| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of venous thromboembolism in patients who have been hospitalized for a medical illness |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012108 |
| E.1.2 | Term | Deep venous thrombosis prophylaxis |
|
| 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 |
The objective of this study is to demonstrate (1) the superior efficacy of VTE prophylaxis with oral rivaroxaban 10 mg once daily administered for 35 +/- 4 days to SC enoxaparin 40 mg once daily (OD) administered for 10 +/- 4 days in men and women aged 40 years or above who have been hospitalized for a medical illness and (2) the non-inferiority of VTE prophylaxis with oral rivaroxaban 10 mg once daily administered for 10 +/- 4 days to SC enoxaparin 40 mg once daily for 10 +/- 4 days in the same patient population.
The safety of rivaroxaban and enoxaparin will be compared as well. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who meet the following criteria may be included in the study:
1. Male and female patients aged 40 years or more with no upper age limit
2. Patients at risk of venous thromboembolic events being hospitalized for acute
medical conditions as follows:
· Heart failure, NYHA class III or IV
· Active cancer (eg, admitted for chemotherapy or for treatment of a
complication of the active cancer)
· Acute ischemic stroke
· Acute infectious and inflammatory diseases, including acute rheumatic
diseases
· Acute respiratory insufficiency
3. At least one additional risk factor for VTE:
a. Severe varicosis
b. Chronic venous insufficiency
c. History of cancer
d. History of DVT or PE
e. History of heart failure NYHA Class III or IV
f. Thrombophilia (hereditary or acquired)
g. Recent major surgery (6 to 12 weeks)
h. Recent serious trauma (6 to 12 weeks)
i. Hormone replacement therapy
j. Advanced age ≥ 75 years
k. Morbid obesity (body mass index [BMI] ≥ 35 kg/m2)
l. Acute infectious disease contributing to hospitalization
Patients with heart failure NYHA class III or IV who have had previous
hospitalizations for heart failure NYHA class III or IV or are chronically in
NYHA class III or IV status, patients with active cancer and patients with
acute ischemic stroke with lower extremity paresis or paralysis are not
required to have an additional risk factor.
4. Anticipated complete immobilization for at least one day during the
hospitalization and anticipated decreased level of mobility for at least 4 days
following randomization in any type of care setting (eg, hospital, intermediate
care or rehabilitation centre, managed care in home, etc), and additional
anticipated ongoing decreased mobility thereafter.
Definition of complete immobilization, decreased mobility and ongoing
decreased mobility are as follows:
Complete Immobilization: The patient is totally confined by his or her illness
to bed or chair. The patient may be allowed to use a bedside commode or with
assistance may be allowed bathroom privileges.
Decreased Level of Mobility: Immobilization caused by the illness requiring
the patient to remain in bed or chair more than 50% of the time during daytime
hours.
Ongoing Decreased Mobility: Immobilization caused by the illness requiring
the patient to remain in bed or chair during daytime hours more than was
normal and usual for the patient prior to hospitalization.
5. Hospitalized less than 72 hours before randomization
6. Patients’ written informed consent for participation after receiving detailed
written and oral information prior to any study specific procedures.
Analphabetic or illiterate patients may be enrolled by verbal informed consent
if allowed by local regulations and approved by the local Institutional Review
Board (IRB) or Ethics Committee (EC). The patient’s decision to withdraw
from the study at any time will be respected.
|
|
| E.4 | Principal exclusion criteria |
1. Conditions that contraindicate the use of antithrombotic therapy with the LMWH enoxaparin
2. Conditions that may increase the risk of bleeding, including intracranial hemorrhage, such as:
• Clinically significant bleeding, within 30 days of randomization
• Major surgery, biopsy of a parenchymal organ, ophthalmic surgery, or serious trauma within 6 weeks before randomization
• A presenting diagnosis for which surgery is intended during hospitalization (eg, cholecystitis and planned cholecystectomy)
• Have a known coagulopathy or bleeding diathesis (eg, disseminated intravascular coagulation, clinically relevant thrombocytopenia) or an international normalized ratio (INR) known to be > 1.5 at the time of screening unrelated to VKA therapy
• History of hemorrhagic stroke at any time in the past, evidence of primary intracranial hemorrhage on CT or MRI scan of the brain, or clinical presentation consistent with intracranial hemorrhage (eg, severe headache or new neurologic deficit after fibrinolytic therapy)
• Recent severe head trauma within 30 days of randomization which includes concussion, skull fracture, or hospitalization for head injury
• Known intracranial neoplasm, cerebral metastases, arteriovenous malformation, or aneurysm
3. Required drugs or procedures, such as:
• More than 2 days of prophylactic use of anticoagulants. Up to 2 doses of LMWH or up to 6 doses of unfractionated heparin pre-randomization are allowed.
• Systemic treatment with more than 2 doses of strong inhibitors of cytochrome P450 3A4 (CYP 3A4), such as ketoconazole or protease inhibitors, within 4 days before randomization or planned treatment during the time period of the study drug administration
• Indication for fibrinolysis or need for continued treatment with anticoagulant agents for more than 14 days
• Treatment with or use of mechanical thromboprophylaxis (eg, pneumatic compression devices, foot pumps) for VTE prevention
4. Concomitant conditions or diseases, such as:
• Known allergy to rivaroxaban or any of its excipients
• Severe renal insufficiency (ie, calculated creatinine clearance <30 mL/min, see Appendix 10.4 for Cockcroft-Gault formula)
• Known significant liver disease (eg, acute clinical hepatitis, chronic active hepatitis, cirrhosis), or LFT abnormalities (confirmed with repeat testing) which would require study medication discontinuation, ie, ALT > 5 x ULN or ALT > 3 x ULN plus total bilirubin > 2 x ULN and the ratio of direct to total bilirubin ≥ 50% (see Section 4.3)
• Known human immunodeficiency virus (HIV) infection at screening
• Sustained uncontrolled systolic blood pressure of ≥ 180 mmHg or diastolic pressure of ≥ 100 mmHg at time of screening despite treatment
• History of ongoing drug or alcohol abuse
• Cardiogenic or septic shock with the need for vasopressor(s), such as noradrenaline, and/or inotropes, such as dobutamine or milrinone
• Any severe condition that would limit life expectancy to less than 6 months, ie, advanced malignancy, etc
5. General:
• Unilateral or bilateral above knee lower extremity amputation
• Inability to take oral medication or otherwise unable or unwilling to undergo/perform study-specified procedures
• Have received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment
• Pregnancy or breast-feeding or any plan to become pregnant during the study. Women with child-bearing potential not using adequate birth control method. Note that as an adequate method of birth control, any effective method including abstinence, barrier contraception and other recognized effective methods are acceptable. Oral contraceptive agents should be carefully assessed to determine if the risk of their use in patients at increased risk of venous thromboembolic complications is warranted.
• Previous participation in this study or any other study of rivaroxaban
• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
There are two primary efficacy endpoints:
Primary Efficacy Endpoint 1 (test of superiority – Day 35 ± 4 days)
Primary Efficacy Endpoint 1 is defined as a composite endpoint of the following
components:
• Asymptomatic proximal lower extremity DVT detected by mandatory bilateral lower extremity venous ultrasonography up to Day 35 +/- 4 days
• Symptomatic lower extremity DVT (proximal or distal) up to Day 35 + 4 days
• Symptomatic non fatal PE up to Day 35 + 4 days
• VTE related death up to Day 35 + 4 days
Primary Efficacy Endpoint 2 (test of non-inferiority – Day 10 +/- 4 days)
Primary Efficacy Endpoint 2 is defined as a composite endpoint of the
following components:
• Asymptomatic proximal lower extremity DVT detected by mandatory
bilateral lower extremity venous ultrasonography up to Day 10 + 4 days
Symptomatic lower extremity DVT (proximal or distal) up to Day 10 + 4
days
• Symptomatic non fatal PE up to Day 10 + 4 days
• VTE related death up to Day 10 + 4 days
It should be noted that early VTE events (ie asymptomatic DVTs as well as
symptomatic DVTs, PEs and VTE-related deaths) will be carried forward to
Primary Efficacy Endpoint 1.
The analysis of the primary efficacy endpoints will be solely based on the assessments made by the UAC and the CEAC.
The major secondary endpoint is defined as the composite of the Primary Efficacy Endpoint 1 (as above), with the component of VTE-related death substituted by all-cause mortality, up to Day 35 + 4 days.
Further secondary endpoints are given by:
• Incidence of symptomatic VTE (DVT or PE) up to Day 35 + 4 days
• ‘Net clinical benefit’ as assessed by the composite endpoint comprising
Primary Efficacy Endpoint 1 and treatment-emergent major bleeding or
non-major clinically relevant bleeding
• Incidence of the composite of cardiovascular death, acute myocardial infarction
or acute ischemic stroke up to Day 35 + 4 days
• Incidence of each of the components of Primary Efficacy Endpoint 1
• Incidence of symptomatic VTE (DVT or PE) up to Day 10 + 4 days
• Incidence of the composite of Primary Efficacy Endpoint 2 (as above), with the
component of VTE-related death substituted by all-cause mortality, up to
Day 10 + 4 days
• ‘Net clinical benefit’ as assessed by the composite endpoint comprising Primary Efficacy Endpoint 2 and treatment-emergent major bleeding or non-major clinically relevant bleeding during the enoxaparin treatment phase
Incidence of the composite of cardiovascular death, acute myocardial
infarction or acute ischemic stroke up to Day 10 + 4 days
• Incidence of each of the components of Primary Efficacy Endpoint 2
• Incidence of all-cause mortality up to Day 90 + 7 days
• Incidence of symptomatic VTE (DVT or PE) up to Day 90 + 7 days
• Incidence of the composite of cardiovascular death, acute myocardial
infarction or acute ischemic stroke up to Day 90 + 7 days
The analysis of the secondary efficacy endpoints will be solely based on the assessments made by the UAC and the CEAC.
Efficacy endpoints and methods for their documentation are defined in the
Ultrasonography and Clinical Event Manual (hereafter referred to as the
committee manual).
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 225 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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