To conduct a pivotal study to determine the independent predictive validity of several soluble biomarkers (e.g. MMP3, CTX-II, CTX-1, OPG, RANKL) considered to be high priority candidates for predicting structural damage in RA according to the…
ID
Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Radiographic joint progression according to the modified Sharp/Van der Heijde
score (SHS) (range of 0-448) assessed on radiographs of the hands and feet
obtained at baseline and after 6 months of follow up on standard DMARD therapy
or combination DMARD/anti-TNF therapy.
Secondary outcome
1. Radiographic progression according to the SHS after 1 year of follow up on
standard DMARD or combination DMARD/anti-TNF therapy.
2. Radiographic progression according to the SHS after 2 years of follow up
on standard DMARD or combination DMARD/anti-TNF therapy.
3. Radiographic progression as assessed by only the SHS erosion score (range
0-280).
4. 3-month change in biomarker level from baseline following the
introduction of standard DMARD therapy.
5. 3-month change in biomarker level from baseline following the
introduction of methotrexate monotherapy.
6. 3-month change in biomarker level from the start of a change in standard
DMARD therapy.
7. 3-month change in biomarker level from the start of treatment with
combination DMARD/anti-TNFα therapy.
8. 6-month change in biomarker level from baseline following the
introduction of standard DMARD therapy.
9. 6-month change in biomarker level from the start of a change in standard
DMARD therapy.
10. 6-month change in biomarker level from the start of treatment with
combination DMARD/anti-TNFα therapy.
11. Corresponding changes in DAS44, swollen joint count, tender joint count,
patient pain NRS, patient global NRS, physician global NRS,
HAQ, ESR, CRP, Hb, Platelet count, IgM-RF etc.
Background summary
There is consensus in the rheumatological community on a fundamental research
and clinical imperative: the identification and validation of biomarkers that
reflect structural damage endpoints in clinical trials and in clinical
practice. The severity of disease is generally measured using clinical outcomes
that remain difficult to quantify and whose predictive validity for structural
damage endpoints tends to be poor. Traditional inflammation parameters, ESR and
CRP,lack specificity and correlate poorly with damage at the individual patient
level. Plain radiography remains the gold standard though it does not allow
detection of early joint damage
and does not identify patients at particular risk of joint damage. The poor
prognosis associated with early and destructive RA, and the benefit of
aggressive treatment strategies, has led to an emphasis on early diagnosis and
aggressive treatment regimens incorporating a TNF inhibitor.
A major problem related to the management of RA patients is the early
identification of patients that are at risk of developing severe and
destructive disease. Identification of soluble biomarkers that are predictive
of radiographic progression would be extremely valuable to both clinical
research and clinical practice:
1. It would allow for the selection of patients at high risk for radiographic
progression in clinical trials reducing sample size requirement and duration of
study.
2. It would allow for the identification of patients in clinical practice at
high risk for disease progression and therefore requiring aggressive
intervention early in the disease course.
3. It would optimize ongoing management of patients during the course of
disease by providing an *early-warning signal* to clinicians that more
aggressive treatment is warranted to minimize the development of structural
joint damage.
If active and agressive rheumatic disease could be identified early in the
disease course through the simple measurement of feasible biomarkers this would
support the early introduction of anti-TNFαtherapy as opposed to the delay
incurred by the use of standard DMARD agents.
The proposed study will therefore assess the predictive validity of standard
clinical and laboratory variables that are used to evaluate disease severity as
well as high priority candidate soluble biomarkers. The data collected in the
present study will also be used to derive risk
assessment and prognostic tools based on clinical and biological parameters,
particularly for patients on standard DMARD therapies. In addition, results
from this trial will be used to evaluate the impact of different treatments
strategies on various biomarkers.
The results from the present study will have significant implications not only
for individual patients but also from the societal perspective since it will
enhance the overall understanding and application of different treatment
approaches. Moreover, by proposing risk assessment and
prognostic tools, the current study will facilitate the appropriate and timely
use of expensive biological drug therapies for those patients where the
benefits will clearly outweigh the risks.
Study objective
To conduct a pivotal study to determine the independent predictive validity of
several soluble biomarkers (e.g. MMP3, CTX-II, CTX-1, OPG, RANKL) considered to
be high priority candidates for predicting structural damage in RA according to
the criteria developed by the OMERACT Biomarker working group in patients
receiving standard DMARD and anti-TNF therapy.
Study design
This OMERACT study is an observational study. The study design will facilitate
capture of the following essential data components:
A. Change in biomarker following change/institution of standard DMARD therapy
or following addition of anti-TNFalpha therapy.
