 
| Change from baseline in Peak Velocity of Excursion (RV S') pressures | Key Right Ventricular (RV) function endpoints such as RV S' are to be assessed with electrocardiography | Baseline, week 26, week 52 | 
| Change from baseline in Fractional Area Change (FAC) pressures | Key Right Ventricular (RV) function endpoints such FAC are to be assessed with electrocardiography | Baseline, week 26, week 52 | 
| Change from baseline in Quality of Life measured by emPHasis-10 questionnaire | emPHasis-10 is a questionnaire with 10 questions and is designed to determine how pulmonary hypertension affects a participant's life | Baseline to Week 52 | 
| Change from baseline in Quality of Life measured by PAH-SYMPACT questionnaire | PAH-SYMPACT is a questionnaire used to assess pulmonary arterial hypertension symptoms and their impact | Baseline to Week 52 | 
| Time to Clinical Worsening | Time to any of the following: Death Hospital stay greater than 24 hours due to worsening of PAH. Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy Initiation of parenteral prostanoid therapy, chronic oxygen therapy, or any other PAH-specific therapies or need for increase of diuretics for more than 4 weeks due to worsening of PAH Disease progression Significant drop in 6MWD | Baseline to Week 52 | 
| Change from baseline in N-terminal fragment of the prohormone B-type natriuretic peptide (NT-ProBNP) | NT-proBNP is a blood biomarker to assess right ventricular distress | Baseline to Week 52 | 

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