The primary objective is to demonstrate the non-inferiority of edoxaban (preceded by a short course of LMWH compared with dalteparin for theprevention of the combined outcome of recurrent venous thromboembolism (VTE) or major bleeding in subjects…
ID
Source
Brief title
Condition
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study outcome is the composite of recurrent VTE, and major bleeding.
Recurrent VTE is either:
* symptomatic confirmed (new) DVT or (new) PE;
* unsuspected (new) proximal DVT of the legs or unsuspected (new) PE located in
segmental or more proximal arteries:
* Unsuspected DVT or PE are thrombi that are detected during imaging testing
performed for other reasons (eg, computed tomography (CT) for cancer staging)
and not for suspicion of DVT or PE.
* fatal PE (including unexplained death for which PE cannot be ruled out).
Secondary outcome
Secondary Outcomes:
* Recurrent VTE;
* Major bleeding;
* CRNM bleeding;
* Major + CRNM bleeding;
* All bleedings;
* Event-free survival, defined as the proportion of subjects over time free of
recurrent VTE, major bleeding events, and death;
* VTE-related death;
* Mortality from all causes;
* Recurrent DVT;
* Recurrent PE;
* Healthcare resource utilization for potential recurrent VTE and bleed events.
Other outcomes include:
* Cardiovascular events (MI, stroke, SEE ;
* Thrombotic events at other locations ;
* Reason for permanent early discontinuation of study drug.
Background summary
Venous thromboembolism (VTE) is a common and clinically important disease in
cancer patients and current standard treatment consists of long-term
low-molecular weight heparin (LMWH). Although subcutaneous (SC) injections
with LMWH are effective they are often difficult to tolerate and inconvenient
for long-term use by cancer patients. Therefore, if oral medications, such as
the current direct oral anticoagulants (DOACs) are effective and safe without
the need for SC punctures, they are potentially an attractive alternative in
this population. The Hokusai VTE study has shown that edoxaban, an oral direct
Factor Xa (FXa) inhibitor, was effective and safe in the treatment of VTE. In
a subgroup analysis among 771 cancer patient randomized to the Hokusai VTE
study, edoxaban was non-inferior in terms of efficacy and associated with a
relative risk reduction of 19% in clinically relevant bleeding compared to
warfarin. In view of these results, a clinical study with edoxaban versus
LMWH in cancer-associated VTE is proposed
Study objective
The primary objective is to demonstrate the non-inferiority of edoxaban
(preceded by a short course of LMWH compared with dalteparin for the
prevention of the combined outcome of recurrent venous thromboembolism (VTE) or
major bleeding in subjects with VTE
associated with cancer during a 12-month study period. If noninferiority is
established, LMWH / edoxaban will be compared with
dalteparin for superiority.
Secondary Objectives are to compare LMWH/edoxaban with dalteparin with regards
to rates of:
1. Recurrent VTE;
2. Major bleeding;
3. Clinically relevant non-major (CRNM) bleeding;
4. Major + CRNM bleeding;
5. All bleedings;
6. Event-free survival, defined as the proportion of subjects over time free of
recurrent VTE, major bleeding events, and death;
7. VTE-related death;
8. Mortality from all causes;
9. Recurrent deep vein thrombosis (DVT);
10. Recurrent pulmonary embolism (PE);
11. Healthcare resource utilization for potential recurrent VTE and bleed
events.
Exploratory Objectives are to compare LMWH/edoxaban with dalteparin with
regards to:
1. Cardiovascular events (myocardial infarction [MI], stroke, systemic embolic
events [SEE; see Appendix 17.5.1]);
2. Thrombotic events at other locations (see Appendix 17.5.2)
3. Reason for permanent early discontinuation of study drug.
Study design
This is a multinational, prospective, randomized, open-label, blind-evaluator
(PROBE), non-inferiority study comparing edoxaban with dalteparin for
prevention of the combined outcome of recurrent VTE or major bleeding in
patients with VTE associated with cancer. One thousand subjects (1000) will be
equally randomized to 1 of the 2 treatment groups.
After a subject*s eligibility is confirmed, the subject will be stratified by
1) bleeding risk, and 2) the need for dose adjustment, and then randomly
assigned via interactive voice/web response system (IXRS) in a 1:1 ratio to
treatment with either LMWH/edoxaban or dalteparin.
The intended treatment duration and follow-up for all subjects is 12 months,
except for the final subject(s) randomized to the study. Once 1000 subjects
are randomized, a global End-of-Treatment (EOT) date will be established that
ensures a minimum of 6 months of study treatment and follow-up for the final
subject(s) randomized. All subjects will permanently discontinue study
treatment on or before the EOT date.
After randomization subjects will be assessed at Month 1, Month 3, and
quarterly thereafter for up to 12 months until they complete the study.
Subjects requiring additional anti-coagulation therapy who complete their
treatment and full 12-month post randomization follow-up or whose treatment is
truncated due to the global End of Treatment date will be managed according to
local practice.
Guidance for switching from edoxaban to other anticoagulants is provided in
Appendix 17.2.
Intervention
LMWH/Edoxaban group: Therapeutic doses of LMWH (subcutaneous [SC]) will be
administered for at least 5 days; this 5 day period may include the
pre-randomization LMWH (if applicable). The choice of this parenteral LMWH is
up to the treating physician. Thereafter, edoxaban will be started orally at
60 mg once daily [QD] (2 × 30 mg tablets) (30 mg QD for subjects requiring dose
adjustment) for the remainder of the treatment period.
Dalteparin group: After randomization, dalteparin will be administered at a
dose of 200 IU/kg SC (maximum daily dose 18,000 IU) for 30 days. The 30 day
period may include the pre-randomization anticoagulant treatment if dalteparin
was used in therapeutic doses. Thereafter (approximately Day 31 forward),
dalteparin will be administered at a dose of 150 IU/kg SC (~ 75% - 83% of the
initial dose) for the remainder of the treatment period.
Study burden and risks
Acute deep vein thrombosis of the leg (DVT) or pulmonary embolism (PE) are
serious medical conditions that require immediate treatment for which patients
are seen regularly by the treating physician especially when these disorders
are associated with cancer as in the current study. In accordance with the
current guidelines the minimum treatment duration is 6 months. During the
study, the physician will decide how long the treatment will last (6 or 12
months). This decision is made on the basis of an evaluation of the risk of
bleeding, weighed against the thrombosis risk in consultation with the patient.
If recurrent VTE is suspected diagnostic tests are done as e.g. a compression
ultrasound for DVT or a spiral CTscan (sCT) for PE . These tests are in
accordance with the common guidelines (i.e. no additional investigations in the
framework of the study).
During the entire study an additional blood sample at inclusion is needed, the
other blood tests during the study are considered routine in these patients
e.g. hematology (platelets, Hb) liver function, kidney function. These blood
samples can be analysed in the local laboratory. In the intended study period
of 12 months there are 7 evaluations planned: at month 1 and then every 3
months (flow chart in the protocol (p. 93-94). At every visit (as long as
patient is still on treatment) the weight is measured and there is an anamnesis
to evaluate the overall state of health and to see if there are any side
effects. Also compliance with intake of study medication will be evaluated.
Taken together, compared to the standard treatment and follow-up there will be
some extra blood sampling, the risk of the blood sampling is small and the
additional burden of weight measurement, medical history and compliance
control is not excessive and justified within the framework of the study .
Thornall Street 399
Edison NJ 08837
US
Thornall Street 399
Edison NJ 08837
US
Listed location countries
Age
Inclusion criteria
Inclusion Criteria:
1. Male or female subjects with age * 18 years or the otherwise legal lower age according to the country of residence;
2. Confirmed symptomatic or unsuspected lower extremity proximal DVT (ie, popliteal, femoral, iliac or inferior vena cava vein thrombosis), or confirmed symptomatic PE, or unsuspected PE of a segmental or larger pulmonary artery;
3. Cancer, other than basal-cell or squamous-cell carcinoma of the skin. Cancer should be active (see Section 6.1) or diagnosed within 2 years prior to randomization. The diagnosis/history of cancer must be objectively documented;
4. Intention for long-term treatment (at least 6 months) with parenteral LMWH;
5. Able to provide written informed consent.
Exclusion criteria
1. Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current (index) episode of DVT and/or PE;
2. More than 72 hours pre-treatment with therapeutic dosages of anticoagulant treatment (LMWH, unfractionated heparin, and fondaparinux per local labeling), oral direct anticoagulants or vitamin K antagonist (VKA) prior to randomization to treat the current (index) episode;
3. Treatment with therapeutic doses of an anticoagulant including dalteparin for an indication other than VTE prior to randomization;
4. Active bleeding or any contraindication for treatment with LMWH/dalteparin or edoxaban;
5. Indication for dalteparin other than DVT and/or PE;
6. An Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 or 4 at the time of randomization (see Appendix 17.6);
7. Calculated creatinine clearance (CrCL) < 30 mL/min;
8. History of heparin associated thrombocytopenia;
9. Acute hepatitis, chronic active hepatitis, liver cirrhosis;
10. Hepatocellular injury with concurrent transaminase (alanine transaminase [ALT]/aspartate transaminase [AST] > 3 x upper limit of normal [ULN]) and bilirubin (> 2 x ULN) elevations in the absence of a clinical explanation;
11. Life expectancy < 3 months;
12. Platelet count < 50,000/mL;
13. Uncontrolled hypertension as judged by the Investigator (eg, systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg despite antihypertensive treatment);
14. Women of childbearing potential without proper contraceptive measures, and women who are pregnant or breast feeding;
15. Chronic treatment with non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) including both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors for * 4 days/week anticipated to continue during the study;
16. Treatment with aspirin in a dosage of more than 100 mg/per day or dual antiplatelet therapy (any 2 antiplatelet agents including aspirin plus any other oral or intravenous antiplatelet drug) anticipated to continue during the study;
17. Systemic use of the P-gp inhibitors ketoconazole, itraconazole, erythromycin, azithromycin or clarithromycin at the time of randomization; subsequent use is permitted (with appropriate dose reduction of edoxaban);
18. Subjects with any condition that as judged by the Investigator would place the subject at increased risk of harm if he/she participated in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004708-30-NL |
| ClinicalTrials.gov | NCT02073682 |
| CCMO | NL52598.018.15 |