| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Reduction of the risk of symptomatic recurrent venous thromboembolic complications in patients with acute symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE) |
|
| E.1.1.1 | Medical condition in easily understood language |
DVT is a condition when a blood clot develops in a vein or veins of the
legs and decreases blood flow. PE occurs when a clot gets dislodged and travels up to the pulmonary artery where it gets stuck |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037377 |
| E.1.2 | Term | Pulmonary embolism |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051055 |
| E.1.2 | Term | Deep vein thrombosis |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate whether initial (Low Molecular Weight) heparin followed by edoxaban only ([LMW] heparin/edoxaban) is non-inferior to initial (LMW) heparin overlapping with warfarin, followed by warfarin only ([LMW] heparin/warfarin) in the treatment of subjects with acute symptomatic VTE for the prevention of symptomatic recurrent VTE during the 12-month study period |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare (LMW) heparin/edoxaban to (LMW) heparin/warfarin with regard to clinically relevant bleeding (i.e., major or clinically relevant nonmajor bleeding) occurring during treatment or within 3 days of interrupting or stopping study drug
2. To compare (LMW) heparin/edoxaban to (LMW) heparin/warfarin with regard to the composite clinical outcome of symptomatic recurrent DVT, non-fatal symptomatic recurrent PE, and all-cause mortality during the 12-month study period |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study Addendum A - Health Economics Study, 08 December 2009, Version 1.0
Primary objective - To evaluate the medical resource utilization
associated with edoxaban and warfarin therapies over the duration of observation of the HOKUSAI VTE study.
"Accuracy of Two Risk Stratification Rules in Patients with Clincally
Stable Pulmonary Embolism" sub-study - Memo #008, 05 August 2010
To compare the 3 rules for the early risk stratification of these patients.
|
|
| E.3 | Principal inclusion criteria |
1. Male or female subjects older than the minimum legal adult age (country specific)
2. Acute symptomatic proximal DVT and/or symptomatic PE confirmed at the site by appropriate diagnostic imaging
3. Able to provide written informed consent |
|
| E.4 | Principal exclusion criteria |
1. Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT and/or PE
2. Indication for warfarin other than DVT and/or PE
3. More than 48 hours pre-treatment with therapeutic dosages of anticoagulant treatment (LMWH, UFH, and fondapiranux per local labeling) or more than a single dose of a VKA prior to randomization to treat the current episode
4. Treatment with any investigational drug within 30 days prior to randomization
5. Calculated CrCL < 30 mL/min
6. Significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis) or alanine transaminase (ALT) ≥ 2 times the upper limit of normal (ULN), or total bilirubin (TBL) ³ 1.5 times the ULN
7. Patients with active cancer for whom long term treatment with LMW(heparin) is anticipated
8. Life expectancy < 3 months
9. Active bleeding or high risk for bleeding contraindicating treatment with (LMW) heparin or warfarin
10. Uncontrolled hypertension as judged by the investigator (e.g., systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg despite antihypertensives)
11. Women of childbearing potential without proper contraceptive measures, and women who are pregnant or breast feeding
Note: Childbearing potential without proper contraceptive measures (i.e., a method of contraception with a failure rate < 1 % during the course of the study (including the observational period). These methods of contraception according to the note for guidance on non-clinical safety
studies for the conduct of human trials for pharmaceuticals (CPMP/ICH/286/95, modification) include consistent and correct use of hormone containing implants and injectables, combined oral contraceptives, hormone containing intrauterine
devices, surgical sterilization, sexual abstinence, and vasectomy for the male partner)
12. Any other contraindication listed in the local labeling of LMWH, UFH, or warfarin
13. Chronic treatment with non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) including both cyclooxygenase-1 (COX-1) and cyclooxygenase-2
(COX-2) inhibitors for ³ 4 days/week anticipated to continue during the study
14. Treatment with aspirin in a dosage of more than 100 mg/per day or dual antiplatelet therapy (any two antiplatelet agents including aspirin plus any other oral or invravenous (IV) antiplatelet drug) anticipated to continue during the study
15. Treatment with the potent P-gp inhibitors ritonavir, nelfinavir, indinavir, or saquinavir anticipated to continue during the study
16. Systemic use of the anti-arrythmic drug dronedarone at the time of randomization (subjects randomized to study prior to Amendment 2 will have their edoxaban dose reduced)
17. Systemic use of the strong P-gp inhibitors erythromycin, azithromycin, clarithromycin, ketoconazole or itraconazole at the time of randomization; subsequent use is permitted
18. Known history of positive Hepatitis B antigen or Hepatitis C antibody
19. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is symptomatic recurrent VTE (i.e., the composite of DVT, non-fatal PE, and fatal PE). CEC adjudication results will be the basis for the final analyses
The primary safety endpoint is clinically relevant bleeding (i.e., major or clinically relevant non-major bleeding) occuring during treatment or within 3 days after interrupting or stopping study drug. Bleeding definitions were adopted from Büller, HR, et al (NEJM; 2007; 357:1094-1104). Adjudicated results will be the basis for the final analyses |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the participation in the study. Information on possible
endpoints will also be collected during 1 month follow-up after
treatment termination. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint is the composite clinical outcome of
symptomatic recurrent DVT, non-fatal symptomatic recurrent PE, and allcause mortality during the 12-month study period. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the participation in the study. Information on possible
endpoints will also be collected during 1 month follow-up after
treatment termination. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 176 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belarus |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Czech Republic |
| Denmark |
| Estonia |
| France |
| Germany |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Philippines |
| Poland |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
As per protocol: Based on the EOR date a global End of Treatment [EOT] date will be established that ensures a minimum of 6 months of treatment for the last subject(s) randomized to study. All subjects must permanently
discontinue study treatment on or before the EOT date. A global Final Study Visit [FSV] date will be set one month following the EOT date. All subjects must complete their follow-up
safety visit and permanently discontinue study on or before the FSV date.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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