1. increased dose of methotrexate by >=10 mg weekly to a maximum dose of 25mg
weekly.
2. add-on of alternative DMARD.
3. switch to alternative DMARD.
4. add-on of anti-TNFalpha therapy.
B. Change in biomarker in relation to change in co-variates/predictors during
the study.
Disease activity will be monitored systematically every 3 months by the DAS44.
Changes in standard DMARD and/or anti-TNFalpha therapy will be implemented
according to 2010 EULAR recommendations which state a target of remission
(DAS44 <1.6) for patients receiving standard DMARD therapy in the setting of
early disease and a target of low disease activity state (LDAS;DAS44 <=2.4) for
patients receiving anti-TNFalpha therapy in the setting of established disease.
Biomarker samples will be collected every 3 months and prior to change in DMARD
and/or anti-TNFalpha therapy (specific criteria, see protocol).
C.Change in biomarker in relation to radiographic damage endpoint. Radiography
will be conducted every 6 months (baseline, 6, 12, 18, 24 months).
Study burden and risks
Patients are treated according to international guidelines. No specific risks
are associated with participation in this study. During 2 years patients will
spend 8-9 hours at the study. Blood samples will be taken and X-rays every 6
months. Questionnaires will be carried out at almost every visit. The
measurements will not cause an extra risk to the patients.
4570 Enterprise Square, 10230 Jasper Avenue
Edmonton, Alberta T5J 4P6
CA
4570 Enterprise Square, 10230 Jasper Avenue
Edmonton, Alberta T5J 4P6
CA
Listed location countries
Age
Inclusion criteria
• 18 years of age or older;
• RA according to the 2010 Rheumatoid Arthritis Classification Criteria;
• Joint symptoms for >= 3 months prior to screening;
• DAS44 > 2.4;
• About to start DMARD therapy (methotrexate, salazopyrin, hydroxychloroquine,
chloroquine, leflunomide) or
- increased dose of methotrexate by >=10 mg weekly to a maximum dose of 25mg
weekly (if already receiving >15mg will require add-on DMARD/anti-TNF or
switch to alternative DMARD),
- add-on of alternative DMARD,
- switch to alternative DMARD,
- start of first anti-TNFα agent (adalimumab, etanercept, infliximab, certolizumab
pegol, golimumab);
• If already on DMARD therapy this has been stable for the 3 months prior to the baseline
visit;
• If already on systemic steroid, dose must be stable (prednisone <= 7.5mg/day) for 1 month
prior to the baseline visit;
• Agreed to participate in the study by signing an informed consent;
• Patient will be available for follow up for a minimum of 24 months from the baseline visit.
Exclusion criteria
• Intra-articular steroid injection within 4 weeks prior to the baseline visit;
• Prior treatment with anti-TNFα or other biological agent (rituximab, abatacept,
tocilizumab);
• Malignancy within past 5 years (other than basal cell carcinoma that has been adequately
treated or excised, squamous cell cancer of the skin, and cervical carcinoma in situ);
• A serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level >= 3
times the upper limit of normal;
• A serum creatinine level >150 µmoles/liter or an estimated creatinine clearance <75 ml/
minute;
• Concurrent pregnancy or breast feeding, wishes to conceive during the study period, or
inadequate contraception;
• Alcohol and/or drug abuse as determined by investigator;
• History of:
a. Significant renal, hepatic, hematological, gastrointestinal, endocrine,
pulmonary, neurological or dermatological disease;
b. Significant cardiac disease, myocardial infarction within 6 months of
screening, unstable angina, congestive heart failure (New York Heart
Association [NYHA] Class III-IV), known arrhythmias of ventricular
etiology;
c. Serious infection (defined as requiring parenteral antibiotics or
hospitalization) within 3 months prior to the baseline visit;
d. Active tuberculosis or history of tuberculosis without documented
curative treatment
• For patients starting anti-TNF therapy, a positive TB screening test and no record of effective prophylaxis according to local expert recommendations;
• Significant trauma or major surgery within 3 months prior to the baseline visit, or known
planned surgery during the next year;
• Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis
C;
• Any clinically significant active infection including herpes lesions;
• Hematopoetic disorder:
a. Hgb <= 10g/dL or Hct <= 32%;
b. Absolute WBC count <= 3.0 × 109/L (3000/mm3);
c. Neutrophil count <= 1.2 × 109/L (1200/mm3);
d. Platelet count <= 100 × 109/L (100,000/mm3);
• Patient with any condition that would prevent participation in the study and completion
of the study procedures, including language limitation;
• Patient is not willing to sign an informed consent.
Design
Recruitment
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 |
|---|---|
| CCMO | NL38200.096.11 |