There are two phases in this trial with 2 objectives:In phase I of the trial it will be assessed which dose of rivaroxaban is the most safe and effective (most optimal benefit:risk profile). In phase II this dose will be further investigated to…
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Stage (Phase) 1 Dose Escalation
The primary objective of Stage 1 of this study is to evaluate the safety of
rivaroxaban in subjects with recent ACS (including STEMI, NSTEMI, or UA) who
are treated with aspirin alone or aspirin plus a thienopyridine. The dose,
dosing regimen and background therapy strata with a promising benefit:risk
profile will be selected based on the results of Stage 1 for a more extensive
efficacy evaluation in Stage 2.
Stage (Phase) 2: Dose Confirmation
The primary objective of Stage 2 of this study is to evaluate the ability of
rivaroxaban to reduce the combined incidence of death, MI (or reMI), stroke
(ischemic, hemorrhagic or unknown), or severe recurrent ischemia requiring
revascularization in subjects with recent ACS (including STEMI, NSTEMI, or UA)
who are treated with aspirin alone or aspirin plus thienopyridine after medical
therapy or PCI as acute treatment.
Secondary outcome
Stage 1: Dose Escalation
· to evaluate primary and secondary efficacy endpoints to enable a benefit:risk
assessment
· to evaluate the PK/PD of rivaroxaban assessing drug exposure using
rivaroxaban plasma concentrations and exposure/response relationships using
factor Xa activity and PT
· to evaluate the ability of rivaroxaban to reduce thrombin generation, as
assessed by biomarkers such as fragment F1.2 levels
· to assess the overall safety of rivaroxaban treatment
Stage 2: Dose Confirmation
· to evaluate the ability of rivaroxaban to reduce the composite of death, MI,
or stroke through 6 months of treatment
· to evaluate the ability of rivaroxaban to reduce the composite of death, MI,
stroke or severe recurrent ischemia through 6 months of treatment
· to assess the net clinical benefit of rivaroxaban by measuring the composite
of death, MI, stroke, severe recurrent ischemia requiring revascularization,
TIMI major bleed or TIMI minor bleed through 6 months
· to evaluate the ability of rivaroxaban to reduce each component of the
primary composite efficacy endpoint
· to evaluate the ability of rivaroxaban to reduce ischemia as measured by
continuous ST segment monitoring in a subset of subjects
· to evaluate the ability of rivaroxaban to reduce the incidence of left
ventricular (LV) thrombus at Day 10 to 14 after randomization in a subset of
subjects presenting with anterior STEMI
· to assess the overall safety or rivaroxaban treatment
Background summary
Heart and blood vessel disease is one of the major causes of death in the
western world. After having a myocardial infarction and unstable angina (pain
on the chest in rest), anti-coagulant medication is prescribed
(*bloodthinners*) to prevent the formation of new bloodclots which can block
the (coronary) arteries again. The coronary arteries are the vessels which
transport blood to the heart.
Aspirin is one of the most prescribed medications after a myocardial infarction
and unstable angina. Besides aspirin a number of other blood thinners is
prescribed with different modes of action (eg. thienopyridines). Often,
combinations of blood thinners are prescribed.
Rivaroxaban is a member of the category of factor Xa inhibitors (factor Xa
plays a part in blood clotting). In this trial it will be investigated whether
rivaroxaban can make a substantial contribution to the prevention of new
myocardial infarctions, unstable angina or strokes when it is given in
combination with aspirin alone or in combination with aspirin and a
thienopyridine. The trial consists of 2 phases (see also question 5), where in
phase I the dose with the most optimal benefit-risk profile is being assessed,
after which in fase II this dose is further investigated and in which it will
be investigated if rivaroxaban is an effective medication to prevent new
myocardial infarctions, strokes, etc. in patients with acute coronary syndrome.
Study objective
There are two phases in this trial with 2 objectives:
In phase I of the trial it will be assessed which dose of rivaroxaban is the
most safe and effective (most optimal benefit:risk profile). In phase II this
dose will be further investigated to evaluate if rivaroxaban is an effective
medication to prevent new myocardial infarctions, strokes etc. in patients with
acute coronary syndromes.
