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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Levosimendan 2.5mg/mL Injectable Solution | Experimental | 0.075 - 0.1µg/kg/min for 24 hrs (weekly) |
|
| Matching Placebo | Placebo Comparator | 0.075 - 0.1µg/kg/min for 24 hrs (weekly) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Levosimendan | Drug | 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 |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Baseline, Week 6 |
| Measure | Description | Time Frame |
|---|---|---|
| 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)) | Baseline, Week 6 |
| Change in Pulmonary Vascular Resistance (PVR) Effect at Rest and With Exercise |
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Inclusion Criteria:
Criteria to enter Open-label, Lead-in Dose Phase:
Criterion for Randomization to Double-blind Phase:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford Healthcare | Stanford | California | 94305 | United States | ||
| Northwestern Memorial Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34716759 | Derived | 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. | |
| 33839076 | Derived | 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. |
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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
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | Matching Placebo |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 15, 2019 | Apr 29, 2021 |
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|
| Matching Placebo | Drug | 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 |
|
|
Change in Pulmonary Vascular Resistance (PVR) effect at rest and with exercise at Week 6 |
| Baseline, Week 6 |
| Change in PCWP When Supine and Legs Elevated | Change in Pulmonary Capillary Wedge Pressure, Baseline to Week 6 | Baseline, 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) (minimum total score 5pts, maximum total score 25 pts) (no comparison to baseline as no instrument used at baseline) | Baseline, Week 6 |
| Exercise Duration Via 6 Minute Walk Test | Change in 6-minute walk test at Week 6 vs baseline | Baseline, 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). | Baseline, Week 6 |
| Number of Participants With Composite Events of Death or Hospitalization | Number of Participants with Composite Events of death or hospitalization through Week 6 | Baseline, Week 6 |
| Chicago |
| Illinois |
| 60611 |
| United States |
| Tufts Medical Center | Boston | Massachusetts | 02111 | United States |
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| Brigham and Women's Hospital | Boston | Massachusetts | 02215 | United States |
| University of Minnesota Medical Center | Minneapolis | Minnesota | 55455 | United States |
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| University of Nebraska Medical Center | Omaha | Nebraska | 68198 | United States |
| North Shore University Hospital | Manhasset | New York | 11030 | United States |
| New York Presbyterian Hospital-Weill Cornell Medicine | New York | New York | 10021 | United States |
| Ichan School of Medicine at Mount Sinai | New York | New York | 10029 | United States |
| Christ Hospital | Cincinnati | Ohio | 45219 | United States |
| Hospital of the University of Pennsylvania | Philadelphia | Pennsylvania | 19104 | United States |
| University of Pittsburgh Presbyterian Hospital | Pittsburgh | Pennsylvania | 15213 | United States |
| Medical University of South Carolina | Charleston | South Carolina | 29425 | United States |
| UW Health University Hospital | Madison | Wisconsin | 53792 | United States |
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 |
| COMPLETED |
|
| NOT COMPLETED |
|
One placebo patient failed to complete 6 weeks on study and was replaced as per protocol.
One placebo patient was not able to return for Week 6 visit due to COVID-19 scheduling
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | patients completing Baseline and Week 6 visit with hemodynamic data | Posted | Mean | Standard Deviation | mmHg | Baseline, Week 6 |
|
|
| ||||||||||||||||||||||||||||
| 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)) | patients completing Baseline and Week 6 visit with hemodynamic data | Posted | Mean | Standard Deviation | L/min/m^2 | Baseline, Week 6 |
|
| |||||||||||||||||||||||||||||
| 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 | patients completing Baseline and Week 6 visit with hemodynamic data | Posted | Mean | Standard Deviation | mmHg.min/L | Baseline, Week 6 |
|
| |||||||||||||||||||||||||||||
| Secondary | Change in PCWP When Supine and Legs Elevated | Change in Pulmonary Capillary Wedge Pressure, Baseline to Week 6 | patients completing Baseline and Week 6 visit with hemodynamic data | Posted | Mean | Standard Deviation | mmHg | Baseline, Week 6 |
|
| |||||||||||||||||||||||||||||
| 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) | Posted | Median | Inter-Quartile Range | units on a scale | Baseline, Week 6 |
|
| ||||||||||||||||||||||||||||||
| Secondary | Exercise Duration Via 6 Minute Walk Test | Change in 6-minute walk test at Week 6 vs baseline | Posted | Mean | Standard Deviation | meters | Baseline, Week 6 |
|
| ||||||||||||||||||||||||||||||
| 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). | Posted | Count of Participants | Participants | Baseline, Week 6 |
|
| |||||||||||||||||||||||||||||||
| Secondary | Number of Participants With Composite Events of Death or Hospitalization | Number of Participants with Composite Events of death or hospitalization through Week 6 | Posted | Count of Participants | Participants | Baseline, Week 6 |
|
|
6 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 0 | 18 | 3 | 18 | 13 | 18 |
| EG001 | 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 | 0 | 19 | 1 | 19 | 8 | 19 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Device related infection | Infections and infestations | MedDRA (21.0) | Systematic Assessment | PICC LINE INFECTION WITH DUE TO Serious Adverse Event (SAE) associated with Peripherally Inserted Central Venous Catheter (PICC) HOSPITALIZATION |
|
| Bacteremia | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
| |
| Cardiac failure acute | Cardiac disorders | MedDRA (21.0) | Systematic Assessment |
| |
| Cardiogenic Shock | Cardiac disorders | MedDRA (21.0) | Systematic Assessment |
| |
| Right ventricular failure | Cardiac disorders | MedDRA (21.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Chills | General disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Infusion site hemorrhage | General disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Infusion site erythema | General disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Edema | General disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Peripheral swelling | General disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Cardiac failure acute | Cardiac disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Cardiogenic shock | Cardiac disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Extrasystoles | Cardiac disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Palpitations | Cardiac disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Right ventricular failure | Cardiac disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Tachycardia | Cardiac disorders | MedDRA (21.0) | Systematic Assessment |
| |
| Ventricular tachycardia | Cardiac disorders | MedDRA (21.0) | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Atypical pneumonia | Infections and infestations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Bacteremia | Infections and infestations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Bronchitis viral | Infections and infestations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Device-related infection | Infections and infestations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Tooth abscess | Infections and infestations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Balance disorder | Nervous system disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Dizziness postural | Nervous system disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Dyspnea | Respiratory, thoracic and mediastinal disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Vascular access site pain | Injury, poisoning and procedural complications | MedDRA (21.0) | Non-systematic Assessment |
| |
| Accidental overdose | Injury, poisoning and procedural complications | MedDRA (21.0) | Non-systematic Assessment |
| |
| Overdose | Injury, poisoning and procedural complications | MedDRA (21.0) | Non-systematic Assessment |
| |
| Underdose | Injury, poisoning and procedural complications | MedDRA (21.0) | Non-systematic Assessment |
| |
| Heart rate increased | Investigations | MedDRA (21.0) | Systematic Assessment |
| |
| Blood creatinine increased | Investigations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Body temperature increased | Investigations | MedDRA (21.0) | Non-systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Device infusion issue | Product Issues | MedDRA (21.0) | Non-systematic Assessment |
| |
| Device dislocation | Product Issues | MedDRA (21.0) | Non-systematic Assessment |
| |
| Device occlusion | Product Issues | MedDRA (21.0) | Non-systematic Assessment |
| |
| Hypokalemia | Metabolism and nutrition disorders | MedDRA (21.0) | Non-systematic Assessment |
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| Hypomagnesemia | Metabolism and nutrition disorders | MedDRA (21.0) | Non-systematic Assessment |
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| Lactic acidosis | Metabolism and nutrition disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Blister | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Skin necrosis | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Non-systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | MedDRA (21.0) | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Peripheral artery stenosis | Vascular disorders | MedDRA (21.0) | Non-systematic Assessment |
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| Thrombophlebitis | Vascular disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Venous thrombosis limb | Vascular disorders | MedDRA (21.0) | Non-systematic Assessment |
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| Vison blurred | Eye disorders | MedDRA (21.0) | Non-systematic Assessment |
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| Delirium | Psychiatric disorders | MedDRA (21.0) | Non-systematic Assessment |
| |
| Acute kidney injury | Renal and urinary disorders | MedDRA (21.0) | Non-systematic Assessment |
|
Hemodynamic effects at Wk6 were measured ~1 week after final levosimendan infusion. Thus, hemodynamic effects at 6 weeks represent effects at trough levels; greater effects might have been observed with earlier assessment.
No previous study evaluated chronic levosimendan in PH-HFpEF. Chose a low dose out of an abundance of caution. It remains possible that higher doses may be more effective in selected patients.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stuart Rich, MD; Chief Medical Officer | Tenax Therapeutics, Inc. | 919 855 2100 | s.rich@tenaxthera.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 18, 2019 | Apr 29, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000077464 | Simendan |
| ID | Term |
|---|---|
| D006835 | Hydrazones |
| D006834 | Hydrazines |
| D009930 | Organic Chemicals |
| D011724 | Pyridazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Class III |
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| Class IV |
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