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Preventing de Novo Portal Vein Thrombosis With Antithrombin-III in Patients With Cirrhosis (PiVoT)

Primary Purpose

Portal Vein Thrombosis, Cirrhosis, Liver

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Antithrombin III
Placebo
Sponsored by
Jonathan Stine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Portal Vein Thrombosis

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Cirrhosis documented by:

  • Liver biopsy OR
  • Clinical, imaging, and laboratory findings consistent with cirrhosis AND

  • Disease process etiologic for cirrhosis (e.g., chronic viral hepatitis, non-alcoholic steatohepatitis, history of alcohol abuse, cholestatic liver disease)

    • Flow in main portal vein less than 15 cm/sec or reversal of flow as assessed by Doppler ultrasonography
    • Age greater than or equal to 18 and less than or equal to 75 years
    • AT-III <70%
    • Platelet count greater than or equal to 55,000 per uL
    • Laboratories reflective of general health status (normal):
  • White blood cell count (4-10.4 K/uL)
  • Hemoglobin (11.7-15.0 g/dL) and hematocrit (35-44%)
  • Creatinine (0.60-1.00 mg/dL) • Child Pugh Turcotte (CPT) Class A cirrhosis

3.2 Exclusion Criteria

  • Allergy to AT-III or one of its ingredients
  • CPT Class B or C cirrhosis
  • Coagulopathy as indicated by International Normalized Ratio (INR) >= 2.2 or an inherited coagulation disorder
  • Active hepatitis C infection expecting to initiate HCV therapy within the next two years
  • Established PVT or cavernoma
  • Transvenous portosystemic shunt (TIPS) placement
  • Previous liver transplantation

  • Increased risk of bleeding:

    • Active pathological bleeding including subjects with actively bleeding esophageal varices
    • History of intracranial bleeding
    • Unexplained gastrointestinal bleeding
    • Subjects with large esophageal varices, or varices with endoscopic stigmata of bleeding (e.g., red wale sign)
    • Subjects with gastric or intestinal varices
    • Subjects who are taking medicines that increase the risk of thrombosis (e.g. tamoxifen)
    • Subjects with any clinically significant bleeding within the last one month
    • Need for therapeutic anticoagulation for another indication
    • Concurrent use of antiplatelet medications excluding aspirin 81 mg once daily as aspirin at this dosage does not increase bleeding when given concomitantly with AT-III
  • Pregnancy or breastfeeding
  • Recent major surgery within six weeks
  • Inability or unwilling to give informed consent
  • Hepatocellular carcinoma [diagnosed by cross-sectional imaging, e.g., computed tomography (CT) or magnetic resonance imaging (MRI)] or another active malignancy
  • Predicted lifespan less than two years
  • Severe concurrent disease threatening successful completion of the trial in the opinion of the study principle investigator
  • Ongoing substance abuse as judged by the study principal investigator and confirmed by an eight-panel urine drug test at screening
  • Significant alcohol consumption (20g/day for women and 30g/day for men)
  • Human Immunodeficiency Virus infection
  • Worsening liver function based on the two initial laboratory values used to establish baseline laboratory measurements (section 7.2.2 Monitoring and Intervention Plan for Drug-induced Liver Injury)

Sites / Locations

  • Penn State College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

AT-III treatment

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Development of PVT
incident of PVT measured by ultrasound at different time points

Secondary Outcome Measures

Full Information

First Posted
August 7, 2019
Last Updated
February 23, 2022
Sponsor
Jonathan Stine
Collaborators
Grifols Therapeutics LLC
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1. Study Identification

