Contact information
Type
Scientific
Primary contact
Prof M. Boers
ORCID ID
Contact details
VU University Medical Center
PK 6Z 185
Department of Clinical Epidemiology and Biostatistics
Amsterdam
1007 MB
Netherlands
+31 (0)20 4444474
keb.info@vumc.nl
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
P03627; NTR80
Study information
Scientific title
Acronym
Study hypothesis
In early rheumatoid arthritis (RA), does treatment intensification (by conventional and biological means) aimed at keeping urine CTX-2 levels below 150 nmol/µmol creatinine lead to a lower radiological progression than treatment intensification aimed at keeping DAS28 at or below 3.2?
Ethics approval
The Ethics Review board of the Vrije University Medical Center has approved this protocol (reference number 2003-186).
Study design
Double blinded randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
Rheumatoid arthritis
Intervention
The study design randomises to two monitoring strategies that lead to subsequent steps in the treatment schedule: either clinical monitoring by DAS28 to achieve and keep the DAS below 2.6 (clinical remission); or: lab monitoring by CTX-2 to achieve and keep the urinary level of CTX-2 below 150 ng/µmol creatinine.
All patients will receive 'traditional' combination DMARD therapy for a minimum of 22 weeks: step 1 is evaluated at week 8, and step 2 at week 22. Patients will receive treatment intensification according to achieved levels of DAS28 (DAS group) or according to achieved levels of CTX-2 (CTX group).
Intervention type
Other
Phase
Not Specified
Drug names
Primary outcome measures
1. DAS28: Disease activity score calculated from swollen and tender joint counts, erythrocyte sedimentation rate (ESR), patient global assessment of disease activity (10 cm Visual Analogue Scale [VAS])
2. CTX-2: measured in spot urine (delivered 1 week before visit) together with creatinine (method Garnero, Lyon)
Secondary outcome measures
1. WHO/ILAR core set; DAS remission, EULAR improvement; ACR remission, ACR20,etc; EuroQoL
2. Efficacy self assessment: RADAI joint score, fatigue VAS
3. Bone Mass: DEXA lumbar spine; Right hip (neck)
Overall trial start date
01/10/2004
Overall trial end date
30/09/2006
Reason abandoned
Eligibility
Participant inclusion criteria
Patients must have:
1. Rheumatoid arthritis (American College of Rheumatology [ACR] criteria met cumulatively)
2. Requiring treatment: 28-item Disease Activity Score (DAS28) greater than 3.2
3. Propensity for radiographic progression: urinary CTX-2 greater than 150 ng/µmol creatinine
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
40
Participant exclusion criteria
1. Unwillingness to participate in the study and comply with its procedures by signing a written informed consent
More chance of harm:
2. Contraindication to study drugs:
2.1. Previous serious adverse reaction or documented allergy to any of the trial drugs or their constituents
2.2. Previous inability to tolerate sulphasalazine (minimum 1 g/d), hydroxychloroquine (minimum 200 mg/d) methotrexate (minimum 7.5 mg/week) or oral prednisolone
3. Active infection or those at high risk of infection:
3.1. Abnormal chest X-ray or positive tuberculin test suggestive of previous TB that has not been adequately treated
3.2. Chronic leg ulcers
3.3. Septic arthritis of a native joint within the last 12 months
3.4. Previous prosthetic joint sepsis within the last 12 months, indefinitely if prosthesis remains in situ
3.5. Bronchiectasis, indwelling urinary catheter and other situation deemed high risk by treating physician
4. Malignancy, excluding basal cell carcinoma and malignancies diagnosed and treated more than 10 years previously, in whom there is a high probability of cure in the opinion of the treating physician
5. Pregnancy, planned pregnancy or lactation. Women of childbearing age (includes women who are less than 1 year postmenopausal and women who become sexually active) must be using an acceptable method of birth control (e.g., hormonal contraceptive, medically prescribed intrauterine device [IUD], condom in combination with spermicide) or be surgically sterilised (e.g., hysterectomy or tubal ligation)
6. Current signs or symptoms of severe, progressive, or uncontrolled renal, haematological, hepatic, respiratory, gastrointestinal, endocrine, cardiac, neurological or cerebral disease. Specifically, this includes cardiac failure (New York Heart Association [NYHA] class 3 or 4)
7. Screening blood tests at baseline which show haemoglobin less than 8 g/l, total white blood cell count (WBC) less than 3.5 or neutrophils less than 1.5, platelets less than 100. Patients will also be excluded if serum alanine aminotransferase (ALT) or alkaline phosphatase are more than twice the upper limit of normal, or impaired renal function: creatinine greater than 100 mumol/L AND Cockroft creatinine clearance less than 40 ml/min
8. Subjects who have used any investigational product within 30 days prior to enrolment
9. Aged less than 18 years
Less chance of benefit:
10. Disease duration greater than 36 months (date of diagnosis by rheumatologist
11. Previous treatment of RA with more than two disease modifying anti-rheumatic drugs (DMARDs). Systemic glucocorticoids are counted as DMARDs. Treatment is defined as a cumulative period of 8 weeks or more.
Measurement difficulties:
12. Insufficient command of local language
13. Illiteracy
14. Inability to comply with the protocol (opinion of treating physician)
Recruitment start date
01/10/2004
Recruitment end date
30/09/2006
Locations
Countries of recruitment
Netherlands
Trial participating centre
VU University Medical Center
Amsterdam
1007 MB
Netherlands
Sponsor information
Organisation
Vrije University Medical Centre (VUMC) (The Netherlands)
Sponsor details
Departments of Clinical Epidemiology and Biostatistics and Rheumatology
P.O. Box 7057
Amsterdam
1007 MB
Netherlands
+31 (0)20 444 4474
keb.info@vumc.nl
Sponsor type
University/education
Website
Funders
Funder type
Industry
Funder name
Schering-Plough (The Netherlands)
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
corporate
Location
United States of America
Funder name
Vrije University Medical Centre (VUMC) (The Netherlands)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Results - basic reporting
Publication summary
Results in http://www.ncbi.nlm.nih.gov/pubmed/18625629
Publication citations
-
Results
van Tuyl LH, Lems WF, Voskuyl AE, Kerstens PJ, Garnero P, Dijkmans BA, Boers M, Tight control and intensified COBRA combination treatment in early rheumatoid arthritis: 90% remission in a pilot trial., Ann. Rheum. Dis., 2008, 67, 11, 1574-1577, doi: 10.1136/ard.2008.090712.