Clinical trial NCT06729034: A Study of Direct Oral Anticoagulants in Patients with Painful Venous Malformations with Localized Intravascular Coagulation
Official title: A Single-center Blinded Crossover Study Investigating the Efficacy of Apixaban in Patients with Painful Venous Malformations with Localized Intravascular Coagulation
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Venous Malformation, Low Flow
Anticoagulants
Keywords: apixaban
venous malformation
localized intravascular coagulation
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
First posted: 2024-12-11
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized study, crossover design, double-blind
Primary purpose: TREATMENT

Brief summary: There are two parts of the study. In Part 1, the invesitgaotrs want to investigate whether treatment with apixaban improves pain and quality of life in patients with painful venous malformations The participants are randomized to different treatment orders of the two treatment periods with apixaban and placebo. Arm 1 starts apixaban followed by placebo and arm 2 starts with placebo followed by apixaban. Between the treatment sequences there will be a washout period of minimum one week.

The participants will register pain and use og pain medication in a diary every day for one week before start of treatment and before evaluation of effect. Also, a quality of life form will be filled out before each consultation.

In Part 2, the investigators will investigate long-term effect and safety of apixaban and reduce dose after 3 months to find the minimal effective dose.

Part 2 includes participants from Part 1 study who experienced effect of treatment or who agree to continue apixaban treatment. Study start of Part 2 is at the end of Part 1. All participants receive the same dose of apixaban as in part 1 (5 mg twice daily), and after 3 months (visit 2) the dose is reduced to 2.5 mg twice daily.

Detailed description: There are no established universal guidelines on the hematologic management of patients with venous malformations (VM) with and without localized intravascular coagulopathy (LIC). Anticoagulation treatment with low molecular weight heparin (LMWH) has improved functionality and decreased pain in patients with VM with localized LIC.

The aim is to study the effect of the direct oral anticoagulant apixaban in patients with painful venous malformations with localized intravascular coagulation.

Apixaban is an oral direct acting anticoagulant shown to be as effective and safe as LMWH and warfarin in treating venous thrombosis.

single-center, prospective double-blind crossover superiority study including patients with venous malformations at age 18-85 years. The participants are randomized to different treatment orders of the two treatment periods with apixaban and placebo. Masking of participants and study personell. Randomization at screening to arm 1 or arm 2. Arm 1 starts apixaban followed by placebo and arm 2 starts with placebo followed by apixaban. Between the treatment sequences there will be a washout period of one week.

Part 2: The AVA Long study is an open-label observational study including participants from the AVA study who experienced effect of treatment or who agree to continue apixaban treatment. Study start of AVA long (part 2) is at study end of part 1. The participants receive the dose of apixaban as in part 1 (5 mg twice daily), but open-label, and after 3 months (visit 2) the dose is reduced to 2.5 mg twice daily. The investigators will investigate long-term efficacy and safety of apixaban and find the minimal effective dose.

Eligibility criteria: Inclusion Criteria:

* 1. Participant must be 18-85 years of age at the time of signing the informed consent form (ICF).

  2. Participants who have simple VM with LIC. VM must be diagnosed by MRi and LIC is defined as d-dimer \> 2 x upper reference area (21).

  3. Patients must experience pain from the malformation, NRS ≥4. Pain is defined as local pain in the malformation, and the participant must have pain that inhibits daily activity or pain during nighttime that interferes with sleep.

  4. Body weight over 50 kg. 5. Pregnancy test at time of inclusion must be negative 6. Capable of giving written informed consent

Exclusion Criteria:

1. History of major bleeding, known disease of the GI tractus with risk of bleeding (ulcera, IBD, tumor), known hemostatic disorder/hemophilia, bariatric surgery or other condition resulting in impaired adsorption of drug, active cancer
2. Lesion or condition if considered a significant risk factor for major 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, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities
3. Current treatment with platelet inhibitor, any other anticoagulation treatment e.g. unfractionated heparin, low molecular weight heparin (dalteparin, enoxaparin), heparin derivates (fondaparinux), oral anticoagulants (warfarin, dabigatran, rivaroxaban, edoxaban), NSAIDs, cancer therapy with chemotherapy
4. Current treatment with sirolimus
5. Current treatment with azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole)
6. Current treatment with HIV protease inhibitors (e.g., ritonavir)
7. Weight \<50 kg
8. Known hypersensitivity to the active substance or to any of the excipients listed in the SmPC.
9. Impaired renal function (eGFR \< 50 ml/min)
10. Impaired liver function, INR \> 1.3 or aminotransferases \> 3 times upper limit
11. Pregnancy or breastfeeding
12. Low platelet count (\<100 x 109/mL)
13. Any condition that in the view of the investigator would suggest that the patient is unable to comply with the study protocol and procedures

Primary outcomes:
measure: Difference between apixaban and placebo in change of self-reported pain intensity before and 8 weeks after starting treatment Change in type, dose and frequency of pain medication
timeFrame: From enrollment to the end of treatment at 8 and 17 weeks
measure: Change in pain medication
timeFrame: From enrollment to the end of treatment at 8 and 17 weeks
Secondary outcomes:
measure: Difference between apixaban and placebo in change of quality of life before and 8 weeks after starting treatment
timeFrame: From enrollment until end of treatment, at 8 and 17 weeks
measure: Difference between apixaban and placebo in change of quality of life before and 8 weeks after starting treatment
timeFrame: From enrollment until end of treatment, at 8 and 17 weeks]
measure: Difference between apixaban and placebo in change in coagulation parameters before and 8 weeks after
timeFrame: From enrollment until after end of treatment at 8 and 17 weeks
measure: Change in pain intensity after 3 months treatment
timeFrame: From enrollment of Part 2 until completion of treatment at 6 months
measure: Change in pain intensity three months after reducing dose
timeFrame: At changing dose at 3 months after enrollment of Part 2 and after 6 months ( end of treatment)
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Oslo University Hospital
Study officials:
References:
citation: Liu H, Hu L, Yang X, Xu Z, Gu H, Chen H, Lin X. Dabigatran etexilate is efficacious in consumptive coagulopathy and pain associated with venous malformations. J Vasc Surg Venous Lymphat Disord. 2023 Mar;11(2):397-403.e1. doi: 10.1016/j.jvsv.2022.09.015. Epub 2022 Oct 31.