LEVosimendan to Improve Exercise Limitation in Patients With PH-HFpEF

Study Overview
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Brief Summary
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This study will evaluate the efficacy of TNX-103 (levosimendan) compared with placebo in subjects with PH-HFpEF as measured by the change in 6-Minute Walk Distance (6 MWD; Day 1 to Week 12).

Detailed Description
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This is a Phase 3, double-blind, randomized, placebo-controlled study of levosimendan in patients with PH-HFpEF. There will be a Screening Period of up to 30 days. Subjects will provide written informed consent prior to completing any study procedures. Upon meeting all eligibility criteria, patients will continue to the 12-week randomized, double-blind treatment phase. Approximately 152 subjects will be randomized in a 1:1 ratio to receive an oral dose of levosimendan or placebo 2 mg/day for Weeks 1 to 4 and 3 mg/day for Weeks 5 to 12. Subjects will return to the clinical site at Weeks 4, 8, and 12. All randomized subjects will have the option to enter the 92-week OLE following the completion of all study events at Week 12.

Official Title
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A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Levosimendan in Pulmonary Hypertension Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction (PH-HFpEF)

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: TNX-103
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women, greater than or equal to18 to 85 years of age. NYHA Class II or III or ambulatory NYHA class IV symptoms. A diagnosis of World Health Organization (WHO) Group 2 PH-HFpEF with qualifying hemodynamics A qualifying Baseline RHC performed within 120 days. The RHC can be a historical RHC done prior to study consent. A qualifying echocardiogram performed within 30 days showing an LVEF greater than or equal to 40% A qualifying 6-MWD of at least 100 meters, but not more than 450 meters at Screening A 48-hour ambulatory cardiac rhythm monitor during the Screening Period to establish the resting heart rate (HR) and rhythm. Chronic medications for heart failure with preserved ejection fraction (HFpEF) or other serious underlying cardiac or pulmonary conditions should be administered at a stable dose for greater than or equal to 30 days prior to the day of the Baseline 6-MWT. Female subjects of childbearing potential must have a negative urine pregnancy test result at the Screening Visit and a negative urine pregnancy test and must not be pregnant, lactating, or planning a pregnancy from the Screening Visit to 7 months after the last dose of study drug. Female subjects of childbearing potential will be included if they are either sexually inactive (abstinent) for 90 days prior to the first dose of study drug, or are using a highly effective birth control method Female subjects of nonchildbearing potential will be included if they meet the following definition of nonchildbearing potential: are either surgically sterile or postmenopausal. Male patients with female partners of childbearing potential must use highly effective methods of birth control during their participation in the study and for a period of 4 months after the last dose of study drug. Patients must agree to abstain from egg or sperm donation through 7 months for female patients and 4 months for male patients after administration of the last dose of study drug. Ability to adhere to study visit schedule and understand and comply with all protocol requirements. Signed informed consent document indicating that they understand the purpose and procedures required for the study and are willing to participate in the study. Exclusion Criteria: A diagnosis of PH WHO Groups 1, 3, 4, or 5. Walking activity that is limited by anything other than shortness of breath or fatigue attributed to PH-HFpEF. Echocardiographic evidence for hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, cardiac amyloidosis, or infiltrative cardiomyopathy Structural heart repair or replacement of the aortic valve or mitral valve (surgical or percutaneous) within the past 12 months. OR, planned valve intervention in the next 6 months. OR, the presence of echocardiographic findings of significant valve disease as assessed from the qualifying echocardiogram Any of the following clinical laboratory values within 30 days as specified: Hemoglobin <10 g/dL per local laboratory. Serum alanine aminotransferase or aspartate aminotransferase levels >3× upper limit of normal (ULN) or total bilirubin >3× ULN. Electrocardiogram (ECG) with a QTcF >450 msec for males and >470 msec for females at Screening and Baseline in the absence of right bundle branch block. Platelet count <75,000/mm3. A diagnosis of pre-existing lung disease Recent documentation of significant underlying lung disease Documentation of pulmonary thromboembolism in the last 12 months Cardiovascular co-morbidities Receipt of any approved pulmonary arterial hypertension-specific therapies Hospitalization for any indication within 30 days Receipt of any intravenous (IV) inotropes within 30 days Body mass index greater than or equal to 50 kg/m2. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 Known history of chronic liver disease Prior exposure to levosimendan Current enrollment in or completion of any other investigational product study within 30 days of Screening. Initiation of an exercise program for cardiopulmonary rehabilitation within 45 days History of severe allergic or anaphylactic reaction or hypersensitivity to the excipients in the investigational product. Major surgery within 60 days. Subjects must have completely recovered from any previous surgery. Prior heart, lung, or heart-lung transplants or life expectancy of <12 months Pregnancy or breastfeeding in females History of active malignancy, with the exception of fully treated basal cell carcinoma, cervical carcinoma in situ, or squamous cell carcinomas of the skin. History of clinically significant other diseases that may limit or complicate participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Interventional Model Description: Double blind, randomized, placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|
| Active Comparator: TNX-103<br>levosimendan | Drug: TNX-103<br>* levosimendan 1 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-minute walk distance from Baseline to Week 12 |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| KCCQ | Change in KCCQ - Overall Summary Score | 12 weeks | 
| Clinical Worsening Events |  | 12 weeks | 
| Change in NT-proBNP | Decreases in NT-proBNP may indicate an improvement insymptoms | 12 weeks | 
| Change NYHA functional class | On a scale of I-IV. Lower scores may indicate improvement in symptoms | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HFpEF, Pulmonary hypertension group 2, PH-HFpEF