Apixaban for Intrahepatic Non Cirrhotic Portal Hypertension (APIS)

Intrahepatic non-cirrhotic portal hypertension (INCPH) is a rare disease mostly affecting adults in their forties, characterized by portal hypertension related to alterations of intrahepatic microcirculation in the absence of cirrhosis.The only therapeutic options currently available for patients with INCPH include prophylaxis for variceal bleeding using betablockers and/or endoscopic band ligation and TIPSS (transjugular intrahepatic portosystemic shunt) or liver transplantation for severe cases.

The investigators hypothesize that anticoagulation using Apixaban in patients with INCPH might prevent occurrence or extension of portal, splenic or mesenteric veins thromboses and thus the development of chronic portal vein thrombosis and associated complications, but also avoid intrahepatic thromboses and consequently liver disease progression and variceal bleeding.

The Primary Objective is to evaluate the effect of 24 months low dosing of apixaban (2.5 mg x 2/day) versus placebo on the occurrence or the extension of portal venous system thrombosis (including splenic, mesenteric veins, portal trunk or left or right portal branches) at 24 months in patients with INCPH.

166 patients will be included in 21 centers in a prospective, national multicentric, phase III, superiority comparative randomized (1:1) double-blinded clinical trial with two parallel arms: apixaban versus placebo.

Study Overview

• Status: Active, not recruiting
• Conditions: Intrahepatic Non Cirrhotic Portal Hypertension
• Intervention / Treatment: Drug: Apixaban; Drug: Placebo

Detailed Description

Intrahepatic non-cirrhotic portal hypertension (INCPH) is a rare disease mostly affecting adults in their forties, characterized by portal hypertension related to alterations of intrahepatic microcirculation in the absence of cirrhosis.The only therapeutic options currently available for patients with INCPH include prophylaxis for variceal bleeding using betablockers and/or endoscopic band ligation and TIPSS (transjugular intrahepatic portosystemic shunt) or liver transplantation for severe cases.

The investigators hypothesize that anticoagulation using Apixaban in patients with INCPH might prevent occurrence or extension of portal, splenic or mesenteric veins thromboses and thus the development of chronic portal vein thrombosis and associated complications, but also avoid intrahepatic thromboses and consequently liver disease progression and variceal bleeding.

The Primary Objective is to evaluate the effect of 24 months low dosing of apixaban (2.5 mg x 2/day) versus placebo on the occurrence or the extension of portal venous system thrombosis (including splenic, mesenteric veins, portal trunk or left or right portal branches) at 24 months in patients with INCPH.

The Secondary Objectives are :

1. To assess the safety of apixaban on: (a) any major bleeding as defined by the ISTH (International Society on Thrombosis and Haemostasis) guidelines; (b) liver toxicity; (c) adverse events and reactions.

2. To compare the effect of 24 months low dosing of apixaban (2.5 mg x 2/day) versus placebo on the following outcomes, assessed during the 24 months of treatment:

   1. - at least one event among: deep vein thrombosis in any location, arterial thrombosis, major bleeding, death
   2. - the occurrence of deep vein thrombosis in any location or arterial thrombosis
   3. - mortality (global, liver related, non-liver related), and mortality or liver transplantation
   4. - each and any event among: liver decompensation, complications of portal hypertension including portal hypertensive related gastrointestinal bleeding, liver transplantation or death;
   5. - portal hypertension related features (spleen size, platelet count, size of esophageal varices, portal blood flow velocity) and markers of bacterial translocation and inflammation
   6. - liver function
   7. - quality of life
3. To evaluate the effect of 24 months low dosing of apixaban (2.5 mg x 2/day) versus placebo on the occurrence or the extension of portal venous system thrombosis (including splenic, mesenteric veins, portal trunk or left or right portal branches) at 24 months after randomisation in patients with INCPH according to HIV status

4. To identify predictors of portal venous system thrombosis and liver related events:

   • in the control group: liver and spleen stiffness; portal blood flow velocity; specific coagulation tests; markers of bacterial translocation and inflammation
   • in the group receiving apixaban: plasma apixaban levels
5. To assess treatment compliance
6. To study the occurrence or extension of portal venous system thrombosis or occurrence of deep vein thrombosis in any location or arterial thrombosis in the 6 months after the 24-month treatment with apixaban versus placebo.

166 patients will be included in 21 centers in a prospective, national multicentric, phase III, superiority comparative randomized (1:1) double-blinded clinical trial with two parallel arms: apixaban versus placebo.

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Pierre Emmanuel RAUTOU; Phone Number: +33 140875283; Email: pierre-emmanuel.rautou@aphp.fr
• Study Contact Backup: Name: Dominique VALLA; Phone Number: +33 140875283; Email: dominique.valla@aphp.fr

Study Locations

• France
  • Clichy, France, 92110
    • Beaujon hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 and ≤ 90 year old male and female patients,
• For child-bearing aged women, contraception using progestatives, or intrauterine device or mechanical contraception
• Adequate prophylaxis against variceal bleeding according to EASL (European association for the study of the liver) guidelines

• Intrahepatic non cirrhotic portal hypertension (INCPH), defined according to the recent VALDIG workshop (Feb. 2017, Ascona, Italy) as having one of the following simultaneous associations:

  1. absence of cirrhosis on an adequate liver biopsy, and one or more signs specific for portal hypertension
  2. absence of cirrhosis on an adequate liver biopsy, and one or more signs not specific for portal hypertension and one or more histological signs for INCPH
  3. in the absence of adequate liver biopsy, 2 reliable liver stiffness values determined using transient elastography (Fibroscan) < 10 kPa and one or more signs specific for portal hypertension

Exclusion Criteria:

• Myeloproliferative disease treated with aspirin to prevent vascular events, paroxysmal nocturnal hemoglobinuria.
• Ongoing oestroprogestative contraception
• Pregnant or breastfeeding women
• Complete thrombosis of superior mesenteric vein and/or inferior mesenteric vein
• Complete portal vein thrombosis or portal cavernoma
• Recent (<6 months) partial portal venous system thrombosis
• Mandatory indication or contraindication for anticoagulation according to guidelines of the American college of chest physicians
• Concomitant treatment with any other anticoagulant agent unless when bridging from one to the other is performed
• Disease at high risk of bleeding (except for portal hypertension)
• Active clinically significant bleeding:. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
• Platelet < 40000/mm3, or prothrombin index <40% in the absence of anti-vitamin K or Factor V < 40% or Fibrinogen < 1.0g/L
• Transjugular intrahepatic portosystemic shunt (TIPSS) or surgical portosystemic shunt
• Participation in another interventional trial
• Creatinine clearance < 30 mL/min
• Hepatitis C with detectable HCV RNA at inclusion
• Positive HBs Ag, except patients with HBeAg-negative chronic HBV infection, previously termed 'inactive carriers' [characterised by the presence of serum antibodies to HBeAg (anti-HBe), undetectable or low (<2,000 IU/mL) HBV DNA levels and normal serum ALT levels] that can be included
• Alcohol intake >210 g/week for men and 140 g/week for women
• Mandatory indication to aspirin or other antiplatelet agents including P2Y12 receptor antagonists according to guidelines of the American Heart Association
• Patient who underwent liver transplantation less than 3 years before screening
• Severe hepatic impairment or significant active liver injury (serum ALT level > 5 times the upper limit of normal values)
• Life expectancy <12 months
• Specific causes of portal hypertension or specific vascular liver diseases: history of bone marrow transplantation, Budd-Chiari syndrome / hepatic venous outflow obstruction, hepatic schistosomiasis diagnosed on liver biopsy (an isolated positive serology is not an exclusion criterion), cardiac failure, Fontan surgery, Abernethy syndrome, Hereditary hemorrhagic telangiectasia, chronic cholestatic diseases, liver infiltration by tumor cells
• Concomitant use of potent inhibitors of CYP3A4 or P-gp. In case of moderate interactions with apixaban (for example, immunosuppressive treatment), the dose of CYP3A4 inhibitor will be adapted according to its plasmatic level in the study patient.
• Hypersensitivity to the active substance or to any of the excipients including lactose.
• Patients unable to give consent (under guardianship or curatorship)
• No written informed consent for participation in the study
• No coverage for medical insurance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: APIXABAN; Apixaban, 1 pill of 2.5 mg per os twice a day (one in the morning and one in the evening) for 24 months.	Drug: Apixaban; Administration of Apixaban ; 2 clinical examinations; blood tests, 3 liver and spleen stiffness measurements, 2 contrast enhanced echocardiographies, 1 hepatic ultrasonography, Biological samples collections to identify predictors of thrombosis and liver related events
Placebo Comparator: PLACEBO; Placebo, 1 pill per os twice a day (one in the morning and one in the evening) for 24 months.	Drug: Placebo; Administration of placebo ; 2 clinical examinations; blood tests, 3 liver and spleen stiffness measurements, 2 contrast enhanced echocardiographies, 1 hepatic ultrasonography,

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Portal venous system thrombosis	Occurrence or extension of portal venous system thrombosis (including splenic, mesenteric veins, portal trunk or left or right portal branches) at 24 months in patients with INCPH.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of side effects	Any major bleeding as defined by the International Society on Thrombosis and Haemostasis guidelines; liver toxicity; adverse events and reactions.	24 months
Composite endpoint including thrombosis and major bleeding	Cumulative incidence of one event among: deep vein thrombosis in any location, arterial thrombosis, major bleeding, death	24 months
Occurence of vein or arterial thrombosis	Compare the effect of 24 months low dosing of apixaban (2.5 mg x 2/day) versus placebo on one event among: deep vein thrombosis in any location, arterial thrombosis,	24 months
Mortality or liver transplantation	cumulative incidence of death (global, liver related, non liver related) or liver transplantation	24 months
Complications of liver disease	cumulative incidence of liver decompensation, complications of portal hypertension including portal hypertensive related gastrointestinal bleeding, liver transplantation or death;	24 months
Portal hypertension related features	change in size of oesophageal varices	24 months
Portal hypertension related features	platelet count	24 months
Markers of bacterial translocation and inflammation	circulating concentrations of CRP	24 months
Liver function	change in child pugh score	24 months
Liver function	change in MELD score	24 months
Measure of Quality of life	change in quality of life assessed using SF36 questionnaire	24 months
Measure of quality life	change in quality of life assessed using CLDQ questionnaire	24 months
occurrence or the extension of portal venous system thrombosis at 24 months after randomisation in patients with INCPH according to HIV status	Compare the effect of 24 months low dosing of apixaban (2.5 mg x 2/day) versus placebo on the occurrence or the extension of portal venous system thrombosis (including splenic, mesenteric veins, portal trunk or left or right portal branches) at 24 months after randomisation in patients with INCPH according to HIV status	24 months
predictors of portal venous system thrombosis and liver related events	In group receiving Apixaban : plasma Apixaban levels	24 months
predictors of portal venous system thrombosis and liver related events	in the control group : portal blood flow Velocity	24 months
predictors of portal venous system thrombosis and liver related events	in the control group : stiffness measured using Fibroscan	24 months
predictors of portal venous system thrombosis and liver related events	in the control group : levels of specific coagulation tets (D-dimeres)	24 months
treatment compliance	number of compliant patient	24 months
occurrence or extension of portal venous system thrombosis or occurrence of deep vein thrombosis in any location or arterial thrombosis in the 6 months after the 24-month treatment with apixaban versus placebo	cumulative incidence of extension of portal venous system thrombosis or deep vein thrombosis in any location or arterial thrombosis in the 6 months after the 24-month treatment with apixaban versus placebo	30 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Pierre Emmanuel RAUTOU, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2019
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 24, 2019
• First Submitted That Met QC Criteria: July 1, 2019
• First Posted (Actual): July 5, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Hypertension; Hypertension, Portal; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: P170916J

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No