Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF (HELP)

• ClinicalTrials.gov Identifier: NCT03541603
• Recruitment Status: Completed
• First Posted: May 30, 2018
• Last Update Posted: April 10, 2020
• Sponsor: Tenax Therapeutics, Inc.
• Information provided by (Responsible Party): Tenax Therapeutics, Inc.

Study Description

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

Condition or disease	Intervention/treatment	Phase
Hypertension Pulmonary Secondary; Heart Failure, Right Sided; Heart Failure With Normal Ejection Fraction	Drug: Levosimendan; Drug: Matching Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Randomized, Placebo-Controlled Study of Levosimendan in Pulmonary Hypertension Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction (PH-HFpEF)
• Actual Study Start Date: November 14, 2018
• Actual Primary Completion Date: April 7, 2020
• Actual Study Completion Date: April 7, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Levosimendan 2.5mg/mL Injectable Solution; 0.075 - 0.1µg/kg/min for 24 hrs (weekly)	Drug: Levosimendan; 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; Other Name: Levosimendan 2.5 mg/mL Injectable Solution
Placebo Comparator: Matching Placebo; 0.075 - 0.1µg/kg/min for 24 hrs (weekly)	Drug: Matching Placebo; 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; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change from baseline Pulmonary Capillary Wedge Pressure (PCWP) with bicycle exercise [ Time Frame: Week 6 ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Stanford Healthcare

Stanford, California, United States, 94305

United States, Illinois

Northwestern Memorial Hospital

Chicago, Illinois, United States, 60611

United States, Massachusetts

Tufts Medical Center

Boston, Massachusetts, United States, 02111

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02215

United States, Minnesota

University of Minnesota Medical Center

Minneapolis, Minnesota, United States, 55455

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, Nebraska

University of Nebraska Medical Center

Omaha, Nebraska, United States, 68198

United States, New York

North Shore University Hospital

Manhasset, New York, United States, 11030

New York Presbyterian Hospital-Weill Cornell Medicine

New York, New York, United States, 10021

Ichan School of Medicine at Mount Sinai

New York, New York, United States, 10029

United States, Ohio

Christ Hospital

Cincinnati, Ohio, United States, 45219

United States, Pennsylvania

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh Presbyterian Hospital

Pittsburgh, Pennsylvania, United States, 15213

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Wisconsin

UW Health University Hospital

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

Tenax Therapeutics, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Tenax Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03541603
• Other Study ID Numbers: TNX-LVO-04
• First Posted: May 30, 2018
• Last Update Posted: April 10, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tenax Therapeutics, Inc.:

PH-HFpEF

Additional relevant MeSH terms:

Hypertension, Pulmonary; Hypertension; Heart Failure; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Lung Diseases; Respiratory Tract Diseases; Simendan; Cardiotonic Agents; Vasodilator Agents; Phosphodiesterase 3 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs