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| ID | Type | Description | Link |
|---|---|---|---|
| 5K23HL145140 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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The advent of continuous flow (CF) pumps for patients with severe heart failure has led to marked improvements in survival; however, pump operation remains fraught with adverse thrombotic events. This climbing rate of thrombosis and stroke during CF pump support has led to a recent warning by the US Food and Drug Administration. Despite a rising incidence of pump thrombosis and its downstream complications of stroke, the hematologic mechanisms behind these devastating adverse events remain uncertain. Recently, it has been recognized that CF pump induced hemolysis precedes and is associated with thrombosis. In-vitro studies show increased platelet function with exposure to products of hemolysis, which is also known to occur in diseases of intravascular hemolysis such as sickle cell anemia. This proposal will investigate if hemolysis associated increased platelet function can be reduced by a potentiation of nitric oxide signaling by an oral phosphodiesterase-5 inhibitor, sildenafil. Elucidating mechanisms of hemolysis induced thrombosis may inform best strategies for prevention of end organ damage and maintaining optimal CF pump operation.
Despite the remarkable improvements in survival with durable continuous flow (CF) pumps and the clear lifesaving effects of Impella and veno-arterial extracorporeal membrane oxygenation (VA ECMO), serious adverse hematological events such as bleeding and thrombosis create substantial morbidity and mortality and remain major barriers for further expansion of this technology. In particular, thrombosis is a devastating adverse event during CF pump support as it can lead to stroke, device stoppage, and hemodynamic collapse. Although the annual incidence of pump thrombosis has been reported to range from 8 to nearly 30%, the pathobiological mechanisms of thrombus formation during CF pump support with ongoing anticoagulation remain elusive. Our preliminary data associates hemolysis, which is inherent to such devices due to high shear stress, with subsequent formation of thrombosis and stroke, possibly through increasing platelet activation and aggregation. Our prelim data and drawing from a body of literature from diseases of intravascular hemolysis such as sickle cell anemia suggest that free hemoglobin released during hemolysis, which reduces NO levels, may be activating platelets. In retrospective analysis, we have noted a significant reduction in mean platelet volume (potential in-vivo marker of platelet activation), thrombosis and stroke with concurrent sildenafil administration. However, this mechanism and efficacy of NO signaling enhancers such as sildenafil remains to be proven during CF pump support.
Aim: To conduct a randomized placebo controlled study to test the hypothesis that platelet activation and aggregation, endothelial dysfunction and pro-thrombotic inflammation in outpatients on chronic CF pump support can be reduced by sildenafil.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sildenafil | Active Comparator | Baseline blood samples and study measurements will be acquired. Then 20 mg of the study drug will be administered. Then BP will be recorded every 30 minutes for two hours. If BP is stable (drop is < 5 mmHg after 2 hours and patient is asymptomatic), patient will proceed to take 20 mg of the study drug every 8 hours. The patient will return to clinic on day 8 and 20 mg of the study drug will be administered. After 2 hours blood samples and study measurements will be collected and the patient will resume 20 mg of the study for the next two doses. The patient will return for a third clinic visit on the next day and if BP is in the acceptable range, 40 mg of the study drug will be administered. If BP remains stable for 2 hours, then the patient will continue taking 40 mg every 8 hours. The patient will return to clinic on day 15 for a final study visit and will be given the last 40 mg dose of the study drug and after 2 hours blood samples and study measurements will be taken. |
|
| Placebo Oral Tablet | Placebo Comparator | Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sildenafil | Drug | To conduct a randomized placebo controlled study to test the hypothesis that platelet activation and aggregation during ongoing low level hemolysis in outpatients on chronic CF pump support can be reduced by sildenafil. |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Curve for Adenosine Diphosphate (ADP) | During the study period platelet activation and aggregation will be measured from drawn blood samples. Platelet rich plasma will be isolated from these samples and platelet aggregometry will be used to measure platelet activation and aggregation. Platelet activation and aggregation is measured as an area under the curve (AUC) derived as the resistance (ohms) x time (s). There is no reference range for ADP induced AUC. Higher values of AUC indicate greater platelet aggregation. | Baseline, day 8 and day 15 |
| Measure | Description | Time Frame |
|---|---|---|
| Pro-thrombotic Inflammation as Measured by High-sensitivity C-reactive Protein (hs CRP) | During the study period pro-thrombotic inflammatory markers, including hs CRP (mg/L) in serum will be measured by ELISA. The upper limit of normal reference for hs CRP is 0.5 mg/dL. Higher values of hs CRP indicate greater pro-thrombotic inflammation. | Baseline, day 8 and day 15 |
| Measure | Description | Time Frame |
|---|---|---|
| Serum Angiopoietin-2 to Angiopoietin-1 Ratio | Mediator of vascular remodeling. This is a relative unit and there is no reference range in the context of magnetically levitated left ventricular assist device support. A higher Angiopoietin-2 to Angiopoietin-1 ratio indicates greater microvascular remodeling and inflammation. | Baseline, day 8 and day 15 |
Inclusion:
-Adult outpatients (≥18 years old) with ongoing durable CF pump support.
Exclusion:
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| Name | Affiliation | Role |
|---|---|---|
| Omar Saeed, MD | Montefiore Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Montefiore Medical Center | The Bronx | New York | 10467 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Sildenafil | Baseline blood samples and study measurements will be acquired. Then 20 mg of the study drug will be administered. Then BP will be recorded every 30 minutes for two hours. If BP is stable (drop is < 5 mmHg after 2 hours and patient is asymptomatic), patient will proceed to take 20 mg of the study drug every 8 hours. The patient will return to clinic on day 8 and 20 mg of the study drug will be administered. After 2 hours blood samples and study measurements will be collected and the patient will resume 20 mg of the study for the next two doses. The patient will return for a third clinic visit on the next day and if BP is in the acceptable range, 40 mg of the study drug will be administered. If BP remains stable for 2 hours, then the patient will continue taking 40 mg every 8 hours. The patient will return to clinic on day 15 for a final study visit and will be given the last 40 mg dose of the study drug and after 2 hours blood samples and study measurements will be taken. Sildenafil: To conduct a randomized placebo controlled study to test the hypothesis that platelet activation and aggregation during ongoing low level hemolysis in outpatients on chronic continuous flow (CF) pump support can be reduced by sildenafil. |
| FG001 | Placebo Oral Tablet | Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil. Placebo Oral Tablet: Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Sildenafil | Baseline blood samples and study measurements will be acquired. Then 20 mg of the study drug will be administered. Then BP will be recorded every 30 minutes for two hours. If BP is stable (drop is < 5 mmHg after 2 hours and patient is asymptomatic), patient will proceed to take 20 mg of the study drug every 8 hours. The patient will return to clinic on day 8 and 20 mg of the study drug will be administered. After 2 hours blood samples and study measurements will be collected and the patient will resume 20 mg of the study for the next two doses. The patient will return for a third clinic visit on the next day and if BP is in the acceptable range, 40 mg of the study drug will be administered. If BP remains stable for 2 hours, then the patient will continue taking 40 mg every 8 hours. The patient will return to clinic on day 15 for a final study visit and will be given the last 40 mg dose of the study drug and after 2 hours blood samples and study measurements will be taken. Sildenafil: To conduct a randomized placebo controlled study to test the hypothesis that platelet activation and aggregation during ongoing low level hemolysis in outpatients on chronic CF pump support can be reduced by sildenafil. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Area Under the Curve for Adenosine Diphosphate (ADP) | During the study period platelet activation and aggregation will be measured from drawn blood samples. Platelet rich plasma will be isolated from these samples and platelet aggregometry will be used to measure platelet activation and aggregation. Platelet activation and aggregation is measured as an area under the curve (AUC) derived as the resistance (ohms) x time (s). There is no reference range for ADP induced AUC. Higher values of AUC indicate greater platelet aggregation. | 1 participant in the sildenafil group was not able to tolerate 40 mg and did not reach the 15 day endpoint. | Posted | Median | Inter-Quartile Range | omhs x seconds (AUC) | Baseline, day 8 and day 15 |
|
15 days
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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 | Sildenafil | Baseline blood samples and study measurements will be acquired. Then 20 mg of the study drug will be administered. Then BP will be recorded every 30 minutes for two hours. If BP is stable (drop is < 5 mmHg after 2 hours and patient is asymptomatic), patient will proceed to take 20 mg of the study drug every 8 hours. The patient will return to clinic on day 8 and 20 mg of the study drug will be administered. After 2 hours blood samples and study measurements will be collected and the patient will resume 20 mg of the study for the next two doses. The patient will return for a third clinic visit on the next day and if BP is in the acceptable range, 40 mg of the study drug will be administered. If BP remains stable for 2 hours, then the patient will continue taking 40 mg every 8 hours. The patient will return to clinic on day 15 for a final study visit and will be given the last 40 mg dose of the study drug and after 2 hours blood samples and study measurements will be taken. Sildenafil: To conduct a randomized placebo controlled study to test the hypothesis that platelet activation and aggregation during ongoing low level hemolysis in outpatients on chronic CF pump support can be reduced by sildenafil. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | Systematic Assessment | 1 participant experienced a transient headache and could not tolerate 40 mg of sildenafil. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Omar Saeed | Montefiore Einstein | 718-920-2626 | osaeed@montefiore.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 10, 2023 | Jun 10, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 11, 2023 | Jun 10, 2024 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D013927 | Thrombosis |
| D006461 | Hemolysis |
| ID | Term |
|---|---|
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D000068677 | Sildenafil Citrate |
| ID | Term |
|---|---|
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013450 | Sulfones |
| D013457 |
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Placebo controlled randomized trial with 1:1 enrollment in each study arm.
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| Placebo Oral Tablet | Drug | Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil. |
|
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| Pro-thrombotic Inflammation as Measured by Fibrinogen | During the study period pro-thrombotic inflammatory markers including fibrinogen (mg/dL) will be measured by ELISA. The upper limit of normal reference for fibrinogen is 187-502 mg/dl. Higher values of fibrinogen indicate greater thrombo-inflammation. | Baseline, day 8 and day 15 |
| Concentration of Serum Endothelin-1 | Mediator of vascular fibrosis. The normal reference is 1-2 pg/ml. Higher values indicate greater deviation from normal. | Baseline, day 8 and day 15 |
| BG001 | Placebo Oral Tablet | Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil. Placebo Oral Tablet: Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| OG001 | Placebo Oral Tablet | Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil. Placebo Oral Tablet: Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil. |
|
|
| Secondary | Pro-thrombotic Inflammation as Measured by High-sensitivity C-reactive Protein (hs CRP) | During the study period pro-thrombotic inflammatory markers, including hs CRP (mg/L) in serum will be measured by ELISA. The upper limit of normal reference for hs CRP is 0.5 mg/dL. Higher values of hs CRP indicate greater pro-thrombotic inflammation. | 1 participant in the sildenafil group was not able to tolerate 40 mg and did not reach the 15 day endpoint. | Posted | Median | Inter-Quartile Range | mg/L | Baseline, day 8 and day 15 |
|
|
|
| Secondary | Pro-thrombotic Inflammation as Measured by Fibrinogen | During the study period pro-thrombotic inflammatory markers including fibrinogen (mg/dL) will be measured by ELISA. The upper limit of normal reference for fibrinogen is 187-502 mg/dl. Higher values of fibrinogen indicate greater thrombo-inflammation. | 1 participant in the sildenafil group was not able to tolerate 40 mg and did not reach the 15 day endpoint. | Posted | Median | Inter-Quartile Range | mg/dl | Baseline, day 8 and day 15 |
|
|
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| Other Pre-specified | Serum Angiopoietin-2 to Angiopoietin-1 Ratio | Mediator of vascular remodeling. This is a relative unit and there is no reference range in the context of magnetically levitated left ventricular assist device support. A higher Angiopoietin-2 to Angiopoietin-1 ratio indicates greater microvascular remodeling and inflammation. | 1 participant in the sildenafil group was not able to tolerate 40 mg and did not reach the 15 day endpoint. | Posted | Median | Inter-Quartile Range | ratio | Baseline, day 8 and day 15 |
|
|
|
| Other Pre-specified | Concentration of Serum Endothelin-1 | Mediator of vascular fibrosis. The normal reference is 1-2 pg/ml. Higher values indicate greater deviation from normal. | 1 participant in the sildenafil group was not able to tolerate 40 mg and did not reach the 15 day endpoint. | Posted | Median | Inter-Quartile Range | pg/ml | Baseline, day 8 and day 15 |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 1 |
| 10 |
| EG001 | Placebo Oral Tablet | Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil. Placebo Oral Tablet: Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil. | 0 | 10 | 0 | 10 | 0 | 10 |
|
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| D013568 |
| Pathological Conditions, Signs and Symptoms |
| Sulfur Compounds |
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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