Efficacy and Safety of Rivaroxaban in the Prevention of Venous Thromboembolism in Glioma Patients

NCT ID: NCT06196918

Last Updated: 2024-01-09

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

320 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-11-01

Study Completion Date

2025-02-28

Brief Summary

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Glioma is a common brain tumor with a high risk of venous thromboembolism during treatment, especially in the months after surgery. Postoperative lower extremity dyskinesia in patients with gliomas is considered as a high-risk factor for venous thromboembolism. Rivaroxaban, as an oral anticoagulants, has similar effect in the prevention and treatment of tumor-related venous thromboembolism compared to low molecular weight heparin. Given the lack of prospective supporting data, the efficacy and safety of rivaroxaban in the prevention of postoperative venous thromboembolism in glioma patients with postoperative lower extremity dyskinesia need to be established.

Detailed Description

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Venous thromboembolism (VTE) is a disorder in which blood clots abnormally in the veins, resulting in complete or incomplete blockage of blood vessels, including deep vein thrombosis and pulmonary embolism of the lower extremities, and is a common complication in patients with malignancy. In a retrospective analysis of the causes of death in patients with active cancer receiving chemotherapy, thromboembolic disease was the second leading cause of death, with VTE accounting for the vast majority. The risk of venous thromboembolism varies depending on the type of cancer, but it has been reported that the incidence of brain tumors can be greater than 20 percent per year, especially in the early postoperative period. High-grade gliomas are common brain tumors with a 20 to 30 percent risk of venous thrombosis during treatment, and postoperative lower extremity dysfunction in patients with high-grade gliomas is considered a high-risk factor for venous thrombosis. Because many high-grade gliomas are located in or adjacent to functional areas, such as frontopariparietal glioma, parietal glioma, thalamic glioma, and others, patients are more likely to develop limb dysfunction. Therefore, it is necessary to prevent venous thromboembolism for patients with high-grade glioma with lower extremity dysfunction after surgery.

Risk factors for venous thromboembolism can be divided into patient-related, tumor-related, and treatment-related. Patient-related factors include age \>65 years, weight gain, hypertension, A or AB blood type, previous history of venous thrombosis or pulmonary embolism, and paraparesis. Risk factors associated with tumors include high-grade glioma, tumor diameter \>5 cm, and residual tumor after surgery. Treatment-related risk factors include early postoperative period (within 30 days), surgery time \>4 hours, chemotherapy, anti-vascular endothelial growth factor therapy, hormonal therapy, and central venous catheterization. Lower extremity dysfunction in patients with glioma is both tumor-related and treatment-related. In the past, clinicians did not routinely administer prophylactic anticoagulation to glioma patients with lower limb disorders because the use of anticoagulants would increase the chance of postoperative intracranial hemorrhage. However, it was reported that the risk of venous thromboembolism in patients with lower extremity dysfunction was 2.6 to 3.6 times than in those without lower extremity dysfunction, and recent studies have shown that the combination of perioperative compression stockings, pneumatic plantar venous pumps and low molecular weight heparin (LMWH) maximizes the prevention of venous thromboembolism in critically neurosurgical patients without a high risk of bleeding. Moreover, a previous randomized, double-blind prospective clinical trial evaluated the safety of heparin in the perioperative period of brain tumors, and the results suggested that the perioperative use of low-dose heparin in brain tumors was safe and effective, and did not increase the risk of bleeding compared with controls. Another meta-analysis further confirmed the safety of LMWH or unfractionated heparin for the prevention of venous thromboembolism after neurosurgery.

However, there are few studies on the use of LMWH in this population, and there is no consensus on the safety of LMWH for the prevention of venous thromboembolism in this population. A phase III randomized controlled trial in patients with high-grade glioma, initiated in 2002, evaluated the safety and efficacy of postoperative LMWH for the prevention of venous thromboembolism, suggesting that LMWH can reduce the occurrence of venous thrombosis but also increase the risk of bleeding. The Eastern Cooperative Oncology Group has also evaluated the use of LMWH for the prevention of glioblastoma, and the use of LMWH reduced thrombosis without increasing the probability of intracranial hemorrhage. In addition, the scale and number of cases in the above studies were small. Therefore, there is an urgent need to explore an effective and safe method to prevent postoperative venous thromboembolism in glioma patients with lower limb dysfunction.

Rivaroxaban is an oral anticoagulant that directly inhibits Xa and thrombin and is widely used in noncancer-associated VTE due to its oral availability, high bioavailability with no need for frequent coagulation monitoring. In the study of tumor-related VTE, rivaroxaban has preliminarily shown no less effect than LMWH in the prevention and treatment of venous thromboembolism. Mohamed et al. systematically reviewed and meta-analyzed the efficacy and complications of LMWH and rivaroxaban in cancer-related thrombosis, and the results suggested that rivaroxaban had a lower risk of VTE recurrence and all-cause mortality, and that the main bleeding risk was no different from that of LMWH. In a phase III SELECT-D pilot study comparing the efficacy and complications of cancer-related thrombosis with the two agents, rivaroxaban was associated with a low risk of VTE recurrence and a low risk of major and non-major bleeding. Therefore, rivaroxaban has a good role in the prevention of tumor-related VTE. And because of its convenience of being oral and not requiring frequent monitoring, it is of great significance for clinical treatment.

In summary, in view of the current lack of research on postoperative prophylactic anticoagulation therapy in patients with glioma, our center plans to lead a multi-center, randomized, double-blind controlled prospective clinical trial in glioma patients with lower limb dysfunction after surgery. To determine whether the addition of rivaroxaban has a more active preventive effect on postoperative venous thromboembolism, and to explore the safety of rivaroxaban in preventing postoperative venous thromboembolism in glioma patients lower limb dysfunction.

Conditions

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Glioma, Malignant

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Rivaroxaban group

Patients with highly suspected, newly diagnosed, untreated glioma undergo surgical resection. CT scan within 24 hours after surgery is performed to rule out intracranial hemorrhage and/or infarction. Then those patients with postoperative lower extremity dyskinesia are treated with rivaroxaban (10 mg/day) and compression stockings until 1 month after surgery.

Group Type EXPERIMENTAL

Rivaroxaban 10 MG

Intervention Type DRUG

Patients with postoperative lower extremity dyskinesia are treated with rivaroxaban (10 mg/day) and compression stockings until 1 month after surgery.

Placebo group

Patients with highly suspected, newly diagnosed, untreated glioma undergo surgical resection. CT scan within 24 hours after surgery is performed to rule out intracranial hemorrhage and/or infarction. Then those patients with postoperative lower extremity dyskinesia are treated with placebo and compression stockings until 1 month after surgery.

Group Type ACTIVE_COMPARATOR

Placebo

Intervention Type DRUG

Patients with postoperative lower extremity dyskinesia are treated with placebo (10 mg/day) and compression stockings until 1 month after surgery.

Interventions

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Rivaroxaban 10 MG

Patients with postoperative lower extremity dyskinesia are treated with rivaroxaban (10 mg/day) and compression stockings until 1 month after surgery.

Intervention Type DRUG

Placebo

Patients with postoperative lower extremity dyskinesia are treated with placebo (10 mg/day) and compression stockings until 1 month after surgery.

Intervention Type DRUG

Other Intervention Names

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Jiangsu Zhongbang pharmaceutical CO., LTD; Serial numbers: H20203733 Jiangsu Zhongbang pharmaceutical CO., LTD

Eligibility Criteria

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Inclusion Criteria

* Individuals aged 18-80 years old with highly suspected (as assessed by study surgeon), newly diagnosed, untreated glioma.
* Patients without heart insufficiency, lungs insufficiency, renal insufficiency, hepatic insufficiency, autoimmune diseases and other organ diseases with severe dysfunction.
* Individuals who agree to undergo surgical resection.
* Individuals with dyskinesia after surgery.
* All patients giving written informed consent.

Exclusion Criteria

* Individuals with age \< 18 years or \> 80 years.
* Patients with heart insufficiency, lungs insufficiency, renal insufficiency, hepatic insufficiency, autoimmune diseases and other organ diseases with severe dysfunction.
* Individuals have acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), have peptic ulcer and gastrointestinal bleeding in the past 5 years.
* Patients have history of long-term (current) use of anticoagulants, spontaneous intracranial hemorrhage, and venous thromboembolism.
* Individuals have intracranial hemorrhage after surgery, or other active bleeding.
* Postoperative coagulation disorders (INR \>1.5 or platelet counts \< 100x10\^9/L).
* Patients are allergic to Rivaroxaban.
* Pregnancy or breast-feeding women.
* Inability to give written informed consent.
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Nanfang Hospital, Southern Medical University

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Guanglong Huang, M.D.

Role: PRINCIPAL_INVESTIGATOR

Nanfang Hospital, Southern Medical University

Locations

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Beijing Tiantan Hospital

Beijing, Beijing Municipality, China

Site Status RECRUITING

Fujian provincial hospital

Fuzhou, Fujian, China

Site Status RECRUITING

The First People's Hospital of Foshan

Foshan, Guangdong, China

Site Status RECRUITING

The First Affiliated Hospital of Shantou University Medical College

Shantou, Guangdong, China

Site Status RECRUITING

Longgang Central Hospital of Shenzhen

Shenzhen, Guangdong, China

Site Status RECRUITING

Guangxi Medical University Cancer Hospital

Nanning, Guangxi, China

Site Status RECRUITING

Hainan general hospital

Haikou, Hainan, China

Site Status RECRUITING

The First Affiliated Hospital of Nanjing Medical University

Nanjing, Jiangsu, China

Site Status RECRUITING

Countries

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China

Central Contacts

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Tianshi Que, M.D.

Role: CONTACT

+86-020-61641806

Facility Contacts

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Lei Wang, M.D.

Role: primary

Shihao Zheng, M.D.

Role: primary

Lianxu Cui, M.D.

Role: primary

Yiming Xu, M.D.

Role: primary

Xiaofeng Shi, M.D.

Role: primary

Ligen Mo, M.D.

Role: primary

Chengpeng Wang, M.D.

Role: primary

Yongping You, M.D.

Role: primary

References

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Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007 Mar;5(3):632-4. doi: 10.1111/j.1538-7836.2007.02374.x. No abstract available.

Reference Type BACKGROUND
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Reference Type BACKGROUND
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Brandes AA, Scelzi E, Salmistraro G, Ermani M, Carollo C, Berti F, Zampieri P, Baiocchi C, Fiorentino MV. Incidence of risk of thromboembolism during treatment high-grade gliomas: a prospective study. Eur J Cancer. 1997 Sep;33(10):1592-6. doi: 10.1016/s0959-8049(97)00167-6.

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Simanek R, Vormittag R, Hassler M, Roessler K, Schwarz M, Zielinski C, Pabinger I, Marosi C. Venous thromboembolism and survival in patients with high-grade glioma. Neuro Oncol. 2007 Apr;9(2):89-95. doi: 10.1215/15228517-2006-035. Epub 2007 Feb 27.

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Reference Type BACKGROUND
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Reference Type BACKGROUND
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Tucha O, Smely C, Preier M, Lange KW. Cognitive deficits before treatment among patients with brain tumors. Neurosurgery. 2000 Aug;47(2):324-33; discussion 333-4. doi: 10.1097/00006123-200008000-00011.

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Chaichana KL, Pendleton C, Jackson C, Martinez-Gutierrez JC, Diaz-Stransky A, Aguayo J, Olivi A, Weingart J, Gallia G, Lim M, Brem H, Quinones-Hinojosa A. Deep venous thrombosis and pulmonary embolisms in adult patients undergoing craniotomy for brain tumors. Neurol Res. 2013 Mar;35(2):206-11. doi: 10.1179/1743132812Y.0000000126. Epub 2012 Dec 13.

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Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost. 2010 Feb;8(2):221-7. doi: 10.1111/j.1538-7836.2009.03690.x. Epub 2009 Nov 13.

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Misch M, Czabanka M, Dengler J, Stoffels M, Auf G, Vajkoczy P, Stockhammer F. D-dimer elevation and paresis predict thromboembolic events during bevacizumab therapy for recurrent malignant glioma. Anticancer Res. 2013 May;33(5):2093-8.

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Perry JR, Julian JA, Laperriere NJ, Geerts W, Agnelli G, Rogers LR, Malkin MG, Sawaya R, Baker R, Falanga A, Parpia S, Finch T, Levine MN. PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost. 2010 Sep;8(9):1959-65. doi: 10.1111/j.1538-7836.2010.03973.x.

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Mohamed MFH, ElShafei MN, Ahmed MB, Abdalla LO, Ahmed I, Elzouki AN, Danjuma MI. The Net Clinical Benefit of Rivaroxaban Compared to Low-Molecular-Weight Heparin in the Treatment of Cancer-Associated Thrombosis: Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost. 2021 Jan-Dec;27:1076029620940046. doi: 10.1177/1076029620940046.

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Reference Type BACKGROUND
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Other Identifiers

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NFEC-2023-314

Identifier Type: -

Identifier Source: org_study_id

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