Cancer, Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Venous Thromboembolism (VTE)
Conditions
Keywords
Active Cancer with Metastasis
Brief summary
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 non-inferiority is established, LMWH/edoxaban will be compared with dalteparin for superiority.
Interventions
DRUGEdoxaban
After the 5 day treatment with LMWH, patients receive edoxaban 60 mg once daily (QD) as 2 × 30 mg tablets (or 1 x 30 mg tablet QD for patients requiring dose adjustment) for the remainder of the treatment period.
DRUGDalteparin
Dalteparin was administered via subcutaneous injection at a dose of 200 IU/kg (maximum daily dose 18,000 IU) for 30 days, and at a dose of 150 IU/kg from Day 31 to the end of treatment.
DRUGLow molecular weight heparin
Therapeutic doses of subcutaneous LMWH were administered for at least 5 days (to patients in the edoxaban group); this 5-day period may have included the pre-randomization LMWH (if applicable). The choice of parenteral LMWH was up to the treating physician.
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects with age ≥ 18 years or the otherwise legal lower age according to the country of residence; * Confirmed acute lower extremity proximal DVT or PE for which long term treatment with low molecular weight heparin (LMWH) is indicated; * Cancer, other than basal-cell or squamous-cell carcinoma of the skin; * Able to provide written informed consent.
Exclusion criteria
* Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current (index) episode of DVT and/or PE; * Treatment with therapeutic doses of an anticoagulant other than that used for pretreatment of the current (index) VTE episode prior to randomization; * Active bleeding or high risk for bleeding contraindicating treatment with LMWH or edoxaban; * Any other contraindication listed in the local labeling of dalteparin, enoxaparin, or edoxaban;
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Adjudicated Recurrent Venous Thromboembolism (VTE) or Major Bleeding Event | 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Recurrent Venous Thromboembolism (VTE) During the Overall Study Period | 12 months | — |
| Number of Participants With Recurrent Deep Vein Thrombosis (DVT) During the Overall Study Period | 12 months | — |
| Number of Participants With Adjudicated Major Bleeding Events While on Treatment | 12 months | The primary safety endpoint was major bleeding events during the On-Treatment Study Period (defined as on-study drug or up to 3 days after the last dose of study drug). |
| Number of Participants With VTE-Related Death | 12 months | — |
| Number of Participants With Recurrent VTE, Major Bleed or All-Cause Death | 12 months | — |
| Number of Participants With Recurrent Non-Fatal Pulmonary Embolism (PE) During the Overall Study Period | 12 months | — |
Countries
Belgium, France, Hungary, Italy, Netherlands, United States
Participant flow
Recruitment details
1050 participants were randomized from 114 sites in Western Europe (31), Central Europe (11), South Europe (36), Australia/New Zealand (13) and North America (23)
Pre-assignment details
Of 1050 participants randomized, 1046 took study drug and were included in the modified Intent to Treat (mITT) and Safety Analysis Sets
Participants by arm
| Arm | Count |
|---|---|
| Edoxaban Group After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily | 522 |
| Dalteparin Group Participants received dalteparin daily | 524 |
| Total | 1,046 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 79 | 62 |
| Overall Study | Cancer Cured | 10 | 15 |
| Overall Study | Cancer Progression | 53 | 33 |
| Overall Study | Death | 86 | 100 |
| Overall Study | ID: Benefit/Risk Judgment | 32 | 46 |
| Overall Study | ID: Palliative Treatment Only | 10 | 7 |
| Overall Study | ID: Patient Noncompliance | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Low Creatinine Clearance | 1 | 2 |
| Overall Study | No reason provided | 11 | 9 |
| Overall Study | PD: Inconvenience of Dosing | 21 | 78 |
| Overall Study | Platelet Count <50,000/mL | 1 | 2 |
| Overall Study | Prohibited Concomitant Medication Use | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Start of New Chemotherapy Regimen | 6 | 3 |
| Overall Study | Surgery/Medical Procedure | 3 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 8 |
Baseline characteristics
| Characteristic | Edoxaban Group | Dalteparin Group | Total |
|---|---|---|---|
| Age, Continuous | 66 years | 65 years | 65 years |
| Age, Customized 18-64 Years | 246 Participants | 261 Participants | 507 Participants |
| Age, Customized 65-84 Years | 267 Participants | 254 Participants | 521 Participants |
| Age, Customized 85 years and over | 9 Participants | 9 Participants | 18 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 13 Participants | 19 Participants |
| Race/Ethnicity, Customized Black or African American | 17 Participants | 21 Participants | 38 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 33 Participants | 44 Participants | 77 Participants |
| Race/Ethnicity, Customized White | 453 Participants | 427 Participants | 880 Participants |
| Region of Enrollment Australia | 16 participants | 16 participants | 32 participants |
| Region of Enrollment Austria | 13 participants | 15 participants | 28 participants |
| Region of Enrollment Belgium | 22 participants | 19 participants | 41 participants |
| Region of Enrollment Canada | 98 participants | 102 participants | 200 participants |
| Region of Enrollment Czechia | 11 participants | 10 participants | 21 participants |
| Region of Enrollment France | 58 participants | 64 participants | 122 participants |
| Region of Enrollment Germany | 30 participants | 29 participants | 59 participants |
| Region of Enrollment Hungary | 17 participants | 16 participants | 33 participants |
| Region of Enrollment Italy | 45 participants | 45 participants | 90 participants |
| Region of Enrollment Netherlands | 61 participants | 57 participants | 118 participants |
| Region of Enrollment New Zealand | 12 participants | 13 participants | 25 participants |
| Region of Enrollment Spain | 35 participants | 35 participants | 70 participants |
| Region of Enrollment United States | 104 participants | 103 participants | 207 participants |
| Sex: Female, Male Female | 245 Participants | 261 Participants | 506 Participants |
| Sex: Female, Male Male | 277 Participants | 263 Participants | 540 Participants |
| Type of Cancer Haematological Malignancy | 56 Participants | 55 Participants | 111 Participants |
| Type of Cancer Solid Tumor | 465 Participants | 467 Participants | 932 Participants |
| Type of Cancer Solid Tumor and Haematological Malignancy | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 206 / 522 | 192 / 524 |
| other Total, other adverse events | 75 / 522 | 67 / 524 |
| serious Total, serious adverse events | 276 / 522 | 251 / 524 |
Outcome results
Primary
Number of Participants With Adjudicated Recurrent Venous Thromboembolism (VTE) or Major Bleeding Event
Time frame: 12 months
Population: modified Intent to Treat (mITT), equating to the Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban Group | Number of Participants With Adjudicated Recurrent Venous Thromboembolism (VTE) or Major Bleeding Event | 67 Participants |
| Dalteparin Group | Number of Participants With Adjudicated Recurrent Venous Thromboembolism (VTE) or Major Bleeding Event | 71 Participants |
p-value: 0.005695% CI: [0.696, 1.359]Cox proportional hazard
p-value: 0.8712Cox proportional hazard
Secondary
Number of Participants With Adjudicated Major Bleeding Events While on Treatment
The primary safety endpoint was major bleeding events during the On-Treatment Study Period (defined as on-study drug or up to 3 days after the last dose of study drug).
Time frame: 12 months
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban Group | Number of Participants With Adjudicated Major Bleeding Events While on Treatment | 32 Participants |
| Dalteparin Group | Number of Participants With Adjudicated Major Bleeding Events While on Treatment | 16 Participants |
Comparison: The HR, 2-sided CI and p-value are based on the Cox regression model with counting process approach for on-treatment including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.p-value: 0.025495% CI: [1.089, 3.657]Regression, Cox
Secondary
Number of Participants With Recurrent Deep Vein Thrombosis (DVT) During the Overall Study Period
Time frame: 12 months
Population: mITT (Safety Analysis Set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban Group | Number of Participants With Recurrent Deep Vein Thrombosis (DVT) During the Overall Study Period | 19 Participants |
| Dalteparin Group | Number of Participants With Recurrent Deep Vein Thrombosis (DVT) During the Overall Study Period | 35 Participants |
Comparison: The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.p-value: 0.039495% CI: [0.318, 0.972]Cox proportional hazard
Secondary
Number of Participants With Recurrent Non-Fatal Pulmonary Embolism (PE) During the Overall Study Period
Time frame: 12 months
Population: mITT (Safety Analysis Set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban Group | Number of Participants With Recurrent Non-Fatal Pulmonary Embolism (PE) During the Overall Study Period | 21 Participants |
| Dalteparin Group | Number of Participants With Recurrent Non-Fatal Pulmonary Embolism (PE) During the Overall Study Period | 24 Participants |
Comparison: The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.p-value: 0.732495% CI: [0.502, 1.624]Cox proportional hazard
Secondary
Number of Participants With Recurrent Venous Thromboembolism (VTE) During the Overall Study Period
Time frame: 12 months
Population: mITT (Safety Analysis Set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban Group | Number of Participants With Recurrent Venous Thromboembolism (VTE) During the Overall Study Period | 41 Participants |
| Dalteparin Group | Number of Participants With Recurrent Venous Thromboembolism (VTE) During the Overall Study Period | 59 Participants |
Comparison: The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.p-value: 0.093195% CI: [0.476, 1.059]Cox proportional hazard
Secondary
Number of Participants With Recurrent VTE, Major Bleed or All-Cause Death
Time frame: 12 months
Population: mITT (Safety Analysis Set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban Group | Number of Participants With Recurrent VTE, Major Bleed or All-Cause Death | 235 Participants |
| Dalteparin Group | Number of Participants With Recurrent VTE, Major Bleed or All-Cause Death | 228 Participants |
Comparison: The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.p-value: 0.419995% CI: [0.898, 1.293]Cox proportional hazard
Secondary
Number of Participants With VTE-Related Death
Time frame: 12 months
Population: mITT (Safety Analysis Set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban Group | Number of Participants With VTE-Related Death | 6 Participants |
| Dalteparin Group | Number of Participants With VTE-Related Death | 4 Participants |
Comparison: The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.p-value: 0.487395% CI: [0.444, 5.505]Cox proportional hazard