The aim of this study is to assess whether oral apixaban in non-inferior to the subcutaneous LMWH dalteparin for the treatment of newly diagnosed proximal DVT and/or PE in patients with cancer.
ID
Source
Brief title
Condition
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy outcome: Objectively confirmed recurrent VTE occurring during
the study treatment period, that means the composite of:
Proximal DVT of the lower limbs (symptomatic or unsuspected)
DVT of the upper limb (symptomatic)
PE (symptomatic or unsuspected)
Primary safety outcome is major bleeding, defined (as per ISTH guidelines), as
acute clinically overt bleeding associated with one or
more of the following:
- decrease in hemoglobin of 2 g/dl (1.2 mmol/L) or more;
- transfusion of 2 or more units of packed red blood cells;.
- bleeding that occurs in at least one critical site
[intracranial,intra-spinal, intraocular (within the corpus of the eye; thus, a
conjunctival bleed is not an intraocular bleed), pericardial, intraarticular,
intramuscular with compartment syndrome, or retroperitoneal];
- bleeding that is fatal;
- bleeding that necessitates acute surgical intervention
Secondary outcome
Secondary efficacy outcomes:
The individual components of the primary efficacy outcome
Symptomatic recurrence of the VTE
All cause death
The composite of primary efficacy outcome plus major bleeding
The composite of primary efficacy outcome plus major bleeding plus all cause
death
The composite of primary efficacy outcome plus all cause death
Any major cardiovascular event, fatal or non fatal (including acute Myocardial
Infarction or ischemic stroke)
All venous thromboembolic events (including splanchnic vein thrombosis and
cerebral vein thrombosis)
Quality of Life according to the Anti-Cot Treatment Scale (ACTS) (see appendix
2)
Secondary safety outcomes include:
· Clinically relevant non-major bleeding event defined as acute clinically
overt bleeding that does not meet the criteria for major
and consists of:
- any bleeding compromising hemodynamics;
- spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic
cause;
- intramuscular hematoma documented by ultrasonography;
- epistaxis or gingival bleeding requiring tamponade or other medical
intervention or bleeding from venipuncture for >5 minutes;
- hematuria that was macroscopic and was spontaneous or lasted for more than 24
hours after invasive procedures;
- hemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or
other medical intervention;
- or any other bleeding considered to have clinical consequences for a patient
such as medical intervention, the need for unscheduled contact (visit or
telephone call) with a physician, or temporary cessation of a study drug, or
associated with pain or impairment of activities of daily
life.
· Clinically relevant bleeding defined as the composite of major and clinically
relevant non-major bleeding
· Permanent early discontinuation of study drug due to safety reasons.
Background summary
Venous thromboembolism (VTE) is a common clinical event in patients with
cancer. The development of VTE is presumed to be due to the production of
pro-coagulant molecules by cancer cells and to the pro-coagulant effective
cancer cells spread into the circulation. It should be taken into account that
cancer surgery and chemotherapy are associated with a substantial increase in
the risk of VTE (1). The risk for bleeding complications on anticoagulant
therapy is also higher in cancer patients than in non-cancer patients such
making crucial the balance between benefit and risk (1). The CLOT study,
performed more than 15 years ago, showed that in patients with cancer
associated VTE, anticoagulant treatment with the LMWH dalteparin was more
effective and similarly safe compared to vitamin K antagonists (2). These
results were confirmed in studies with a more limited number of patients (3).
Thus, current guidelines recommend the use of :MWH, given subcutaneously, for
the acute and long term treatment of VTE in cancer patients (4-5). In the
recently published CATCH study in cancer patients, the LMWH tinzaparin was
associated with a non-significant 35% risk reduction in recurrence of VTE
compared to vitamin K antagonists (6).In the CTACH study, there were no
differences in the incidence of major bleeding between the two treatment
groups. Due to the high risk for recurrence, cancer patients who experience VTE
are candidate to indefinite treatment duration or to prolong treatment until
cancer is completely cured (4-5). The availability of an oral anticoagulant
treatment, as effective and safe as LMWH would be a substantial advantage for
patient with cancer who develop VTE. During the last years, new oral
anticoagulants given at fixed doses without the need of laboratory monitoring
and dose adjustments were shown to be as effective as and probably safer than
vitamin K antagonists for the treatment of VTE (7). The results of phase III
clinical trialled to their approval for the acute and long term treatment of
VTE. Unfortunately, the clinical trials on the treatment of VTE with the new
oral anticoagulants included only a limited number of patients with cancer.
Thus, whether the results obtained in the general population of patients with
VTE also attain to cancer patients remains undefined. Subgroup analysis on the
efficacy and safety profile of the anti-Xa oral agent apixaban for the
treatment of VTE in cancer patients have been recently reported (8-11). In
these patient with all the limitations related to a subgroup analysis, apixaban
appeared to be at least as effective as LMWH given with and followed by vitamin
K antagonists (10). A recent meta-analysis in cancer patients showed a similar
efficacy and safety profile of of new oral anticoagulants in comparison with
LMWH given with and followed by vitamin K antagonists for the treatment of VTE
(12).
Study objective
The aim of this study is to assess whether oral apixaban in non-inferior to the
subcutaneous LMWH dalteparin for the treatment of newly diagnosed proximal DVT
and/or PE in patients with cancer.
Study design
This is a multinational, prospective, randomized, open table, blinded end-point
(PROBE) non-inferiority study comparing apixaban to the LMWH dalteparin in the
treatment of VTE in patients with cancer.
Intervention
Subcutaneous injections with the anticoagulant as well as blood sampling 4
times during the study.
Study burden and risks
The nature and extend of the burden and risks for participants in this study
are:
In general, the subjects will need to take an anticoagulant with its risks.
However, the subjects will have to take this for there current diagnosis (VTE_
anyway and therefore there is no additional burden for the subject in
participating in this trial as far as anticoagulation other than the ones
described already under E9.
There will be visits to the clinic for this trial and the estimated duration of
those visits are approximately 4.5 hours for the entire participation, and this
includes the screening visit 9which is 72 hours or less until enrollment), the
enrollment visit, the 4 week and 3 months and 6 months visit and the end of
study visit, as well as potentially any unscheduled visit. The subjects will
undergo blood sampling for hematology and chemistry.
If the subject is randomized to the injectable anticoagulant, there will also
be the daily subcutaneous injections of those.
Risks that are not expected are potential risk of allergy and potentially any
unknown or unexpected reaction.
The potential benefit is that oral anticoagulant can may prescribed in future
of this patients.
Via F. Grossi Gondi 49
Rome 00162
IT
Via F. Grossi Gondi 49
Rome 00162
IT
Listed location countries
Age
Inclusion criteria
A newly diagnosed, objectively confirmed symptomatic or unsuspected, proximal
lower limb DVTor a symptomatic PE or an unsuspected PE in a segmental or more
proximal pulmonary artery. and any type of cancer (other than basal cell or
squamous cell carcinoma of the skin, primary brain tumors or intracerebral
metastasis and acute leukemia that meets at least one of the following: Active
cancer defined as diagnosis of cancer within 6 months before the study
inclusion, or receiving treatment for cancer at the time of inclusion or any
treatment for cancer during 6 months prior to randomization, or recurrent
locally advanced or metastatic cancer. Cancer diagnosed within 2 years before
the study inclusion (history of cancer).
Exclusion criteria
less than 18 years of age. ECOG performance status III or IV. Life expectancy
of less than 6 months. Related to anti coagulant therapy: administration of
therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for
more than 72 hours before randomization. Three or more doses of a vitamin K
antagonist before randomization. Thrombectomy, vena cava filter insertion, or
thrombolysis used to manage the index episode. Indication for anti coagulant
treatment for a disease other than the index VTE. Concomitant use of strong
inhibitors or inducers of both cytochrome P-450 3A4 and P-Glycoprotein. Related
to bleeding risks: concomitant thienopyridine therapy (clopidogrel, pasugrel or
ticagrelor) or aspirin over 165 mg daily oe dual antiplatlet therapy. Active
bleeding or a high risk of bleeding contraindicating anticoagulant therapy.
`recent (in the last 1 month prior to randomization) brain, spinal or
ophthalmic surgery. Hemoglobin level lower than 8 g/dl (5.0 mmil/Liter or
platelet count less than 75 x 10 to the 9th/L or history of heparin induced
thrombocytopenia. Creatinine clearance less than 30 ml/min based on the
Cockcroft Gault equation. Acute hepatitis, chronic active hepatitis, liver
cirrhosis, or an alanine aminotransferase level 3 times or more and/or
bilirubin level 2 times or more of of the higher of the upper limit of the
normal range. uncontrolled hypertension (systolic BP more than 180 mm HG or
diastolic BP more than 100 mm Hg despite antihypertensive treatment. Standard
criteria: Bacterial endocarditis, hypersensitivity to the study drugs or to any
of their excipients, patients participating in other pharmacy therapeutic
program with an experimental therapy that is know to effect the coagulation
system, women of child bearing potential (WOCBP) who do not practice a
medically accepted high effective contraception during the trial and one months
beyond, pregnancy or breast feeding, any condition that is judged by the
investigator that would place the subject at increased risk or harm if (s)he
participated in the study.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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 | EUCTR003093-40 NL-NL |
| CCMO | NL60090.058.17 |