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

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

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

Study Overview

• Status: Completed
• Conditions: Heart Failure With Normal Ejection Fraction; Heart Failure, Right Sided; Hypertension Pulmonary Secondary
• Intervention / Treatment: Drug: Levosimendan; Drug: Matching Placebo

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 Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Healthcare
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02215
      • Brigham and Women's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10029
      • Ichan School of Medicine at Mount Sinai
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital-Weill Cornell Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Christ Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Presbyterian Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • UW Health University Hospital

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Tenax Therapeutics, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2018
• Primary Completion (Actual): April 7, 2020
• Study Completion (Actual): April 7, 2020

Study Registration Dates

• First Submitted: May 3, 2018
• First Submitted That Met QC Criteria: May 17, 2018
• First Posted (Actual): May 30, 2018

Study Record Updates

• Last Update Posted (Actual): April 10, 2020
• Last Update Submitted That Met QC Criteria: April 9, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: PH-HFpEF
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Hypertension, Pulmonary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: TNX-LVO-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No