Unique Protocol Identification Number
NCT04055389
Brief Title
Preventing de Novo Portal Vein Thrombosis With Antithrombin-III in Patients With Cirrhosis
Acronym
PiVoT
Official Title
Preventing de Novo Portal Vein Thrombosis With Antithrombin-III in Patients With Cirrhosis: A Randomized, Double-blinded, Placebo - Controlled Trial (PiVoT-AC Trial)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Withdrawn
Why Stopped
Challenges with recruitment
Study Start Date
January 1, 2021 (Actual)
Primary Completion Date
February 22, 2022 (Actual)
Study Completion Date
February 22, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jonathan Stine
Collaborators
Grifols Therapeutics LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
To prevent portal vein thrombosis (PVT) in patients with cirrhosis at risk for PVT by pharmacologic prophylaxis with intravenous antithrombin (AT-III).
Detailed Description
PVT is a common complication in patients with cirrhosis, affecting 10% to 25% of patients. PVT is a potentially life-threatening occurrence, complicating transplant candidacy and reducing five-year survival. In addition to the mortality risk posed by PVT, microthrombi within the liver have been linked to decompensation due to the phenomenon of parenchymal extinction. Because of the developing understanding of a baseline hypercoagulable state in many cirrhosis patients, recent studies have demonstrated the benefit of prophylactic anticoagulation with enoxaparin in patients with cirrhosis to prevent PVT. In addition to the benefit in reducing PVT, prophylactic anticoagulation was also found to reduce liver decompensation and improve overall survival. Risk factors for PVT are well described. The strongest independent risk factor for PVT is portal vein velocity. For each 1 cm/s decrease in portal vein velocity, PVT risk increases 16%. Portal vein velocity <15cm/sec is the best-established cutoff for predicting the development of de novo PVT over the ensuing twelve months. In addition, patients with cirrhosis and venous thromboembolism (PVT, deep vein thrombosis, pulmonary embolus) have abnormally low levels of AT-III. A recent report by the NPB-06 study group suggest that administering intravenous AT-III at dosage of 1500 units/day for five consecutive days in patients with cirrhosis and AT-III <70% serum level is a safe and effective treatment for PVT with promising short-term partial and complete resolution of PVT. Despite this, the role of AT repletion in preventing PVT remains unknown.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Portal Vein Thrombosis, Cirrhosis, Liver

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AT-III treatment
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Antithrombin III
Intervention Description
Patients with reversal of flow or sluggish flow in the main portal vein (<15 cm/s by Doppler ultrasound exam) will be enrolled and randomized to either weekly infusions of AT-III (half-life ~4 days) at a weight-based dosage according to the following formula: [Desired level of AT (100%) - Subject level of AT (%)] * subject weight (kg) 1.4 or placebo for 24 weeks of therapy.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
No study drug
Primary Outcome Measure Information:
Title
Development of PVT
Description
incident of PVT measured by ultrasound at different time points
Time Frame
up to 72 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Cirrhosis documented by: Liver biopsy OR Clinical, imaging, and laboratory findings consistent with cirrhosis AND Disease process etiologic for cirrhosis (e.g., chronic viral hepatitis, non-alcoholic steatohepatitis, history of alcohol abuse, cholestatic liver disease) Flow in main portal vein less than 15 cm/sec or reversal of flow as assessed by Doppler ultrasonography Age greater than or equal to 18 and less than or equal to 75 years AT-III <70% Platelet count greater than or equal to 55,000 per uL Laboratories reflective of general health status (normal): White blood cell count (4-10.4 K/uL) Hemoglobin (11.7-15.0 g/dL) and hematocrit (35-44%) Creatinine (0.60-1.00 mg/dL) • Child Pugh Turcotte (CPT) Class A cirrhosis 3.2 Exclusion Criteria Allergy to AT-III or one of its ingredients CPT Class B or C cirrhosis Coagulopathy as indicated by International Normalized Ratio (INR) >= 2.2 or an inherited coagulation disorder Active hepatitis C infection expecting to initiate HCV therapy within the next two years Established PVT or cavernoma Transvenous portosystemic shunt (TIPS) placement Previous liver transplantation Increased risk of bleeding: Active pathological bleeding including subjects with actively bleeding esophageal varices History of intracranial bleeding Unexplained gastrointestinal bleeding Subjects with large esophageal varices, or varices with endoscopic stigmata of bleeding (e.g., red wale sign) Subjects with gastric or intestinal varices Subjects who are taking medicines that increase the risk of thrombosis (e.g. tamoxifen) Subjects with any clinically significant bleeding within the last one month Need for therapeutic anticoagulation for another indication Concurrent use of antiplatelet medications excluding aspirin 81 mg once daily as aspirin at this dosage does not increase bleeding when given concomitantly with AT-III Pregnancy or breastfeeding Recent major surgery within six weeks Inability or unwilling to give informed consent Hepatocellular carcinoma [diagnosed by cross-sectional imaging, e.g., computed tomography (CT) or magnetic resonance imaging (MRI)] or another active malignancy Predicted lifespan less than two years Severe concurrent disease threatening successful completion of the trial in the opinion of the study principle investigator Ongoing substance abuse as judged by the study principal investigator and confirmed by an eight-panel urine drug test at screening Significant alcohol consumption (20g/day for women and 30g/day for men) Human Immunodeficiency Virus infection Worsening liver function based on the two initial laboratory values used to establish baseline laboratory measurements (section 7.2.2 Monitoring and Intervention Plan for Drug-induced Liver Injury)
Facility Information:
Facility Name
Penn State College of Medicine
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Preventing de Novo Portal Vein Thrombosis With Antithrombin-III in Patients With Cirrhosis

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