Clinical trial NCT03541603: Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF
Official title: A Double-Blind, Randomized, Placebo-Controlled Study of Levosimendan in Pulmonary Hypertension Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction (PH-HFpEF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertension Pulmonary Secondary
Heart Failure, Right Sided
Heart Failure With Normal Ejection Fraction
Keywords: PH-HFpEF
Lead sponsor: Tenax Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2018-05-30
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline Pulmonary Capillary Wedge Pressure (PCWP) With Bicycle Exercise
timeFrame: Baseline, Week 6
Secondary outcomes:
measure: Change in Cardiac Index (CI) at Rest and With Exercise.
timeFrame: Baseline, Week 6
measure: Change in Pulmonary Vascular Resistance (PVR) Effect at Rest and With Exercise
timeFrame: Baseline, Week 6
measure: Change in PCWP When Supine and Legs Elevated
timeFrame: Baseline, Week 6
measure: Patient Global Assessment
timeFrame: Baseline, Week 6
measure: Exercise Duration Via 6 Minute Walk Test
timeFrame: Baseline, Week 6
measure: Physician's Assessment of Functional Class
timeFrame: Baseline, Week 6
measure: Number of Participants With Composite Events of Death or Hospitalization
timeFrame: Baseline, Week 6
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford Healthcare
state: California
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital-Weill Cornell Medicine
state: New York
city: New York
country: United States
facility: Ichan School of Medicine at Mount Sinai
state: New York
city: Cincinnati
country: United States
facility: Christ Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Presbyterian Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Madison
country: United States
facility: UW Health University Hospital
state: Wisconsin
Study officials:
References:
citation: Burkhoff D, Rich S, Pollesello P, Papp Z. Levosimendan-induced venodilation is mediated by opening of potassium channels. ESC Heart Fail. 2021 Dec;8(6):4454-4464. doi: 10.1002/ehf2.13669. Epub 2021 Oct 30.
citation: Burkhoff D, Borlaug BA, Shah SJ, Zolty R, Tedford RJ, Thenappan T, Zamanian RT, Mazurek JA, Rich JD, Simon MA, Chung ES, Raza F, Majure DT, Lewis GD, Preston IR, Rich S. Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial. JACC Heart Fail. 2021 May;9(5):360-370. doi: 10.1016/j.jchf.2021.01.015. Epub 2021 Apr 7.