Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF

Phase 2

Completed

Conditions: Hypertension Pulmonary Secondary
Heart Failure, Right Sided
Heart Failure With Normal Ejection Fraction

Brief Summary: Phase 2 study to evaluate the efficacy and safety of intermittent levosimendan compared with placebo in hemodynamic improvement with exercise in PH-HFpEF subjects

Detailed Description: Levosimendan and its prolonged active metabolite, OR-1896, have been shown to have favorable hemodynamic effects in subjects with pulmonary hypertension and right heart failure. Clinical studies that have been conducted in subjects with right heart failure and pulmonary hypertension suggest levosimendan may be an effective therapy in treatment of subjects with PH-HFpEF. This study will provide demonstration of levosimendan/OR-1896's effectiveness in critical measures of hemodynamic response in weekly administration of levosimendan and the concomitant response as measured by exercise capacity, subject quality of life, and changes in functional capacity. These data will support and guide the Phase 3 development of levosimendan in PH-HFpEF subjects.

Recruitment & Eligibility

Inclusion Criteria

Criteria to enter Open-label, Lead-in Dose Phase:

Diagnosis of World Health Organization (WHO) Group 2 Pulmonary Hypertension (PH) with Heart Failure with Preserved Ejection Fraction (HFpEF) confirmed at the time of the diagnosis of pulmonary hypertension.
Baseline Pulmonary Arterial Pressure (PAP) ≥35, Pulmonary Capillary Wedge Pressure (PCWP) ≥20, New York Heart Association (NYHA) Class IIb/III, Left Ventricular Ejection Fraction (LVEF) ≥40%
Ability to walk at least 50 meters, but not more than 550 meters in a six-minute walk test.
Stable oxygen treatment (if applicable), and medications for heart failure, hypertension, and respiratory condition

Criterion for Randomization to Double-blind Phase:

Response to Open-label, Lead-in Levosimendan: Patients who demonstrate a ≥4mmHg reduction in PCWP from baseline measured at bicycle exercise (25 watts) with no more than a 10% decrease from baseline in cardiac index

Exclusion Criteria

Subject has a primary diagnosis of PH other than Group 2 PH-HFpEF
Previous Percutaneous Coronary Intervention (PCI) or cardiac surgery (CABG), unless they have a negative stress test in the last 12 months)
Congenital heart disease
Clinically significant lung disease
Planned heart or lung surgery
Cardiac Index >4.0 L/min/m2
Concomitant administration of pulmonary vasodilator therapy or taken within 14 days
Dialysis or Glomerular Filtration Rate (GFR) <30 mL/min/1.73 m2
Liver dysfunction with Child-Pugh Class B or C
Evidence of systemic infection
Weight > 150kg
Symptomatic systolic blood pressure (SBP) cannot be managed to ensure SBP >100 mmHg
Heart rate >= 100 bpm with the study drug, symptomatic and persistent for at least 10 minutes
Hemoglobin < 80 g/L
Serum potassium < 3.0 mmol/L or > 5.5 mmol/L at baseline
Patients having severely compromised immune function
Pregnant, suspected to be pregnant, or breast-feeding

Arm && Interventions

Group	Intervention	Description
Levosimendan 2.5mg/mL Injectable Solution	Levosimendan	0.075 - 0.1µg/kg/min for 24 hrs (weekly)
Matching Placebo	Matching Placebo	0.075 - 0.1µg/kg/min for 24 hrs (weekly)

Primary Outcome Measures

Name	Time	Method
Change From Baseline Pulmonary Capillary Wedge Pressure (PCWP) With Bicycle Exercise	Baseline, Week 6	Change from baseline Pulmonary Capillary Wedge Pressure (PCWP) with bicycle exercise at Week 6

Secondary Outcome Measures

Name	Time	Method
Change in Cardiac Index (CI) at Rest and With Exercise.	Baseline, Week 6	Change in Cardiac Index (CI) at rest and with exercise at Week 6 (CI determined by thermodilution) (CI is a hemodynamic parameter that relates the cardiac output (CO) from left ventricle in one minute to body surface area (BSA))
Patient Global Assessment	Baseline, Week 6	Patient assessment of well-being based on 6 questions assessed on a 5-point Likert Scale ( 1 =worst, 5= best) (minimum total score 5pts, maximum total score 25 pts) (no comparison to baseline as no instrument used at baseline)
Exercise Duration Via 6 Minute Walk Test	Baseline, Week 6	Change in 6-minute walk test at Week 6 vs baseline
Change in Pulmonary Vascular Resistance (PVR) Effect at Rest and With Exercise	Baseline, Week 6	Change in Pulmonary Vascular Resistance (PVR) effect at rest and with exercise at Week 6
Change in PCWP When Supine and Legs Elevated	Baseline, Week 6	Change in Pulmonary Capillary Wedge Pressure, Baseline to Week 6
Physician's Assessment of Functional Class	Baseline, Week 6	Physician's Assessment of New York Heart Association (NYHA) Classification (one of four categories based on how much the patient is limited during physical activity. (Class I, no limitation of physical activity to Class IV, marked limitation of physical activity).
Number of Participants With Composite Events of Death or Hospitalization	Baseline, Week 6	Number of Participants with Composite Events of death or hospitalization through Week 6

Locations (16): North Shore University Hospital
🇺🇸
Manhasset, New York, United States
Northwestern Memorial Hospital
🇺🇸
Chicago, Illinois, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Tufts Medical Center
🇺🇸
Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Brigham and Women's Hospital
🇺🇸
Boston, Massachusetts, United States
University of Minnesota Medical Center
🇺🇸
Minneapolis, Minnesota, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
University of Pittsburgh Presbyterian Hospital
🇺🇸
Pittsburgh, Pennsylvania, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
Stanford Healthcare
🇺🇸
Stanford, California, United States
New York Presbyterian Hospital-Weill Cornell Medicine
🇺🇸
New York, New York, United States
Ichan School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
Hospital of the University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Christ Hospital
🇺🇸
Cincinnati, Ohio, United States
UW Health University Hospital
🇺🇸
Madison, Wisconsin, United States