APIS Apixaban for Intrahepatic Non Cirrhotic Portal Hypertension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

24 Jun 2019 → ongoing

Decision date (initial)

2024-07-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

French Ministry

External identifiers

EU CT number

2024-514348-95-00

EudraCT number

2018-005047-90

ClinicalTrials.gov

NCT04007289

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the effect of 24 months low dosing of apixaban (2.5 mg x 2/day) versus placebo on the occurrence or the progression 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 objectives 6

1. 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. 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: (a)- at least one event among: deep vein thrombosis in any location, arterial thrombosis, major bleeding, death (b)- the occurrence of deep vein thrombosis in any location or arterial thrombosis (c)- mortality (global, liver related, non-liver related), and mortality or liver transplantation (d)- each and any event among: liver decompensation, complications of portal hypertension including portal hypertensive related gastrointestinal bleeding, liver transplantation or death; (e)- portal hypertension related features (spleen size, platelet count, size of esophageal varices, portal blood flow velocity) and markers of bacterial translocation and inflammation (f)- liver function (g)- quality of life
3. 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 progression 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. 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 group receiving apixaban: plasma apixaban levels
5. 5. To assess treatment compliance
6. 6. To study the occurrence or progression 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

Conditions and MedDRA coding

Intrahepatic non-cirrhotic portal hypertension

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. - >/=18 and ≤ 90 year old male and female patients
2. - For child-bearing aged women, contraception using progestatives, or intrauterine device or mechanical contraception
3. - Adequate prophylaxis against variceal bleeding according to EASL (European association for the study of the liver) guidelines
4. - 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: a. absence of cirrhosis on an adequate liver biopsy, and one or more signs specific for portal hypertension b. 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 c. 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 27

1. o Myeloproliferative disease treated with aspirin to prevent vascular events, paroxysmal nocturnal hemoglobinuria.
2. o Ongoing oestroprogestative contraception
3. o Pregnant or breastfeeding women
4. o Complete thrombosis of superior mesenteric vein and/or inferior mesenteric vein
5. o Complete portal vein thrombosis or portal cavernoma
6. o Recent (<6 months) partial portal venous system thrombosis
7. o Mandatory indicationa or contraindication to anticoagulation
8. o Concomitant treatment with any other anticoagulant agent unless when bridging from one to the other is performed
9. o Disease at high risk of bleeding (except for portal hypertension)
10. o 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.
11. o Platelet < 40000/mm3, or prothrombin index <40% in the absence of anti-vitamin K or Factor V < 40% or Fibrinogen < 1.0g/L
12. o Transjugular intrahepatic portosystemic shunt (TIPSS) or surgical portosystemic shunt
13. o Participation in another interventional trial
14. o Creatinine clearance < 30 mL/min
15. o Hepatitis C with detectable HCV RNA at inclusion
16. o 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
17. o Alcohol intake >210 g/week for men and 140 g/week for women
18. o Mandatory indicationb to aspirin or other antiplatelet agents including P2Y12 receptor antagonists
19. o Patient who underwent liver transplantation less than 3 years before screening
20. o Severe hepatic impairment or significant active liver injury (serum ALT level > 5 times the upper limit of normal values)
21. o Life expectancy <12 months
22. o 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
23. o 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.
24. o Hypersensitivity to the active substance or to any of the excipients including lactose.
25. o Patients unable to give consent (under guardianship or curatorship)
26. o No written informed consent for participation in the study
27. o No coverage for medical insurance

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Within 24 months after randomisation, cumulative incidence of occurrence or progression (according to VALDIG PVT criteria) of portal venous system thrombosis (including splenic and/or superior mesenteric vein and/or inferior mesenteric vein and/or portal trunk and/or one of the 2 portal branches), determined using a CT scan with centralized imaging blinded review

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

RAUTOU Pierre-Emmanuel

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

RAUTOU Pierre-Emmanuel

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications