Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: Levosimendan
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Criteria to enter Open-label, Lead-in Dose Phase: Diagnosis of WHO Group 2 Pulmonary Hypertension (PH) with heart failure and preserved ejection fraction (HFpEF) confirmed at the time of the diagnosis of pulmonary hypertension. Baseline Pulmonary Arterial Pressure (PAP) ≥35, PCWP ≥20, 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 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 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 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

Ages Eligible for Study
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Minimum Age: 18 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: Levosimendan 2.5mg/mL Injectable Solution<br>0.075 - 0.1µg/kg/min for 24 hrs (weekly) | Drug: Levosimendan<br>* A sterile 2.5 mg/mL concentrate solution that is diluted in 5% Dextrose or 0.9 Normal Saline to achieve a 50 microgram/min solution for infusion<br>* Other names: Levosimendan 2.5 mg/mL Injectable Solution;|
| Placebo Comparator: Matching Placebo<br>0.075 - 0.1µg/kg/min for 24 hrs (weekly) | Drug: Matching Placebo<br>* A sterile 2.5mg/mL concentrate solution that is diluted in 5% Dextrose or 0.9 Normal Saline to achieve a 50 microgram/min solution for infusion<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline Pulmonary Capillary Wedge Pressure (PCWP) with bicycle exercise |  | Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cardiac Index (CI) at rest and with exercise |  | Week 6 | 
| Change in Pulmonary Vascular Resistance (PVR) effect at rest and with exercise |  | Week 6 | 
| Change in PCWP when supine and legs elevated |  | Week 6 | 
| Patient global assessment | Patient assessment of well-being based on 6 questions assessed on a 5-point Likert Scale ( 1 =worst, 5= best) | Week 6 | 
| Exercise duration via 6 minute walk test |  | Week 6 | 
| Physician's assessment of functional class | 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). | Week 6 | 
| Composite incidence of death or hospitalization |  | Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PH-HFpEF