Heart Failure, Right Sided, Heart Failure With Normal Ejection Fraction, Hypertension Pulmonary Secondary
Conditions
Keywords
PH-HFpEF
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.
Interventions
DRUGLevosimendan
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
DRUGMatching 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
Sponsors
Tenax Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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) |
| 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)) |
| 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 |
| Exercise Duration Via 6 Minute Walk Test | Baseline, Week 6 | Change in 6-minute walk test at Week 6 vs baseline |
Countries
United States
Participant flow
Recruitment details
44 patients satisfied entry criteria for enrollment and received lead-in open-label levosimendan. 37 of the 44 enrolled patients achieved responder criteria following 24hr lead-in open label levosimendan infusion and were randomized to study
Participants by arm
| Arm | Count |
|---|---|
| Levosimendan 2.5mg/mL Injectable Solution 0.075 - 0.1µg/kg/min for 24 hrs (weekly)
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 | 18 |
| Matching Placebo 0.075 - 0.1µg/kg/min for 24 hrs (weekly)
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 | 19 |
| Total | 37 |
Baseline characteristics
| Characteristic | Levosimendan 2.5mg/mL Injectable Solution | Total | Matching Placebo |
|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 7.5 | 68.1 years STANDARD_DEVIATION 9.3 | 67.4 years STANDARD_DEVIATION 11 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 33 Participants | 17 Participants |
| Region of Enrollment United States | 18 participants | 37 participants | 19 participants |
| Sex: Female, Male Female | 10 Participants | 22 Participants | 12 Participants |
| Sex: Female, Male Male | 8 Participants | 15 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 13 / 18 | 8 / 19 |
| serious Total, serious adverse events | 3 / 18 | 1 / 19 |
Outcome results
Primary
Change From Baseline Pulmonary Capillary Wedge Pressure (PCWP) With Bicycle Exercise
Change from baseline Pulmonary Capillary Wedge Pressure (PCWP) with bicycle exercise at Week 6
Time frame: Baseline, Week 6
Population: patients completing Baseline and Week 6 visit with hemodynamic data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Change From Baseline Pulmonary Capillary Wedge Pressure (PCWP) With Bicycle Exercise | -1.9 mmHg | Standard Deviation 10.07 |
| Matching Placebo | Change From Baseline Pulmonary Capillary Wedge Pressure (PCWP) With Bicycle Exercise | -0.5 mmHg | Standard Deviation 7.87 |
Secondary
Change in Cardiac Index (CI) at Rest and With Exercise.
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))
Time frame: Baseline, Week 6
Population: patients completing Baseline and Week 6 visit with hemodynamic data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Change in Cardiac Index (CI) at Rest and With Exercise. | rest | 0.05 L/min/m^2 | Standard Deviation 0.699 |
| Levosimendan 2.5mg/mL Injectable Solution | Change in Cardiac Index (CI) at Rest and With Exercise. | exercise | 0.24 L/min/m^2 | Standard Deviation 1.106 |
| Matching Placebo | Change in Cardiac Index (CI) at Rest and With Exercise. | rest | -0.15 L/min/m^2 | Standard Deviation 0.262 |
| Matching Placebo | Change in Cardiac Index (CI) at Rest and With Exercise. | exercise | 0.04 L/min/m^2 | Standard Deviation 0.594 |
Secondary
Change in PCWP When Supine and Legs Elevated
Change in Pulmonary Capillary Wedge Pressure, Baseline to Week 6
Time frame: Baseline, Week 6
Population: patients completing Baseline and Week 6 visit with hemodynamic data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Change in PCWP When Supine and Legs Elevated | rest | -5.1 mmHg | Standard Deviation 5.26 |
| Levosimendan 2.5mg/mL Injectable Solution | Change in PCWP When Supine and Legs Elevated | legs elevated | -6.0 mmHg | Standard Deviation 7.75 |
| Matching Placebo | Change in PCWP When Supine and Legs Elevated | rest | -1.7 mmHg | Standard Deviation 6.14 |
| Matching Placebo | Change in PCWP When Supine and Legs Elevated | legs elevated | -0.3 mmHg | Standard Deviation 5.45 |
Secondary
Change in Pulmonary Vascular Resistance (PVR) Effect at Rest and With Exercise
Change in Pulmonary Vascular Resistance (PVR) effect at rest and with exercise at Week 6
Time frame: Baseline, Week 6
Population: patients completing Baseline and Week 6 visit with hemodynamic data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Change in Pulmonary Vascular Resistance (PVR) Effect at Rest and With Exercise | rest | -0.09 mmHg.min/L | Standard Deviation 1.05 |
| Levosimendan 2.5mg/mL Injectable Solution | Change in Pulmonary Vascular Resistance (PVR) Effect at Rest and With Exercise | exercise | -0.44 mmHg.min/L | Standard Deviation 1.539 |
| Matching Placebo | Change in Pulmonary Vascular Resistance (PVR) Effect at Rest and With Exercise | rest | 0.15 mmHg.min/L | Standard Deviation 2.238 |
| Matching Placebo | Change in Pulmonary Vascular Resistance (PVR) Effect at Rest and With Exercise | exercise | -0.16 mmHg.min/L | Standard Deviation 1.81 |
Secondary
Exercise Duration Via 6 Minute Walk Test
Change in 6-minute walk test at Week 6 vs baseline
Time frame: Baseline, Week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Exercise Duration Via 6 Minute Walk Test | 16.6 meters | Standard Deviation 40.03 |
| Matching Placebo | Exercise Duration Via 6 Minute Walk Test | -12.8 meters | Standard Deviation 35.08 |
Secondary
Number of Participants With Composite Events of Death or Hospitalization
Number of Participants with Composite Events of death or hospitalization through Week 6
Time frame: Baseline, Week 6
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Number of Participants With Composite Events of Death or Hospitalization | 3 Participants |
| Matching Placebo | Number of Participants With Composite Events of Death or Hospitalization | 1 Participants |
Secondary
Patient Global Assessment
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)
Time frame: Baseline, Week 6
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Patient Global Assessment | 3 units on a scale |
| Matching Placebo | Patient Global Assessment | 3 units on a scale |
Secondary
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).
Time frame: Baseline, Week 6
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Physician's Assessment of Functional Class | Baseline | Class I | 0 Participants |
| Levosimendan 2.5mg/mL Injectable Solution | Physician's Assessment of Functional Class | Baseline | Class II | 2 Participants |
| Levosimendan 2.5mg/mL Injectable Solution | Physician's Assessment of Functional Class | Baseline | Class III | 16 Participants |
| Levosimendan 2.5mg/mL Injectable Solution | Physician's Assessment of Functional Class | Baseline | Class IV | 0 Participants |
| Levosimendan 2.5mg/mL Injectable Solution | Physician's Assessment of Functional Class | Week 6 | Class I | 0 Participants |
| Levosimendan 2.5mg/mL Injectable Solution | Physician's Assessment of Functional Class | Week 6 | Class II | 8 Participants |
| Levosimendan 2.5mg/mL Injectable Solution | Physician's Assessment of Functional Class | Week 6 | Class III | 10 Participants |
| Levosimendan 2.5mg/mL Injectable Solution | Physician's Assessment of Functional Class | Week 6 | Class IV | 0 Participants |
| Matching Placebo | Physician's Assessment of Functional Class | Week 6 | Class IV | 0 Participants |
| Matching Placebo | Physician's Assessment of Functional Class | Baseline | Class I | 0 Participants |
| Matching Placebo | Physician's Assessment of Functional Class | Week 6 | Class I | 0 Participants |
| Matching Placebo | Physician's Assessment of Functional Class | Baseline | Class II | 3 Participants |
| Matching Placebo | Physician's Assessment of Functional Class | Week 6 | Class III | 12 Participants |
| Matching Placebo | Physician's Assessment of Functional Class | Baseline | Class III | 14 Participants |
| Matching Placebo | Physician's Assessment of Functional Class | Week 6 | Class II | 5 Participants |
| Matching Placebo | Physician's Assessment of Functional Class | Baseline | Class IV | 0 Participants |