A Randomized Phase II Open Label Study to Compare the Safety and Efficacy of Subcutaneous Dalteparin Versus Direct Oral Anticoagulants for Cancer-associated Venous Thromboembolism

NCT ID: NCT03139487

Last Updated: 2020-01-06

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 176 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-07
• Study Completion Date: 2021-09-30

Brief Summary

This is an open label, multi-center, and randomized phase II trial designed to compare the safety and efficacy of direct oral anticoagulants and subcutaneous dalteparin in patients with acute venous thromboembolism and upper gastrointestinal, hepatobiliary, or pancreatic cancer, based on a group sequential design. Enrolled patients will be randomized in a 1:1 ratio. Patients will be stratified by performance status, type of cancer, chemotherapy and medical centers.

Detailed Description

This randomized II clinical trial will enrol patients with advanced upper gastrointestinal, hepatobiliary and pancreatic cancer who have venous thromboembolism (VTE), including pulmonary embolism and deep vein thrombosis. Patients will be randomized in a 1:1 ratio and stratified by performance status, type of cancer and medical centers. The enrolled patients will receive either subcutaneous dalteparin or DOAC(rivaroxaban, apixavan) according to randomization until the end of planned treatment schedules (six months), recurrence of VTE, clinical relevant bleeding, major bleeding, death or discontinuation of study treatment for any other reason (e.g. withdrawal of consent or discretion of the investigator). The primary end-point is the rate of clinical relevant bleeding event as defined as overt bleeding which was associated with medical intervention. In addition to time to clinical relevant bleeding event, time to event of major bleeding, total bleeding including minor event, time to recurrent VTE, overall bleeding rate and overall VTE recurrent rate will be analyzed to compare safety and efficacy of both anticoagulants. The final analysis will be conducted when the last enrolled patient has an event or has completed as least six months follow up in the study. Patients without bleeding and recurrent VTE events at data cut-off are censored at the last date the patient is known to be free of events.

Planned interim analysis will be conducted in the intentions to treatment analysis set. The interim analysis for the randomized portion of the study will be performed when at least 40% of estimated bleeding events have been observed. The purpose of interim analysis is for early stopping of the study for safety. This study will use a Data Monitoring Committee.

Conditions

Cancer-associated Thrombosis; Esophageal Cancer; Stomach Cancer; Hepatocellular Carcinoma; Pancreatic Cancer; Duodenal Cancer; Esophagogastric Junction Cancer; Malignant Gastrointestinal Stromal Tumor; Ampulla of Vater Cancer; Biliary Cancer (Cholangiocarcinoma, Gall Bladder Cancer)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low molecular weight heparin

Dalteparin, 200 IU/kg subcutaneously once daily for 4 weeks followed by 150 IU/kg once daily for 20 weeks

Group Type: ACTIVE_COMPARATOR

Dalteparin

Intervention Type: DRUG

200 IU/kg q24 hours for 4 weeks followed by 150 IU/kg q24 hours for 20 weeks

Direct oral anticoagulant

Rivaroxaban, 15 mg orally twice daily for 3 weeks followed by 20mg once daily for 21 weeks

Apixaban, 10 mg orally twice daily for 7days followed by 5mg twice daily for 21 weeks

Group Type: EXPERIMENTAL

Rivaroxaban

Intervention Type: DRUG

15 mg q12 hours for 3 weeks followed by 20mg q24 hours for 21 weeks

apixaban

Intervention Type: DRUG

10 mg q12 hours for 7days followed by 5mg q12 hours for 21 weeks

Interventions

Rivaroxaban

15 mg q12 hours for 3 weeks followed by 20mg q24 hours for 21 weeks

Intervention Type: DRUG

Dalteparin

200 IU/kg q24 hours for 4 weeks followed by 150 IU/kg q24 hours for 20 weeks

Intervention Type: DRUG

apixaban

10 mg q12 hours for 7days followed by 5mg q12 hours for 21 weeks

Intervention Type: DRUG

Other Intervention Names

Xarelto; Fragmin; eliquis

Eligibility Criteria

Inclusion Criteria

• Histologically or cytologically confirmed locally advanced or metastatic active cancer including Esophageal cancer, Esophagogastric junction cancer, Stomach cancer, Gastrointestinal stromal disease, Ampulla of Vater cancer, Duodenal cancer, Hepatocelluar carcinoma, Biliary cancer (cholangiocarcinoma, gall bladder cancer), Pancreatic cancer
• Newly diagnosed deep vein thrombosis in any site and/or pulmonary thromboembolism on the basis of CT or doppler ultrasound image with or without symptoms
• Male or female ≥ 18 years, < 80 years old age
• Adequate major organ function including the following: Hematopoietic function: Platelet ≥ 75,000/mm3, Hepatic function: alanine aminotransferase levels 3 x upper limit of normal (if, with liver metastasis, alanine aminotransferase levels 5 x upper limit of normal), Aspartate Transaminase levels 3 x upper limit of normal (if, with liver metastasis, Aspartate Transaminase levels 5 x upper limit of normal), Renal function: estimated glomerular filtration rate ≥ 30 ml/min, Adequate coagulation time: prothrombin time ≤ 2 international normalized ratio, activated partial thromboplastin time 1.5 x upper limit of normal
• Able to understand and comply with the requirement of the study and to provide written informed consent

Exclusion Criteria

Patients will be excluded from the study for any of the following reasons:

• Hemodynamically unstable pulmonary thromboembolism
• Use with P-gp and strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) or inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort)
• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome (e.g. patients with partial or total gastrectomy can enter the study, but not those with a jejunostomy probe), or inability to take oral medication
• Patients with current bleeding
• Recent history of major or uncontrolled bleeding within the previous 4 weeks
• Severe malnutrition, BMI < 16
• Patients who are receiving a therapeutic dose of rivaroxaban, low molecular weight heparin, fondaparinux, or unfractionated heparin for more than 72 hours before enrollment
• Administration of a fibrinolytic agent for treatment of the current episode
• Uncontrolled systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg
• Patients who have to keep concurrent antiplatelet agent (e.g. aspirin, clopidogrel)
• Patients who have clinical significant liver cirrhosis (Child Pugh score ≥ 7)
• Inadequate cardiovascular function: New York Heart Association class III or IV heart disease, Unstable angina or myocardial infarction within the past 6 months, History of significant ventricular arrhythmia requiring medication with antiarrhythmics or significant conduction system abnormality
• Serious concurrent infection or nonmalignant illness that is uncontrolled or whose control may be jeopardized by complications of study therapy, including infective endocarditis
• History of or current brain metastases
• Life expectancy less than 3 months

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Asan Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Sook Ryun Park

Associated professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Asan Medical Center

Seoul, , South Korea

Site Status: RECRUITING

Countries

South Korea

Central Contacts

Sook Ryun Park, M.D., Ph.D.

Role: CONTACT

srpark@amc.seoul.kr

+82-2-3010-3210

Seyoung Seo, M.D.

Role: CONTACT

syseo@amc.seoul.kr

Facility Contacts

Sook Ryun Park

Role: primary

srpark@amc.seoul.kr

References

Riaz IB, Fuentes HE, Naqvi SAA, He H, Sipra QR, Tafur AJ, Padranos L, Wysokinski WE, Marshall AL, Vandvik PO, Montori V, Bryce AH, Liu H, Badgett RG, Murad MH, McBane RD 2nd. Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis. Mayo Clin Proc. 2022 Feb;97(2):308-324. doi: 10.1016/j.mayocp.2020.10.041. Epub 2021 Jun 22.

Reference Type: DERIVED

PMID: 34172290 (View on PubMed)

Other Identifiers

S2017-0327

Identifier Type: -

Identifier Source: org_study_id