Apixaban for Intrahepatic Non Cirrhotic Portal Hypertension
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 166
- 试验地点
- 1
- 主要终点
- Portal venous system thrombosis
研究概览
简要总结
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.
详细描述
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 :
- 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.
- 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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Participant)
盲法说明
double blind
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Apixaban (Drug)
PLACEBO
Placebo, 1 pill per os twice a day (one in the morning and one in the evening) for 24 months.
干预措施: Placebo (Drug)
结局指标
主要结局
Portal venous system thrombosis
时间窗: 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.
次要结局
- Occurrence of side effects(24 months)
- Composite endpoint including thrombosis and major bleeding(24 months)
- Occurence of vein or arterial thrombosis(24 months)
- Measure of Quality of life(24 months)
- Mortality or liver transplantation(24 months)
- Complications of liver disease(24 months)
- Portal hypertension related features(24 months)
- Markers of bacterial translocation and inflammation(24 months)
- Liver function(24 months)
- Measure of quality life(24 months)
- occurrence or the extension of portal venous system thrombosis 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(24 months)
- treatment compliance(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(30 months)