Primary ObjectiveThe primary objective of this study is to compare prospectively in patients treated with TCZ or etanercept (ETA), the time to first occurrence of any component of a composite of major adverse cardiovascular events (MACE) consisting…
ID
Source
Brief title
Condition
- Myocardial disorders
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
This event-driven study will continue until 131 adjudicated endpoint events
have been confirmed. The end of data collection for the study will occur when
the last patient, last visit (LPLV) occurs. The LPLV is either the date of the
last patient visit, or the date at which the last data point from the last
patient, which is required for statistical analysis, is received, whichever is
the later date.
Secondary outcome
NA
Background summary
Cardiovascular disease is a leading cause of death in patients with rheumatoid
arthritis (RA), with heart attacks and strokes occurring more often and at an
earlier age in patients with RA than those who do not have RA.
Effective RA treatment may reduce the risk of having a heart attack or stroke.
Tocilizumab and etanercept are two medications that are already approved for
the treatment of patients with RA.
In earlier clinical studies of tocilizumab, patients initially experienced an
increase in cholesterol that stabilized over time.
It is not known if long-term treatment with tocilizumab affects the occurrence
of cardiovascular-related illnesses. This will be the first controlled study of
a medication for RA that will look at the effect of treatment of disease and
cholesterol levels on the risk of cardiovascular illness.
The ENTRACTE Study will compare the effects of tocilizumab with etanercept on
the occurrence of cardiovascular illnesses, including heart attacks, strokes,
and death related to cardiovascular disease.
The study will last for at least 5 years and approximately 2800 patients
worldwide will take part.
If you take part in the ENTRACTE Study, you will be given either tocilizumab or
etanercept.
Study objective
Primary Objective
The primary objective of this study is to compare prospectively in patients
treated with TCZ or etanercept (ETA), the time to first occurrence of any
component of a composite of major adverse cardiovascular events (MACE)
consisting of:
Cardiovascular death
Non-fatal myocardial infarction
Non-fatal stroke of all classifications (ischemic, hemorrhagic, or undetermined
origin)
The criteria and complete definition for CV events is taken from the guidance
entitled, *Standardized Definitions for End Point Events in Cardiovascular
Trials* (October 20, 2010) issued by The Standardized Data Collection for
Cardiovascular Trials Initiative Working Group. All endpoint events will be
adjudicated by an independent cardiovascular events adjudication committee
(CV-EAC).
Secondary Objective
The secondary objective of this study is to investigate the effects of TCZ
compared to ETA on:
The time to first occurrence of an expanded composite endpoint, defined as the
cardiovascular composite of the primary endpoint with the additional of
non-elective coronary revascularization procedures and hospitalization for
unstable angina.
Each of the individual components of cardiovascular death, non-fatal myocardial
infarction, non-fatal stroke of all classifications (including stroke of
ischemic, hemorrhagic, and undetermined origin).
Exploratory Objectives
The exploratory objectives of this study are:
To assess the potential impact of lipid levels and CRP on cardiovascular risk
as well as the potential contribution of concomitant lipid lowering agents in
modifying risk.
To assess the incidence of heart failure requiring hospitalization in patients
treated with TCZ as compared with ETA.
Study design
This is a 2-arm, randomized, open-label, parallel-group, multi-center trial in
patients with a diagnosis of moderate to severe rheumatoid arthritis.
Patients will be stratified by the following criteria:
Previous exposure to an anti-TNF therapy
History of CV event as defined in the study primary objectives or the presence
of clinical atherosclerotic disease defined by at least one of the following:
Clinical CHD
Symptomatic carotid artery disease
Peripheral arterial disease
Abdominal aortic aneurysm.
Intervention
Patients will be randomized to either TCZ or ETA:
TCZ 8 mg/kg IV with or without non-biologic DMARD given every 4 weeks.
OR
ETA 50 mg weekly, injected subcutaneously (SC) with or without non-biologic
DMARD
Once randomized, patients assigned to TCZ study treatment will receive monthly
IV infusions from the study staff. Patients randomized to ETA will be allowed
to self-administer their weekly SC injections once they are trained by the
study staff.
Patients may switch to another RA therapy during the study at the discretion of
the investigator. However, patients randomized to ETA are prohibited from
switching to commercial TCZ for 3 years after the time of randomization.
All patients who are actively participating in the study are assessed for CV
endpoint events monthly for the duration of the study regardless of treatment.
Patients who wish to no longer actively participate in scheduled study visits
but wish to remain in the trial will be re-consented for annual phone follow-up
for CV events. These patients will no longer receive study drug.
Study burden and risks
The study drug and procedures may have risks, cause discomforts, or be
inconvenient. See the patient information for known risks and discomforts for
both treatment arms.
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Listed location countries
Age
Inclusion criteria
1. Patients with RA of > 6 months duration at the time of the baseline visit. RA must be diagnosed according to the revised 1987 American College of Rheumatology (ACR; formerly American Rheumatism Association) criteria (Appendix 3)
2. Inadequate response to at least one non-biologic DMARD
3. Have a CRP > 0.3 mg/dL at screening or at the baseline visit
4. Receiving treatment on an outpatient basis
5. Swollen joint count (SJC) * 8 (66 joint count) and tender joint count (TJC) * 8 (68 joint count) during screening or at the baseline visit.
6. Males and females, age * 50 years
7. Presence of one or more additional Coronary Heart Disease (CHD) risk factor including:
* Cigarette smoking (current)
* Hypertension (BP ><=140/90 mm Hg or on antihypertensive medication)
* Low HDL cholesterol (HDL <50 mg/dL for women; HDL <40 mg/dL for men)
* Family history of premature CHD (CHD in male first-degree relative <55 years of age; CHD in female first-degree relative <65 years of age)
* Diabetes
* Presence of extra-articular disease associated with RA (e.g., rheumatoid nodules, secondary Sjogren's syndrome, serositis, rheumatoid lung disease/ interstitial lung disease, vasculitis, inflammatory peripheral neuropathy, or scleritis/ episcleritis) ;* History of at least one of the following:
o Myocardial infarction
o Stroke of atherothrombotic origin
o Coronary revascularization procedure
o Hospitalization for unstable angina
* The presence of at least one of the following clinical atherosclerotic diseases that confers high risk for coronary heart disease (CHD) events:
o Clinical CHD
o Symptomatic carotid artery disease
o Peripheral arterial disease
o Abdominal aortic aneurysm;8. At the time of randomization, will have discontinued:
* infliximab, adalimumab, golimumab, or certolizumab for * 4 weeks
Exclusion criteria
1. Major surgery (including joint surgery or coronary revascularization) within eight weeks prior to screening or planned major surgery within one year of baseline
2. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus (SLE), Mixed Connective Tissue Disease (MCTD), scleroderma or variants, and polymyositis. Patients with systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis) and secondary Sjögren*s syndrome, and/or nodulosis with RA are permitted (see Inclusion #7). Patients with Felty*s syndrome are not permitted
3. History of or current inflammatory joint disease other than RA (e.g., tophaceous gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease, pseudogout, arthropathy of inflammatory bowel disease)
4. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
5. Current or recent (within the past 3 months) evidence of serious uncontrolled concomitant cardiovascular or cerebrovascular disease (MI, revascularization, ischemic stroke, transient ischemic attack, or acute coronary syndrome)
6. Current or previous (within the past 2 years) evidence of serious uncontrolled concomitant pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or gastrointestinal disease.
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 | EUCTR2010-020065-24-NL |
| ClinicalTrials.gov | NCT01331837 |
| CCMO | NL36154.048.11 |