| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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)
|
| Axial Spondyloarthritis including ankylosing spondylitis and non-radiographic axial spondyloarthrithritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic inflammatory disease of the spine (spondyloarthritis) |
| Axial Spondyloarthritis including ankylosing spondylitis and non-radiographic axial spondyloarthrithritis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| 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 |
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.
|
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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.
- Patients for whom continued treatment with etanercept is considered to be necessary in the opinion of investigator.
For the extension of the study up to week 540 according to amendment 9:
- Patients who participated and completed the phase 5 of the study including week 432, and received treatment with etanercept 25 mg twice weekly subcutaneously.
- Patients who are willing to participate in the phase 6 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.
- Patients for who continued treatment with etanercept is considered to be necessary in the opinion of investigator.
|
|
| E.4 | Principal 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 < 8,5 mg/dl, white blood cell count < 3.5 x109/l, platelet count < 125 x 109 /l, creatinine 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 study. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 48, 108, 216, 264, 432, 540 |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| 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 | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 13 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
