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Apixaban for Intrahepatic Non Cirrhotic Portal Hypertension (APIS)

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ClinicalTrials.gov Identifier: NCT04007289
Recruitment Status : Recruiting
First Posted : July 5, 2019
Last Update Posted : July 5, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief 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.


Condition or disease Intervention/treatment Phase
Intrahepatic Non Cirrhotic Portal Hypertension Drug: Apixaban Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 166 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study will be a prospective, national multicentric, phase III, superiority comparative randomized (1:1) double-blinded clinical trial with two parallel arms: apixaban versus placebo.
Masking: Single (Participant)
Masking Description: double blind
Primary Purpose: Prevention
Official Title: Apixaban for Intrahepatic Non Cirrhotic Portal Hypertension
Actual Study Start Date : June 24, 2019
Estimated Primary Completion Date : February 15, 2024
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Clots
Drug Information available for: Apixaban

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,




Primary Outcome Measures :
  1. Portal venous system thrombosis [ Time Frame: 24 months ]
    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.


Secondary Outcome Measures :
  1. Occurrence of side effects [ Time Frame: 24 months ]
    Any major bleeding as defined by the International Society on Thrombosis and Haemostasis guidelines; liver toxicity; adverse events and reactions.

  2. Composite endpoint including thrombosis and major bleeding [ Time Frame: 24 months ]
    Cumulative incidence of one event among: deep vein thrombosis in any location, arterial thrombosis, major bleeding, death

  3. Occurence of vein or arterial thrombosis [ Time Frame: 24 months ]
    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,

  4. Mortality or liver transplantation [ Time Frame: 24 months ]
    cumulative incidence of death (global, liver related, non liver related) or liver transplantation

  5. Complications of liver disease [ Time Frame: 24 months ]
    cumulative incidence of liver decompensation, complications of portal hypertension including portal hypertensive related gastrointestinal bleeding, liver transplantation or death;

  6. Portal hypertension related features [ Time Frame: 24 months ]
    change in size of oesophageal varices

  7. Portal hypertension related features [ Time Frame: 24 months ]
    platelet count

  8. Markers of bacterial translocation and inflammation [ Time Frame: 24 months ]
    circulating concentrations of CRP

  9. Liver function [ Time Frame: 24 months ]
    change in child pugh score

  10. Liver function [ Time Frame: 24 months ]
    change in MELD score

  11. Measure of Quality of life [ Time Frame: 24 months ]
    change in quality of life assessed using SF36 questionnaire

  12. Measure of quality life [ Time Frame: 24 months ]
    change in quality of life assessed using CLDQ questionnaire

  13. occurrence or the extension of portal venous system thrombosis at 24 months after randomisation in patients with INCPH according to HIV status [ Time Frame: 24 months ]
    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

  14. predictors of portal venous system thrombosis and liver related events [ Time Frame: 24 months ]
    In group receiving Apixaban : plasma Apixaban levels

  15. predictors of portal venous system thrombosis and liver related events [ Time Frame: 24 months ]
    in the control group : portal blood flow Velocity

  16. predictors of portal venous system thrombosis and liver related events [ Time Frame: 24 months ]
    in the control group : stiffness measured using Fibroscan

  17. predictors of portal venous system thrombosis and liver related events [ Time Frame: 24 months ]
    in the control group : levels of specific coagulation tets (D-dimeres)

  18. treatment compliance [ Time Frame: 24 months ]
    number of compliant patient

  19. 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 [ Time Frame: 30 months ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 (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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04007289


Contacts
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Contact: Pierre Emmanuel RAUTOU 140875283 ext +33 pierre-emmanuel.rautou@aphp.fr
Contact: Dominique VALLA 140875283 ext +33 dominique.valla@aphp.fr

Locations
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France
Beaujon hospital Recruiting
Clichy, France, 92110
Contact: Pierre emmanuel RAUTOU    1 40 87 50 00 ext 33    pierre-emmanuel.rautou@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Pierre Emmanuel RAUTOU Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04007289    
Other Study ID Numbers: P170916J
First Posted: July 5, 2019    Key Record Dates
Last Update Posted: July 5, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hypertension, Portal
Hypertension
Vascular Diseases
Cardiovascular Diseases
Liver Diseases
Digestive System Diseases
Apixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants