A Study of Direct Oral Anticoagulants in Patients with Painful Venous Malformations with Localized Intravascular Coagulation (AVA)

A Single-center Blinded Crossover Study Investigating the Efficacy of Apixaban in Patients with Painful Venous Malformations with Localized Intravascular Coagulation

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Anticoagulants; Venous Malformation, Low Flow
• Intervention / Treatment: Drug: Apixaban (Eliquis); Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nina H Schultz, PhD MD; Phone Number: +4797636108; Email: nischu@ous-hf.no

Study Locations

• Norway
  • Oslo, Norway, 0372
    • Oslo University Hospital
    • Contact: Nina H Schultz, MD PhD; Phone Number: +47 97636108; Email: nischu@ous-hf.no
    • Contact: Puneet Kaur, MD; Phone Number: +47 45460140; Email: puneet.kaur@lds.no
    • Contact: Nina H Schultz, MD PhD
    • Contact: Puneet Kaur, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; placebo twice daily
Experimental: Apixaban; Apixaban 5 mg twice daily	Drug: Apixaban (Eliquis); 5 mg twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Average numeric rating scale (NRS) score(score 0-10 where 0 represents no pain and 10 represents worst imaginable pain) last 7 days before assessment	From enrollment to the end of treatment at 8 and 17 weeks
Change in pain medication	Registration of type, dose and frequency of pain medication last 7 days before assessment	From enrollment to the end of treatment at 8 and 17 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference between apixaban and placebo in change of quality of life before and 8 weeks after starting treatment	Outcome Measure for Vascular Malformation (OVAMA) questionnaire	From enrollment until end of treatment, at 8 and 17 weeks
Difference between apixaban and placebo in change of quality of life before and 8 weeks after starting treatment	Short form survey-36 (SF-36)	From enrollment until end of treatment, at 8 and 17 weeks]
Difference between apixaban and placebo in change in coagulation parameters before and 8 weeks after	D-dimer	From enrollment until after end of treatment at 8 and 17 weeks
Change in pain intensity after 3 months treatment	Numeric rating scale (NRS) score at time of evaluation (score 0-10 where 0 represents no pain and 10 represents worst imaginable pain)	From enrollment of Part 2 until completion of treatment at 6 months
Change in pain intensity three months after reducing dose	Numeric rating scale (NRS) score at time of evaluation (score 0-10 where 0 represents no pain and 10 represents worst imaginable pain)	At changing dose at 3 months after enrollment of Part 2 and after 6 months ( end of treatment)

Collaborators and Investigators

• Sponsor: Oslo University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: October 30, 2024
• First Submitted That Met QC Criteria: December 6, 2024
• First Posted (Estimated): December 11, 2024

Study Record Updates

• Last Update Posted (Estimated): December 11, 2024
• Last Update Submitted That Met QC Criteria: December 6, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: apixaban; venous malformation; localized intravascular coagulation
• Additional Relevant MeSH Terms: Congenital Abnormalities; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Anticoagulants; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Apixaban
• Other Study ID Numbers: 2024-511930-11-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data protection regulations does not allow sharing individual participant data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No