E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Venous Thromboembolism (VTE) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
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 |
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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 determine if at least one of the apixaban dose regimens is superior to placebo in the combined endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death in subjects who have an objectively documented index event of symptomatic proximal DVT or symptomatic PE, have completed approximately 6 to 12 months of anticoagulant therapy for the treatment of the index event, and have no objectively documented symptomatic recurrence of VTE after the index event. |
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E.2.2 | Secondary objectives of the trial |
To characterize treatment effects of the two apixaban doses relative to placebo for the following:
• adjudicated composite of recurrent symptomatic VTE or VTE-related death
• adjudicated composite of recurrent symptomatic VTE or CV-related death
• adjudicated symptomatic nonfatal DVT
• adjudicated symptomatic nonfatal PE
• adjudicated VTE-related death
• adjudicated CV-related death
• all-cause death
• adjudicated major bleeding
• the adjudicated composite of major bleeding and clinically relevant non-major bleeding
To characterize the primary efficacy outcome in the subset of subjects with index events of DVT only and in the subset of subjects with index events of PE with or without DVT. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Target Population
a) Subjects who have:
• an unprovoked index event OR a provoked index event with a risk for
recurrence as described in the eligibility checklist.
• an objectively documented index event of symptomatic proximal DVT or symptomatic PE;
(1) Symptomatic proximal DVT is defined as symptomatic DVT with evidence of proximal thrombosis that involves at least the popliteal vein or a more proximal vein, demonstrated by imaging with compression ultrasound (CUS), including grey-scale or color-coded Doppler, or ascending contrast venography.
(2) Symptomatic PE with evidence of thrombosis demonstrated by imaging as follows:
- an intraluminal filling defect in segmental or more proximal branches on spiral CT scan; or
- an intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram; or
- a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS)
completed approximately 6 to 12 months of standard anticoagulant therapy, or completed assigned CV185056 (AMPLIFY) study treatment, for the treatment of the index event; and
• no objectively documented symptomatic recurrence of VTE after the index event.
b) Subjects should be randomized within approximately 7 days of the last dose of their initial 6-to 12-month treatment. If a VKA was used as standard anticoagulant therapy, then an INR must be documented as 2 or less before randomization. If the subject received CV185056 (AMPLIFY) study treatment, then a blinded INR must be documented as 2 or less before randomization.
Every attempt should be made to randomize subjects as soon as possible after discontinuation of their initial treatment.
The index DVT and/or PE will be adjudicated by the ICAC according to the adjudication manual. Investigators are encouraged to assemble and to submit imaging dossiers to the ICAC as soon as possible during the period that extends from the beginning of the screening period up to 2 weeks after randomization.
3) Age and Sex
a) Men and women, ages 18 years or greater.
Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized.
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E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method of birth
control to avoid pregnancy for the entire study
b) Women who are pregnant or breastfeeding
c) Women with a positive pregnancy test on enrollment or prior to investigational product administration
2) Medical History and Concurrent Diseases
a) Subjects with a provoked index event without the existence of a persistent risk factor for recurrence as described in the eligibility checklist.
b) More than 12 months of anticoagulation planned for the most recent DVT or PE (index event).
c) Subjects with indications for long-term treatment with a VKA, such as:
• Mechanical valve
• Atrial fibrillation or atrial flutter with moderate to high risk of systemic thromboembolism
• Multiple episodes of unprovoked DVT or PE
• Documented anti-phospholipid antibodies, anti-thrombin III deficiency, protein C deficiency, protein S deficiency, homozygous factor V Leiden, or homozygous prothrombin gene mutation.
d) Subjects with cancer who will be treated indefinitely with anticoagulation therapy;
e) Serious bleeding prior to randomization (see table under Protocol section 4.2.2 for exact timing of occurence resulting in subject exclusion from the study);
f) Active and clinically significant liver disease (eg, hepatorenal syndrome);
g) Life expectancy < 12 months;
h) Bacterial endocarditis;
i) Uncontrolled hypertension: systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg.
3) Physical and Laboratory Test Findings
a) Platelet count <100,000/mm3
b) Hemoglobin <9 g/dL
c) Serum creatinine >2.5 mg/dL [221 umol/L]
d) Calculated creatinine clearance <25 ml/min (see Section 6.3.2.2.)
e) ALT or AST >2 times upper limit of normal
f) Total bilirubin >1.5 times upper limit of normal (unless an alternative causative factor is identified [eg, Gilbert’s syndrome]).
4) Prohibited Treatments and/or Therapies
a) Subjects requiring ASA >165 mg/day at randomization.
b) Subjects requiring dual anti-platelet therapy (such as ASA plus clopidogrel or ASA plus ticlopidine) at randomization. Subjects who transition from dual anti-platelet therapy to monotherapy prior to randomization will be eligible for the trial.
c) Subjects who have used any oral direct factor Xa inhibitor, any oral direct thrombin inhibitor, or any investigational antithrombotic agent during the period between the onset of the index event to randomization. Subjects who participated in the CV185056 (AMPLIFY) study may participate in this study and are exempt from this exclusion (see Section 5.7)
5) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
c) Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of study treatment (with the exception of approved medications being used for an approved indication, eg, investigating a new dosing regimen for an approved indication).
Subjects who participated in the CV185056 (AMPLIFY) study may participate in this study and are exempt from this exclusion (see Section 5.7)
d) Any condition, which in the opinion of the investigator, would put the subject at an unacceptable risk from participating in the study; or
e) Any other medical, social, logistical, or psychological reason, which in the opinion of the investigator, would preclude compliance with, or successful completion of, the study protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
- The primary efficacy outcome is the incidence of an adjudicated
composite of recurrent symptomatic VTE (nonfatal DVT and/or nonfatal
PE) or all-cause death.
- The primary safety outcome is the incidence of adjudicated major
bleeding during the treatment period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
upon occurrence during study treatment |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
upon occurrence during study treatment |
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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 | 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 | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker and Post-treatment Thromboembolic Events assessments |
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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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 95 |
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 |
Brazil |
Canada |
Chile |
Hong Kong |
Israel |
Korea, Republic of |
Mexico |
Philippines |
Puerto Rico |
Russian Federation |
Singapore |
United States |
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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
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Telephone follow-up call 30 days after final treatment visit
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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 | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |