E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute deep vein thrombosis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 7.0 |
E.1.2 | Level | Code |
E.1.2 | Classification code | 10051055 |
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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 |
The objectives of this Phase II dose finding trial are to assess the efficacy and safety of BAY 59-7939 for the treatment of acute symptomatic proximal deep vein thrombosis (objectively confirmed by complete compression ultrasound - CCUS) in male and female patients aged 18 years or above. Patients with symptomatic pulmonary embolism at study entry will be excluded. Pharmacokinetic and pharmacodynamic parameters (incl, activated partial thrombin time (aPTT), prothrombin time (PT, INR) Factor Xa activity and Heptest) will also be assessed
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Male and female patients aged 18 years or above (For women with childbearing potential pregnancy has to be excluded prior randomization. Females with childbearing potential must use adequate contraception method during the study). Patients with acute symptomatic proximal deep vein thrombosis (objectively confirmed by complete compression ultrasound). Patients must have signed an informed consent form for participation prior to study entry (after receiving detailed written and oral previous information to any study specific procedures)
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E.4 | Principal exclusion criteria |
Related to medical history TIA or ischemic stroke within the last 6 months prior to study entry. History of heparin-induced thrombocytopenia, allergy to heparins. Intracerebral or intraocular bleeding within the last 6 months prior to study entry. History of gastrointestinal bleeding within the last 6 months prior to the study. History or presence of gastrointestinal disease which could result in an impaired absorption of the study drug (eg severe inflammatory bowel disease, short gut syndrome). Related to current symptoms or findings Female with childbearing potential using no adequate contraception method. (NOTE: As adequate method of birth control oral contraception is recommended. If oral contraception is not feasible or not recommended according to local guidelines both partners should use adequate barrier birth control). Pregnant and breastfeeding women. Symptomatic pulmonary embolism. Surgery either major or minor within the last 10 days. Neurosurgery within the last 4 weeks Heart insufficiency NYHA III-IV. Bacterial endocarditis. Known congenital or acquired hemorrhagic diathesis (INR / aPTT not within normal limits) including patients with acquired or congenital thrombopathy. Thrombocytopenia (platelets < 100.000/l). Macroscopic hematuria. Uncontrolled severe hypertension (SBP > 200 mmHg, DBP > 100 mmHg). Impaired liver function (transaminases > 2 x ULN). Impaired renal function (serum creatinine > 1.5 x ULN or creatinine clearence < 30 ml/min). (NOTE: If a patient meet the exclusion criteria regarding renal impairment during the study (serum creatinine > 1.5 x ULN or creatinine clearance < 30 ml/min) and this is confirmed by two consecutive measurements within 24 hours the patient should stop intake of study medication). Patients with known brain metastases. Patients receiving cytotoxic chemotherapy. Life-expectancy < 6 months. Presence of active peptic ulcer or gastrointestinal disease with increased risk of gastrointestinal bleeding or any other increased risk for bleeding (eg diabetic retinopathy). Body weight < 45 kg. Drug-or alcohol abuse.
Related to current treatment Therapy with oral anticoagulants, heparins or factor Xa inhibitors other than study medication are not allowed. Therapy with acetylicsalicylic acid or other platelet aggregation inhibitors (eg clopidogrel, dipyridamole and ticlopidine) must be stopped prior to randomization. Patients where continued treatment with acetylicsalicylic acid or other platelet aggregation inhibitors is clinically indicated will be excluded. The therapy with acetylicsalicyclic acid at daily doses up to 500mg/d is allowed during the study and prior to randomisation. Any treatment prior to randomization with heparins (exception: unfractionated heparin treatment within 36 hours, 2 therapeutic doses of a LMWH 24 hours apart or 3 therapeutic doses of a LMWH 12 hours apart. Prophylactic doses of UFH or LMWH are allowed). Fibrinolytic agents are not allowed during the study. All other drugs influencing coagulation (exception: NSAIDs with half-life < 17 hours) are not allowed during the study. Systemic and local topical treatment with azole compounds (eg ketoconazol, fluconazol, itraconazol) and other strong CYP3A4 inhibitors (eg HIV protease inhibitors). Azole compounds and other strong CYP3A4 inhibitors are not allowed within 4 days prior to randomization and during the study.
Miscellaneous Concomitant participation in another trial or study. Therapy with another investigational product within 30 days prior start of study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the response to treatment as determined by CCUS after three weeks of treatment. A positive response is defined as an improvement in the CCUS score compared to baseline. However, any confirmed symptomatic recurrence of extension of DVT, any confirmed symptomatic PE or any VTE-related death up to Day 21 defines a negative response even in case of an improved CCUS at Day 21
Secondary efficacy endpoints are: Response to treatment at Day 21 as determined by CCUS and perfusion lung scan where a positive response is defined as an improvement in the CCUS and /or perfusion lung scan without any deterioration in either. Response to treatment at Day 84 as assessed by CCUS. Residual vein diameter as assessed by CCUS on Day 84. Incidence of symptomatic and confirmed recurrence or extension of DVT during the 3 months treatment period. Incidence of symptomatic and confirmed PE during the 3 months treatment period. Composite endpoint of symptomatic and confirmed recurrence and extension of DVT and symptomatic PE (nonfatal DVT and/or nonfatal PE) and deaths during the 3 months treatment period. Composite endpoint of symptomatic and confirmed recurrence and extension of DVT and symptomatic PE (nonfatal DVT and/or nonfatal PE) and deaths related to VTE during the 3 months treatment period. Incidence of symptomatic and confirmed recurrence and extension of DVT and symptomatic PE within 30 days after stop of treatment with study drug.
The analysis of the primary and secondary efficacy endpoints will solely be based on the assessments made by the adjudication committees.
A further secondary efficacy endpoint is health care resource utilization (HCRU), assessed by duration of hospitalization and any re-hospitalization during the entire study period, rehabilitation center stay following hospital discharge, physician and nurse consultations excluding study visits, and frequency of vitamin K-antagonist monitoring (INR) following discharge from hospital and until the end of Follow-up.
Safety Variables
The primary safety endpoint will be the incidence of treatment-emergent major bleeding events starting not later than 7 days after last intake of study drug. Major bleeding observed after this period will be considered separately. The analysis of the primary safety endpoint will solely be based on the classification made by the Adjudication Committee.
Other safety variables are: Incidence of minor bleeding events Treatment-emergent adverse events Treatment-emergent serious adverse events Deaths Adverse events starting more than 7 days after stop of treatment Incidence of (prolonged) hospitalization Transfusion requirements Laboratory parameters.
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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 | 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 | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Dose finding and Proof of principle |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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 |
randomized, partially blinded, parallel-group, open-label active comparator controlled |
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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.8.5 | The trial involves multiple Member States | Yes |
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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |