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

Sponsor

Jonathan Stine (Other)

Overall Status

Withdrawn

CT.gov ID

NCT04055389

Collaborator

Grifols Therapeutics LLC (Industry)

Enrollment

Location

Arms

13.7

Actual Duration (Months)

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Portal Vein Thrombosis Cirrhosis, Liver	Drug: Antithrombin III Other: Placebo	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Prevention

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)

Actual Study Start Date :

Jan 1, 2021

Actual Primary Completion Date :

Feb 22, 2022

Actual Study Completion Date :

Feb 22, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AT-III treatment	Drug: Antithrombin III 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.
Placebo Comparator: Placebo	Other: Placebo No study drug

Arm

Intervention/Treatment

Experimental: AT-III treatment

Drug: Antithrombin III

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.

Placebo Comparator: Placebo

Other: Placebo

No study drug

Outcome Measures

Primary Outcome Measures

Development of PVT [up to 72 weeks]
incident of PVT measured by ultrasound at different time points

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts 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)