Contact information
Type
Scientific
Primary contact
Prof Josef Smolen
ORCID ID
http://orcid.org/0000-0002-4302-8877
Contact details
Medical University of Vienna
Department of Internal Medicine III
Division of Rheumatology
Waehringer Guertel 18-20
Vienna
1090
Austria
+43 (0)1 40 400 4300
josef.smolen@wienkav.at
Additional identifiers
EudraCT number
2006-002787-26
ClinicalTrials.gov number
Protocol/serial number
DINORA4
Study information
Scientific title
A double blind, randomised, placebo controlled, multicentre trial of Anti-Tumour Necrotising Factor alpha (Anti-TNFα) chimeric monoclonal antibody (infliximab, Remicade®) in combination with methotrexate in patients with very early inflammatory arthritis
Acronym
DINORA
Study hypothesis
The primary objective of the study is to demonstrate that patients with very early arthritis have a higher probability of achieving a state of clinical remission at end of infliximab therapy if treated with infliximab plus Methotrexate (MTX) when compared to MTX monotherapy or supportive treatment only.
Ethics approval
Ethikkommission der Medizinischen Universität Wien und des Allgemeinesn Krankenhauses der Stadt Wien AKH, 04/07/2006, ref: EK 292/2006
Study design
Double blind randomised placebo controlled multi-centre trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
No participant information sheet available
Condition
Early inflammatory arthritis
Intervention
This is a double blind, randomised, placebo controlled, multi-centre trial in which a total of 89 subjects (36 per DMARD treatment arm and 17 in the supportive treatment arm) will be randomly assigned, stratified by glucocorticoid use to one of the following treatment groups:
Group I: To receive symptomatic therapy as well as oral methotrexate and infliximab
Group II: To receive symptomatic therapy as well as oral methotrexate and placebo infusions
Group III: To receive symptomatic therapy as well as placebo tablets and placebo infusions
The dosage and frequency for MTX/placebo and infliximab/placebo will depend on whether the patients reach remission as defined in the protocol (infliximab) and/or whether there are any side effects (MTX). Infliximab will be given by infusion and MTX intake will be oral.
Intervention type
Drug
Phase
Not Specified
Drug names
Methotrexate, infliximab (Remicade®)
Primary outcome measure
Comparison of presence of clinical remission between treatment with infliximab plus MTX versus MTX monotherapy and supportive treatment only at end of infliximab therapy, i.e. at at least two consecutive visits after month 3 during the first 54 weeks.
Secondary outcome measures
Comparison, Group I versus Group II and Group III of:
1. The presence of persistent clinical remission at week 106
2. The presence of persistent clinical remission at week 54 since start of therapy
3. The presence of persistent clinical remission at week 106
4. Radiographic progression at week 22, 54 and 106
5. The presence of clinical remission at every time point during the trial
6. The presence of clinical remission by Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) at every time point during the trial
7. The presence of remission by Pinals criteria at every time point during the trial
8. The presence of near-remission (28-item Disease Activity Score [DAS28] less than 2.6) at every time point during the trial
9. The duration of clinical remission or near-clinical remission during the entire trial
10. Time to remission
11. Time to relapse after withdrawal of infliximab therapy in patients who achieved persistent clinical remission
12. All variables included in the World Health Organization/International League of Associations for Rheumatology (WHO/ILAR) core set for clinical trials (66-joints swollen joint count, 68-joints tender joint count, pain, patient and evaluator global assessments, Health Assessment Questionnaire [HAQ], C-Reactive Protein [CRP], Erythrocyte Sedimentation Rate [ESR]) at every time point during the trial
13. DAS28, SDAI, CDAI and Rheumatoid Arthritis Disease Activity Index (RADAI) at every time point during the trial
14. American College of Rheumatology (ACR) 50 and 70 response, 36-item Short Form health survey (SF36), fatigue (Visual Analogue Scale [VAS]) and pharmacoeconomics at week 2, 6, 14, 22, 30, 38, 54, 70 and 106
15. Glucocorticoid and Non-Steroidal Anti-Inflammatory Drug (NSAID)/Cyclooxygenase (COX)-2 selective inhibitors (Coxib) dosage at every time point during the trial
16. Number of visits at which relapse from remission was noted
Overall trial start date
04/10/2007
Overall trial end date
07/10/2013
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
All patients to be included into this trial must meet the following inclusion criteria:
1. Men and women, between 18 and 75 years of age, capable of understanding and signing an informed consent
2. The presence of arthritis:
2.1. Must be established in a rheumatology centre
2.2. Must be present in at least two joints of the 66 joint count, of which at least one joint must be an Metacarpophalangeal- (MCP-), or a Proximal Interphalangeal- (PIP-) (Interphalangeal- [IP-]), or a wrist- or a Metatarsophalangeal- (MTP-) joint. Two MTP-joints will not suffice. Any kind of polyarthritis (= 6 joints of any kind) will be sufficient
2.3. Without any previous episodes of inflammatory joint disease
3. Duration of symptoms:
3.1. Must be reported by the subject and should involve the inflamed joints described under point 2
3.2. Must be 2 weeks at least
3.3. Must be 16 weeks at most, as reported by the subject, including the observation period of at least 2 weeks by the physician
4. Confirmation of persistent arthritis:
4.1. Duration must be 2 weeks at least
4.2. Duration must be 12 weeks at most
4.3. Must be documented by the same rheumatology centre that established arthritis at the first visit
4.4. Must involve at least one of the same joints as were involved at the first visit
5. Men and women of childbearing potential must use adequate birth control measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, implantable or injectable contraceptives or surgical sterilisation) for the duration of the study and should continue such precautions for 6 months after receiving the last medication
6. Are considered eligible according to the Tuberculosis (TB) eligibility assessment, screening, and early detection of reactivation rules (defined in the protocol)
7. Chest radiograph (which must not be older than three months at the visit 1/day 0 visit) must show no evidence of malignancy, infection, or fibrosis. The chest radiograph should also show no atypical scarring, cavitary lesions, or calcified granulomas, as evidence of past tuberculosis infections, without a documented history of adequate therapy
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Updated 25/10/2011: 89 (36 per DMARD treatment arm and 17 in the supportive treatment arm) (At time of registration: 200 (80 per DMARD treatment arm and 40 in the supportive treatment arm))
Participant exclusion criteria
Patients must not:
1. Have arthritis with a distinct diagnosis, made after a routine diagnostic work-up (examples are Systemic Lupus Erythematosus [SLE], psoriatic arthritis, systemic sclerosis, gout, pseudogout, Lyme arthritis, reactive arthritis, Parvo viral arthritis)
2. Be incapacitated, largely or wholly bedridden, or confined to a wheelchair, or have little or no ability for self care
3. Weigh more than 100 kg
4. Use glucocorticoids greater than 10 mg/day prednisone or equivalent
5. Have received intramuscular or intra-articular injection of steroids in the previous month
6. Have screening laboratory test results as follows:
6.1. White Blood Cells (WBCs) less than 3.0 x 10^9 cells/L
6.2. Platelets less than 100 x 10^9 cells/L
6.3. Serum creatinine greater than 1.4 mg/dL
6.4. Serum transaminase levels exceeding 2 times the upper limit of normal for the site laboratory
7. Have had any previous treatment with monoclonal antibodies or antibody fragments
8. Have a history of receiving human/murine recombinant products or a known allergy to murine products. A known allergy to murine product is definitely an exclusion criterion
9. Have had prior treatment with MTX and/or other Disease Modifying Anti-Rheumatic Drugs (DMARDs) (except hydroxychloroquine)
10. Have documentation of seropositivity for Human Immunodeficiency Virus (HIV)
11. Have documentation of a positive test for hepatitis B surface antigen or hepatitis C-antibodies
12. Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results
13. Have a known history of serious infections (such as, but not limited to hepatitis, pneumonia, or pyelonephritis) in the previous 3 months
14. Have a known history of a demyelinating disease, such as multiple sclerosis
15. Have or have had an opportunistic infection (e.g., herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 12 months prior to screening
16. Have undergone any joint replacement surgery
17. Have a chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection (e.g., bronchiectasis), sinusitis, recurrent urinary tract infection, open, draining or infected skin wound or ulcer
18. Be considered ineligible according to the TB eligibility assessment, screening, and early detection of reactivation rules (defined in the protocol)
19. Have a chest radiograph at screening that shows evidence of malignancy, infection, or any abnormalities suggestive of TB
20. Have a history of lymphoproliferative disease, including lymphoma or signs suggestive of possible lymphoproliferative disease such as lymphadenopathy of unusual size or location (e.g., nodes in the posterior triangle of the neck, infraclavicular, epitrochlear, or periaortic area), or splenomegaly
21. Currently have any known malignancy other than the condition being treated or have a history of malignancy within the previous 5 years, with the exception of basal cell or squamous cell carcinoma of the skin that has been fully excised with no evidence of recurrence
22. Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, haematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease
23. Be unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access
24. Use any investigational drug within 3 months prior to screening or within five half-lives of the investigational agent, whichever is longer
25. Have presence of a transplanted solid organ (with the exception of a corneal transplant greater than 3 months prior to screening)
26. Have a concomitant diagnosis or history of congestive heart failure (New York Heart Association [NYHA] class III or IV)
27. Be women who are pregnant, nursing, or planning pregnancy within 6 months after the last infusion
Recruitment start date
04/10/2007
Recruitment end date
14/02/2012
Locations
Countries of recruitment
Austria, Germany, Greece, Italy, Netherlands, Spain
Trial participating centre
Medical University of Vienna
Division of Rheumatology
Department of Medicine 3
Waehringer Guertel 18-20
Vienna
1090
Austria
Trial participating centre
Hietzing Hospital
Department of Internal Medicine
Centre for Rheumatic Diseases
Wolkersbergenstraße 1
V ienna
1130
Austria
Trial participating centre
Leiden University Medical Centre
Department of Rheumatology
Albinusdreef 2
Leiden
2300 RC
Netherlands
Trial participating centre
University Medical Center and Faculty of Medicine Carl Gustav Carus at the TU Dresden
Division of Rheumatology
Department of Medicine III
Fetscherstrasse 74
Dresden
01309
Germany
Trial participating centre
Rheumatology Medical School University of Crete
Heraklion and Joint Rheumatology Program
National and Kapodestrian University of Athens
Athens
-
Greece
Trial participating centre
Charité - Universitätsmedizin Berlin
Department of Rheumatology and Clinical Immunology, Charité
Department of Rheumatology and Clinical Immunology, Charité
Berlin
10117
Germany
Trial participating centre
University of Genova
Research Laboratory and Division of Rheumatology
Department of Internal Medicine
Viale Benedetto XV
Genova
16132
Italy
Trial participating centre
Medical University of Graz
Department of Rheumatology
Auenbruggerplatz 15
8036
Styria
Austria
Trial participating centre
Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Department of Internal Medicine 3
Rheumatology and Immunology
Ulmenweg 18
Erlangen
91054
Germany
Trial participating centre
Ludwig Maximilians University of Munich
Division of Rheumatology and Clinical Immunology
Department of Internal Medicine IV
Pettenkoferstraße 8a
Munich
80336
Germany
Trial participating centre
Academic Medical Centre
Amsterdam Rheumatology and Immunology Center
Meibergdreef 9
Amsterdam-Zuidoost
1105 AZ
Netherlands
Trial participating centre
University Hospital Maastricht
. Debyelaan 25
Maastricht
6229HX
Netherlands
Trial participating centre
Atrium Medical Center
Dept. Rheumatology
Henri Dunantstraat 5
Heerlen
6419PC
Netherlands
Trial participating centre
Hospital Universitario La Paz
Poseo de la Castellana 261
Madrid
28046
Spain
Sponsor information
Organisation
Medical University of Vienna (Austria)
Sponsor details
c/o Professor Josef Smolen
MD
Department of Internal Medicine III
Division of Rheumatology
Waehringer Guertel 18-20
Vienna
1090
Austria
+43 (0)1 40 400 4300
josef.smolen@wienkav.at
Sponsor type
University/education
Website
Funders
Funder type
Industry
Funder name
Janssen
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
Basic results (scientific)
Publication list