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Sildenafil To Prevent Clot (SToPClot)

Primary Purpose

Thrombosis, Hemolysis

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Sildenafil
Placebo Oral Tablet
Sponsored by
Montefiore Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Thrombosis focused on measuring Thrombosis during Continuous Flow Pump Support

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion:

-Adult outpatients (≥18 years old) with ongoing durable CF pump support.

Exclusion:

  • Taking sildenafil or nitrates for clinical indications
  • Ongoing infection
  • Unwilling or unable to give written, informed consent

Sites / Locations

  • Montefiore Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Sildenafil

Placebo Oral Tablet

Arm Description

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.

Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil.

Outcomes

Primary Outcome Measures

Change in platelet activation and aggregation (aggregometry)
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.

Secondary Outcome Measures

Change in pro-thrombotic inflammatory markers as measured by hs CRP
During the study period pro-thrombotic inflammatory markers, including hs CRP (mg/L) in serum will be measured by ELISA.
Change in pro-thrombotic inflammatory markers as measured by fibrinogen
During the study period pro-thrombotic inflammatory markers including fibrinogen (mg/dL) will be measured by ELISA.

Full Information

First Posted
June 22, 2017
Last Updated
September 21, 2023
Sponsor
Montefiore Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03199612
Brief Title
Sildenafil To Prevent Clot
Acronym
SToPClot
Official Title
The Role of Hemolysis in Promoting Thrombosis During Mechanical Circulatory Support With Continuous Flow Pumps (Aim 2)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 3, 2019 (Actual)
Primary Completion Date
December 30, 2023 (Anticipated)
Study Completion Date
December 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Montefiore Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Thrombosis, Hemolysis
Keywords
Thrombosis during Continuous Flow Pump Support

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Placebo controlled randomized trial with 1:1 enrollment in each study arm.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
46 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Sildenafil
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo Oral Tablet
Arm Type
Placebo Comparator
Arm Description
Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil.
Intervention Type
Drug
Intervention Name(s)
Sildenafil
Other Intervention Name(s)
Viagra, Revatio
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Tablet
Other Intervention Name(s)
Sildenafil matching placebo
Intervention Description
Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil.
Primary Outcome Measure Information:
Title
Change in platelet activation and aggregation (aggregometry)
Description
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.
Time Frame
Baseline, day 8 and day 15
Secondary Outcome Measure Information:
Title
Change in pro-thrombotic inflammatory markers as measured by hs CRP
Description
During the study period pro-thrombotic inflammatory markers, including hs CRP (mg/L) in serum will be measured by ELISA.
Time Frame
Baseline, day 8 and day 15
Title
Change in pro-thrombotic inflammatory markers as measured by fibrinogen
Description
During the study period pro-thrombotic inflammatory markers including fibrinogen (mg/dL) will be measured by ELISA.
Time Frame
Baseline, day 8 and day 15
Other Pre-specified Outcome Measures:
Title
Change in serum Angiopoietin-2 to Angiopoietin-1 ratio
Description
Mediator of vascular remodeling
Time Frame
Baseline, day 8 and day 15
Title
Change in serum Endothelin-1
Description
Mediator of vascular fibrosis
Time Frame
Baseline, day 8 and day 15

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion: -Adult outpatients (≥18 years old) with ongoing durable CF pump support. Exclusion: Taking sildenafil or nitrates for clinical indications Ongoing infection Unwilling or unable to give written, informed consent
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Julio Ramos, MD
Phone
718-920-2626
Email
jovalleram@montefiore.org
First Name & Middle Initial & Last Name or Official Title & Degree
Omar Saeed, MD
Phone
718-920-2626
Email
osaeed@montefiore.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Omar Saeed, MD
Organizational Affiliation
Montefiore Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Montefiore Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Omar Saeed, MD
Phone
718-920-2626
Email
osaeed@montefiore.org

12. IPD Sharing Statement

Plan to Share IPD
No

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Sildenafil To Prevent Clot

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