E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid arthritis is associated with increased mortality from cardiovascular disease (CVD). Statins have a proven effect in reducing CVD events in at-risk populations, mostly due to their cholesterol-lowering properties, but possibly through anti-inflammatory and immunomodulatory effects. This trial will assess the hypothesis that atorvastatin is more effective than placebo in the primary prevention of cardiovascular events in patients with RA. |
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MedDRA Classification |
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 main objective of the trial is to establish establish whether Atorvastatin used in conjunction with standard therapy for rheumatoid athritis (RA) will protect RA sufferers aged 50 years or over OR RA sufferers of 10 years or more from fatal and non−fatal cardiovascular events, myocardial infarction and stroke.
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E.2.2 | Secondary objectives of the trial |
1) To determine whether Atorvastatin is more effective than placebo for the control of disease activity in patients with rheumatoid athritis.
2) To determine whether Atorvastatin is more effective than placebo in slowing radiographic joint damage
and the long−term decline in physical function in patients with rheumatoid arthritis. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
TRACE RA Disease Activity Substudy: A nested sub-study (TRACE RA-DAS) will investigate the hypothesis that atorvastatin is more effective than placebo as adjunctive therapy in reducing RA disease activity. Patients enrolled in TRACE RA-DAS will have moderately or severely active disease at the time that they are recruited to the main study.
Hypothesis:
• Atorvastatin is more effective than placebo as adjuvant therapy for the control of disease activity in patients with RA
• Atorvastatin is more effective than placebo as adjuvant therapy in slowing radiographic damage and the long-term decline in physical function in patients with RA
• RNA samples will allow gene expression profiling studies in RA. Serum, plasma and DNA samples will also be collected for the substudy. Blood samples collected from this patient population would facilitate research in a broader array gene expression profiling approach and would allow assessment of differential expression of genes without a priori information.
TRACE RA BioBank Substudy:
• To develop a DNA repository for the 3808 patients with rheumatoid arthritis (RA) enrolled in the main TRACE RA study
• To develop a plasma, serum and DNA repository for the above patients.
• To devise and complete peer-reviewed projects on the above samples using the phenotypic and outcome data collected in the TRACE RA trial.
• To take advantage of established population-based record-linkage capability, to allow longitudinal tracking of the subjects, thereby enabling investigation of the relationship between susceptibility genotypes and pertinent clinical features including characteristics at diagnosis, response to treatment, development of RA complications, vascular disease and survival.
• To develop an infrastructure surrounding the collection, storage and use of these samples which concerns itself with ethics, consent, privacy and collaboration, to protect the rights of the patients whilst maintaining the highest standards of clinical research.
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E.3 | Principal inclusion criteria |
•Patients who satisfy 1987 ACR classification criteria for RA applied cumulatively [71]
•Age ≥50 years old OR ≥10 years of RA disease duration
•Written informed consent
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E.4 | Principal exclusion criteria |
Standard Contra−indications to statin therapy:
1)Pregnancy, breast−feeding or women of child−bearing potential not using adequate contraception
2)Known atherosclerotic disease i.e. previous episodes of confirmed Acute Coronary Syndrome (ACS), unstable angina; myocardial infarction with or without ST elevation; or stable CHD/CVD deemed to require statin therapy on clinical grounds, including:
2a) Previous amputation due to severe peripheral vascular disease or severe peripheral arterial disease
2b) Previous central or peripheral revascularisation procedure (including coronary angioplasty, coronary artery bypass graft surgery, peripheral arterial graft surgery)
2c) Accelerated hypertension, severe heart failure (class III or IV), significant dysrhythmia or angina requiring hospitalisation in the 6 months preceding potential study entry
2d) Uncontrolled hypertension (treated or untreated) defined as systolic blood pressure > 200 mmHg and/or diastolic blood pressure > 110 mmHg (identified as the disappearance of all sound (Korotkoff Phase V) after sitting quietly for at least 3 min)
2e) Previous cerebrovascular accident
2f) Other accepted indication for statin therapy according to the investigators¡ current clinical practice
2g)Known familial hyperlipidaemia requiring drug therapy
2h)Known diabetes
3a)Known primary muscle disease
3b)Known hypersensitivity or intolerance to statins
3c)Active liver disease or hepatic dysfunction with AST or ALT >2x upper limit of normal (ULN)
3d)Severe renal dysfunction (Creatinine >200 micromol/l)
Creatinine phosphokinase (CK) >3xULN
3e)Uncontrolled hypothyroidism
3f)Taking any of the following medications:
i)Other HMG−CoA reductase inhibitors (unless warranted as add−in therapy for post−endpoint management of study patients. In such a case during the course of the trial, it will be suggested to the managing physician to start initially Atorvastatin at a dose of 10mg daily (or equivalent dose of another statin of their choice).
ii)Drugs known to be associated with rhabdomyolysis in combination with HMG−CoA reductase inhibitors (e.g. ciclosporin, erythromycin, azo anti−fungals, protease inhibitors and all macrolides)
iii)Drugs (other than beta−blockers, diuretics, ACE inhibitors, other anti−hypertensive agents, oral hypoglycaemic agents and thyroxine replacement therapy) known to affect lipid levels, that interact with the study medications, or that may affect clinical laboratory parameters (such as isotretinoin).
iv)Lipid−regulating drugs: probucol, fibrates and derivatives, bile acid sequestering resins. Patients currently taking a lipid−altering drug may be considered for screening after a 4−week wash−out period except in the case of probucol where medication must have been discontinued for at least 6 months.
v)Drinking more than 1 240ml glass of grapefruit juice per day
4)Participation in another clinical trial (other than observational trials and registries) concurrently or within 30 days prior to screening for entry into this study
5)Other serious illness or significant abnormalities that may compromise the patient's safety or successful participation in the study
6)Any illness which in the doctor's opinion means that the patient is unable to give informed consent
7)Known alcohol abuse
8)For the TRACE RA−DAS sub−study, intermittent systemic (intravenous or intramuscular) steroids are not allowed later than 2 month prior to measurement of clinical and laboratory outcome parameters (both at baseline or follow−up assessments for the purposes of the trial). Intra−articular steroid injections are
allowed, but any joint injected within the previous 2 months will be counted as both tender and swollen in the
28 joint counts. |
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E.5 End points |
E.5.1 | Primary end point(s) |
TRACE RA: Co−primary outcomes
i)Cardiovascular death, non−fatal myocardial infarction or stroke
ii)As above plus coronary and carotid revascularization
TRACE RA DAS sub−study:
EULAR (EUropean League Against Rheumatism) moderate or good response based on Disease Activity
Score (DAS28) at Month 6 visit
Insufficient space to list all cardiovascular co-primary endpoint definitions.
Please see Appendix of TRACE RA trial protocol for definitions. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | 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 | 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.8.3 |
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 | 100 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |