The proposed study is designed to get first data on efficacy and safety of etanercept in the treatment of patients with moderate to severe early axial Spondyloarthritis (SpA) with disease duration of less than 5 years compared to sulfasalazine in the first year of the study (up to week 48) and efficacy and safety of etanercept in the following years (up to week 540)
Conditions
Interventions
Trade Name: Enbrel
Product Name: Enbrel
Product Code: WAY-143050
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: Etanercept
Concentration unit: mg milligram(s)
Concent
Sponsors
Charité Universitätsmedizin Berlin
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients 18 – 50 years of age who have moderate to severe active axial spondyloarthritis. Diagnosis made by :Chronic low back pain (duration > 3 months, onset < 45 years of age)plus 3 out of the 6 following criteria if imaging is positive or 4 out of the following 6 criteria if imaging is negative · Inflammatory back pain Good or very good response to NSAIDs· One or more of the following extraspinal manifestations: uveitis, peripheral arthritis, enthesitis· HLA-B27 positive · Positive imaging: MRI showing acute inflammatory lesions in spine or SIJ (in the past) or bilateral sacroiliitis grade 2-4 or unilateral sacroiliitis grade 3-4 in x-ray not older than 12 months· Positive family history for SpA MRI at screening showing acute inflammatory lesions in SIJ or spine Active disease is defined as a BASDAI score of equal or more than 4, back pain score (BASDAI question 2) of equal or more than 4 despite concurrent NSAID therapy, or intolerance to NSAIDs. Reading a normal chest/ lung x-ray which should have been performed within the last 12 weeks before inclusion. Other inclusion criteria include: If on prednisone, =<7.5 mg per day; stable for 4 weeks prior to baseline. Women of child bearing potential must have a negative pregnancy test at study baseline and use an adequate method of contraception(such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence, vasectomised partner) for a duration of 6 months after stop of etanercept therapy. Sexual active men must use an accepted method of contraception for a duration of 6 months after stop of etanercept therapy. Able to self-administer injectable drug supplies or have a caregiver who will do so. Able to store injectable test article at 2° to 8° C. For the extension of the study up to week 216 according to amendment 5: Patients are eligible to enter the extension (week 108- week 216) if they are responders at week 108. Response is defined as reaching ASAS20 (compared to the screening) at least on one of the two visits at week 96 and week 108. Patients are considered to be non-responders if they do not reach ASAS20 response at week 96 and week 108. For the extension of the study up to week 324 according to amendment 6: - Patients who participated and completed the phase 3 of the study including week 216, and received treatment with etanercept 25 mg twice weekly subcutaneously. - Patients who are willing to participate in the phase 4 of the study by giving informed consent. - Women of childbearing potential willing to continue to use an adequate, effective method of contraception (such as implantable hormonal therapy, combined oral contraceptives, intrauterine devises, sexual abstinence, vasectomised partner) for the entire study period and up to 6 months after the last etanercept administration. - Male patients willing to continue to use an adequate, effective method of contraception for the entire study period and up to 6 months after the last etanercept administration. For the extension of the study up to week 432 according to amendment 8: Inclusion criteria: - Patients who participated and completed the phase 4 of the study including week 324, and received treatment with etanercept 25 mg twice weekly subcutaneously. - Patients who are willing to participate in the phase 4 of the study by giving informed consent. - Women of childbearing potential willing to continue to use an adequate, effective method of contraception (such as implantable hormona
Exclusion criteria
Exclusion criteria: Disease duration of longer than 5 years History of active tuberculosis (TB), histoplasmosis or listeriosis.History of positive HIV status, known hepatitis B or C History of malignancy other than carcinoma in situ of the cervix or adequately treated non?metastatic squamous or basal cell skin carcinoma. Antibiotic treatment within 3 weeks prior to screening. Previous treatment with TNF-alpha blockers Treatment with sulasalazine in the last 6 months before participation in the clinical trial If on DMARDs a washout period of at least 4 weeks is necessary. If Leflunomide was discontinued, it should be stopped at least 3 months or should be washed out within 4 weeks before study start. History of uncontrolled diabetes, unstable ischemic heart disease, active inflammatory bowel disease, active peptic ulcer disease, recent stroke (within 3 months), ongoing congestive heart failure, and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the protocol. Female subjects who are pregnant or breast-feeding. Previous diagnosis or signs of demyelinating diseases History of systemic lupus erythematosus Receipt of any live (attenuated) vaccines within 4 weeks before screening visit Laboratory exclusions are: hemoglobin level 175 µmol/l, liver enzymes or alkaline phosphatase >2 times the upper limit of normal. History of allergic reaction to sulfasalazine, its metabolites, or any other part of the drug (crospovidon, stearic acid, povidon, highly dispersed silicium dioxide magnesium stearate, titandioxide, talcum, carmellose, sodium citrate, macrogol, propylengylcol, methacryl acid-ethyacrylat-copolymer), or to salycylates. Porphyria, severe liver- or renal insufficiency, deficiency of glucose-6-phosphatedehydrogenase.Hypersensitivity to the active substance (etanercept) or any other part of the drug, or other parts of the drug (mannitol, sucrose, trometamol) sepsis or risk of sepsis Participation in trials of other investigational medications within 30 days of entering the study Clinical examination showing significant abnormalities of clinical relevance History or current evidence of abuse of ”hard” drugs (e.g. cocaine/heroine) or alcoholism Contraindication for conducting MRI examinations. For the extension of the study up to week 324 according to amendment 6: - Patients for whom continued treatment with etanercept is not considered appropriate in opinion of investigator (e.g., due to lack of efficacy, safety concerns, contraindications for etanercept). - Patients who were non-compliant or demonstrated major protocol deviation in the phase 3 of the study. For the extension of the study up to week 432 according to amendment 8: - Patients for whom continued treatment with etanercept is not considered appropriate in opinion of investigator (e.g., due to lack of efficacy, safety concerns, contraindications for etanercept). - Patient who were non-compliant or demonstrated major protocol deviation in the phase 4 of the study. For the extension of the study up to week 540 according to amendment 9: - Patients for whom continued treatment with etanercept is not considered appropriate in opinion of investigator (e.g., due to lack of efficacy, safety concerns, contraindications for etanercept). - Patient who were non-compliant or demonstrated major protocol deviation in the previous phase of the stud
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Efficacy – to assess efficacy of etanercept vs. sulfasalazine when added to NSAIDs in patients with moderate to severe active early axial spondyloarthritis duration of ongoing axial symptoms of less than 5 years. Primary outcome is change of active inflammatory lesions in sacroiliac joints and spine as detected by MRI at 12 months and at week 216, sustained reduction of active inflammation up to week 540. ;Secondary Objective: Efficacy Variables: • ASAS 20%, 40%, 70% response, ASAS criteria for partial remission • BASDAI 20%, 50%, 70% improvement • BASFI • Mobility examinations: BASMI, Chest Wall Expansion • CRP, ESR • Quality of Life: SF-36 • Numeric Rating Scale (NRS) – physicians global, patients global, general pain, nocturnal pain • Enthesitis index (Maastricht scale) • swollen joint count • EQ-5D • Socio-economic questionnaire • Chronic changes in MRI at month 6 and 12, week 108, week 156, week 216, week 264, week 324 and week 432 • Reduction of active inflammatory lesions in MRI at 6 months, week 156, week 264 and week 432 • Progression of radiographic damage of the spine on X-rays • Assessment of radiological progression of sacroiliitis as shown by x-rays of the sacroiliac joints • Change in levels of serum biomarkers Safety: Safety of the long-term (up to 8 years) treatment with etanercept;Primary end point(s): Primary endpoint first year (until week 48): Reduction of active inflammatory lesions in MRI at week 48. Primary endpoint fourth year (until week 216): Reduction of active inflammatory lesions in MRI at week 216. Primary endpoint sixth year (until week 324): Sustained reduction of active inflammatory lesions in MRI at week 324. Primary endpoint eigth year (until week 432): Sustained reduction of active inflammatory lesions in MRI at week 432. Primary endpoint eigth year (until week 540): Sustained reduction of active inflammatory lesions in MRI at week 540. ;Timepoint(s) of evaluation of this end point: Weeks 48 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • ASAS 20%, 40%, 70% response, ASAS criteria for partial remission • BASDAI 20%, 50%, 70% improvement • BASFI • Mobility examinations: BASMI, Chest Wall Expansion • CRP, ESR • Quality of Life: SF-36 • Numeric Rating Scale (NRS) – physicians global, patients global, general pain, nocturnal pain • Enthesitis index (Maastricht scale) • Swollen joint count • EQ-5D • Socio-economic questionnaire • Chronic changes in MRI at month 6 and 12, week 108, week 156, week 216, week 264, and week 432 • Reduction of active inflammatory lesions in MRI at 6 months, week 156, week 264 and week 432 • Progression of radiographic damage of the spine on X-rays over 108 weeks (week 216-week 324) and its correlation with MRI findings (for this purpose patients will undergo an x-ray of the spine (cervical spine - lateral view, lumbar spine lateral and anteropostierior views) at week 216 and at week 432. This time interval follows common clinical practice with radiographic control of x-ray changes every 2 years; x-rays will be scored by blinded readers) • Assessment of radiological progression of sacroiliitis as shown by x-rays of the sacroiliac joints at screening, week 108,week 216, week 432 and its correlation with MRI findings (for this purpose patients will undergo an x-ray of the sacroiliac joints at week 108, at week 216, and at week 432; x-rays of the sacroiliac joints will be scored by blinded readers) • Change in levels of serum biomarkers reflecting bone and cartilage destruction/formation over one year (week 264 – week 432) and its correlation with MRI and x-ray findings. ;Timepoint(s) of evaluation of this end point: Weeks 48, 108, 216, 264, 432, 540 | — |
Countries
Germany
Contacts
Public ContactProf. Dr. Joachim Sieper
Charité
Outcome results
None listed