Overview

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).

Eligibility

Inclusion Criteria:

1. Men or women, greater than or equal to18 to 85 years of age.
2. NYHA Class II or III or ambulatory NYHA class IV symptoms.
3. A diagnosis of World Health Organization (WHO) Group 2 PH-HFpEF with qualifying hemodynamics
4. A qualifying Baseline RHC performed within 120 days. The RHC can be a historical RHC done prior to study consent.
5. A qualifying echocardiogram performed within 30 days showing an LVEF greater than or equal to 40%
6. A qualifying 6-MWD of at least 100 meters, but not more than 450 meters at Screening
7. A 48-hour ambulatory cardiac rhythm monitor during the Screening Period to establish the resting heart rate (HR) and rhythm.
8. 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.
9. 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.
10. 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
11. Female subjects of nonchildbearing potential will be included if they meet the following definition of nonchildbearing potential: are either surgically sterile or postmenopausal.
12. 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.
13. 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.
14. Ability to adhere to study visit schedule and understand and comply with all protocol requirements.
15. 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:

1. A diagnosis of PH WHO Groups 1, 3, 4, or 5.
2. Walking activity that is limited by anything other than shortness of breath or fatigue attributed to PH-HFpEF.
3. Echocardiographic evidence for hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, cardiac amyloidosis, or infiltrative cardiomyopathy
4. 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
5. Any of the following clinical laboratory values within 30 days as specified:
   1. Hemoglobin <10 g/dL
   2. Serum alanine aminotransferase or aspartate aminotransferase levels >3× upper limit of normal (ULN) or total bilirubin >3× ULN.
   3. 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.
   4. Platelet count <75,000/mm3.
6. A diagnosis of pre-existing lung disease
7. Recent documentation of significant underlying lung disease
8. Documentation of pulmonary thromboembolism in the last 12 months
9. Cardiovascular co-morbidities
10. Receipt of any approved pulmonary arterial hypertension-specific therapies
11. Hospitalization for any indication within 30 days
12. Receipt of any intravenous (IV) inotropes within 30 days
13. Body mass index greater than or equal to 45 kg/m2.
14. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2
15. Known history of chronic liver disease
16. Prior exposure to levosimendan
17. Current enrollment in or completion of any other investigational product study within 30 days of Screening.
18. Initiation of an exercise program for cardiopulmonary rehabilitation within 45 days
19. History of severe allergic or anaphylactic reaction or hypersensitivity to the excipients in the investigational product.
20. Major surgery within 60 days. Subjects must have completely recovered from any previous surgery.
21. Prior heart, lung, or heart-lung transplants or life expectancy of <12 months
22. Pregnancy or breastfeeding in females
23. History of active malignancy, with the exception of fully treated basal cell carcinoma, cervical carcinoma in situ, or squamous cell carcinomas of the skin.
24. History of clinically significant other diseases that may limit or complicate participation in the study.