Study design
This is an international, randomized, multicenter, double-blind,
placebo-controlled study designed to evaluate the safety and efficacy of
rivaroxaban in subjects with recent ACS (STEMI, NSTEMI, or UA) who are
receiving background low dose aspirin therapy (75 to 100 mg/day) without the
intention to use a thienopyridine therapy (Stratum 1, aspirin only) or with
thienopyridine therapy (Stratum 2, aspirin plus a thienopyridine). The trial
consists of 2 phases:
Phase I: In Phase I the dose of rivaroxaban with the most optimal benefit:risk
profile will be assessed.
Phase II: In Phase II the most optimal dose as assessed in Fase I will be
further investigated and it's role in the prevention of recurrence of acute
coronary sydrome.
Each phase has a screening/baseline phase within the 6 days prior to
randomisation or on the day of randomisation (day 1). The double-blind
treatment period lasts for 6 months, with an endvisit planned at the end of
this period or at the time a patient will leave the trial prematurely.
Approximately 30 days after the last dose of study drug, a posttreatment
follow-up visit will occur and will include assessment of any new adverse
events and follow-up of any ongoing adverse events. The total duration of the
study will be approximately 216 days. Subjects in each stratum will follow the
same Time and Event Schedule for each stage of the study, unless otherwise
specified.
Per stratum and dose level, there are always 3 treatment groups: placebo,
rivaroxaban in a twice daily dose and rivaroxaban in a once daily dose. See
also pages 48 and 49 of the protocol for a schematic overview. Patients will be
randomized with a chance of 1 in 3 to one of the 3 treatment groups.
Intervention
In both phases and in both strata patients receive ór placebo, ór rivaroxaban
in a twice daily dose, ór rivaroxaban in a once daily dose.
The total daily doses tested in phase I are 5, 10 and 20 mg. The most optimal
dose from phase I will be further investigated in phase II.
During the trial extra treatment groups may be added (rivaroxaban in a 15 mg
and 30 mg total daily dose).
Study burden and risks
Burden to the patient: patients will be for a maximum of 216 days in the trial
(including screening and follow-up period). After discharge from the hospital,
patients need to visit the hospital for trial visits for 7 times and will
undergo a number of trial procedures (a.o. blooddrawings, ECG and completion of
questionnaires).
Risks: the side effects of aspirin and thienopyridines are known.
In earlier trials with healthy volunteers no differences were seen in the
incidence of mild side effects between subjects treated with rivaroxaban and
subjects treated with placebo. Side effects which were reported in more than 2%
of these subjects are abdominal distension, upper abdominal pain, nausea,
heartburn, fatigue, headache, rash and sore throat. Rivaroxaban is a
bloodthinner which can make it more difficult for the blood to clot in case of
a bleeding. Therefore, there is a risk of a haemorrhage. The patient will get
an extensive screening vist, before the patient will be randomized. During the
trial, the patient will be followed closely. In case of side effects, extra
visits will be planned to follow up the patient. In case of bleeding, the
guidelines on page 85 of the protocol are given.
Risks of blooddrawing are minimal.
Dr. Paul Janssenweg 150
5026 RH Tilburg
Nederland
Dr. Paul Janssenweg 150
5026 RH Tilburg
Nederland
Listed location countries
Age
Inclusion criteria
- Man/women between 18 and 75 years of age
- Diagnosis of STEMI (ST-segment elevation myocardial infarction) or a diagnosis of NSTEMI (non-ST-segment elevation myocardial infarction) or UA (unstable angina) with at least 1 of the following: elevated cardiac enzyme marker, ><= 1 mm ST-segment deviation or TIMI risk score ><= 3 (see protocol page 50)
- symptoms suggestive of ACS lasting at least 10 minutes at rest occurring within 7 days of randomization
Exclusion criteria
- conditions that may increase the risk of bleeding
- conditions that may increase the risk of intracranial hemorrhage
- required drugs or procedures (need for continued treatment with anticoagulant drugs, planned PCI within 30 days of randomization)
- severe concomitant diseases (such as cardiogenic shock, anemia)
- general (eg. allergy to aspirin, pregnant, employees of the study center)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-004449-40-NL |
| ClinicalTrials.gov | NCT00402597 |
| CCMO | NL15332.060.06 |