Apixaban for Intrahepatic Non Cirrhotic Portal Hypertension

  • STATUS
    Recruiting
  • End date
    Jun 30, 2024
  • participants needed
    166
  • sponsor
    Assistance Publique - Hôpitaux de Paris
Updated on 4 March 2021

Summary

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

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:
  3. - at least one event among: deep vein thrombosis in any location, arterial thrombosis, major bleeding, death
  4. - the occurrence of deep vein thrombosis in any location or arterial thrombosis
  5. - mortality (global, liver related, non-liver related), and mortality or liver transplantation
  6. - each and any event among: liver decompensation, complications of portal hypertension including portal hypertensive related gastrointestinal bleeding, liver transplantation or death;
  7. - portal hypertension related features (spleen size, platelet count, size of esophageal varices, portal blood flow velocity) and markers of bacterial translocation and inflammation
  8. - liver function
  9. - quality of life
  10. 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
  11. 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
  12. To assess treatment compliance
  13. 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 16 centers in a prospective, national multicentric, phase III, superiority comparative randomized (1:1) double-blinded clinical trial with two parallel arms: apixaban versus placebo.

Details
Condition Intrahepatic Non Cirrhotic Portal Hypertension
Treatment Placebo, Apixaban
Clinical Study IdentifierNCT04007289
SponsorAssistance Publique - Hôpitaux de Paris
Last Modified on4 March 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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
absence of cirrhosis on an adequate liver biopsy, and one or more signs specific for portal hypertension
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
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 (Child-Pugh C) 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
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