| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
T cell responses have been demonstrated against proteoglycan (an important cartilage protein) in human arthritides including ankylosing spondylitis. We suggest that a chronic, probably T cell mediated, immune response against cartilage is relevant in the pathogenesis of AS.
Based on the above described findings about the role of T-cells in ankylosing spondylitis we assume that Abatacept has the potential to be an effective drug for treating ankylosing spondylitis.
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| 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 |
| The primary endpint will be the ASAS40 response rate in TNF-blocker naïve and in TNF-blocker failure patients at week 24. We postulate that at least 30% of the patients will achieve an ASAS40 response. Given the good efficacy of the TNF-blocking agents, abatacept would not be an interesting treatment if the response rate were lower. |
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| E.2.2 | Secondary objectives of the trial |
Safety Evaluations: Adverse events, vital signs, physical examination results, and clinical laboratory values until week 36.
Efficacy Evaluations: ASAS 20 response, ASAS criteria for partial remission, duration of response, BASDAI 20%, 50%, 70% improvement, BASFI, mobility examinations: BASMI, Chest Wall Expansion, disease controlling antirheumatic therapy criteria (DC-ART20) (5 out of 6), CRP, ESR, quality of Life: SF-36, AS-QoL, EQ-5D; Numeric Rating Scale (NRS) – physicians global, patients global, general pain, nocturnal pain; enthesitis index (Maastricht scale) swollen and tender joint count; socio-economic questionnaire, course of change of active and chronic inflammatory lesions in MRI after 24 weeks Immune monitoring at inclusion and monthly thereafter for 24 weeks: number of T cells, activation of T cells, parameters of apoptosis. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Only patients with moderate to severe ankylosing spondylitis will be included. This implies that only patients with radiological evidence of sacroiliitis (fulfilling the modified New York criteria for AS) will be included.
1) Patients 18- 65 years of age who have moderate to severe ankylosing spondylitis.
2)
Group 1: TNFalpha inhibitor naïve patients: active AS patients with inadequate response to conventional therapy (e.g. NSAIDs, glucocorticosteroids or DMARDs) or with intolerance of conventional therapy.
Group 2: TNFalpha inhibitor failures: active AS patients with inadaequate response to treatment with TNFalpha inhibitors (= patients with previous treatment with TNFalpha inhibitors who showed an inadaquate response according to the international ASAS recommendations; NOT AS patients who had to discontinue TNFalpha inhibitor treatment because of intolerance)
3) active disease is defined as a BASDAI score of >= 4, back pain score (BASDAI question 2) of >= 4 despite concurrent NSAID therapy, or intolerance to NSAIDs (first group) or prior treatment with TNFalpha inhibitors (second group)
4) if on NSAIDs, dosage must be stable 2 weeks prior to baseline. During the study dosage should be stable but is allowed to be reduced if documentated.
5) If on prednisone, <=10.0 mg per day, must be stable for 4 weeks prior to baseline and should be kept stable during the study
6) If on sulfasalazine or methotrexate, must be stable for 4 weeks prior to baseline
7) If on TNFalpha blocking agent (infliximab, etancercept, adalimumab), the TNFalpha-blocking therapy must have been terminated at least 4 weeks prior to baseline if etanercept was used and at least 8 weeks if infliximab or adalimumab were used. |
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| E.4 | Principal exclusion criteria |
1) Current clinical or laboratory evidence of active or latent tuberculosis (TB) and subjects with a history of active TB treated within the last 3 years --> all potential subjects will have a screening chest x-ray at baseline (acceptable if present within the last 3 months); all potential subjects will have a Tuberculin skin test at screening
2) Patients with other chronic inflammatory articular disease or systemic autoimmune disease, e.g. Systemic lupus erythematosus, Sjögren’s syndrome, active rheumatoid vasculitis, a history of systemic diseases associated with arthritis, chronic fatigue syndrome (other manifestations of spondyloarthritis such as psoriasis, inflammatory bowel disease, arthritis, uveitis are not regarded as exclusion criteria)
3) Any active infection, a history of recurrent clinically significant infection, a history of recurrent bacterial infections with encapsulated organisms
4) Hepatitis B or C or HIV
5) Primary or secondary immunodeficiency.
6) History of cancer with curative treatment not longer than 5 years ago except basal-cell carcinoma of the skin that had been excised
7) A history of pulmonary or cardiac insufficiency, or serious and/or uncontrolled diseases that are likely to interfere with the evaluation of the patient's safety and of the study outcome
8) Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease ( e.g. heart failure class III/IV NYHA, cardiac infarct within last 6 month)
9) nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders
10) Neuropathy that can interfere with quality of life and/or pain assessment.
11) Patients with a history of a severe psychological illness or condition such as to interfere with the patient's ability to understand the requirements of the study.
12) History of current evidence of abuse of “hard” drugs (e.g. cocaine/ heroine) or alcoholism
13) Known hypersensitivity to any component of the study medication
14) Women lactating, pregnant, nursing or of childbearing potential with a positive pregnancy test (urine test)
15) Males or females of reproductive potential not willing to use effective contraception (e.g. contraceptive pill, IUD, physical barrier)
16) History of alcohol, drug or chemical abuse within 6 month prior to screening
Exclusion criteria related to medications:
1) if previously on TNFalpha blocking agents, discontinuation of TNFalpha-blocking agents because of intolerance.
2) If on leflunomide, leflunomide must have been terminated at least 8 weeks prior to the first abatacept administration (or ≥ 28 days after 11 days of standard cholestyramine or activated charcoal washout).
3) If on TNFalpha blocking agent (infliximab, etancercept, adalimumab), the TNFalapha therapy must have been terminated at least 4 weeks prior to the first abatacept adminstration if etanercept was used and at least 8 weeks if infliximab or adalimumab were used
4) Previous treatment with abatacept or rituximab
5) If on sulfasalazine or methotrexate, must be stable for 4 weeks prior to baseline
6) Corticosteroids at doses exceeding 10 mg per day of prednisolone or the equivalent within the last 4 weeks prior to the first abatacept administration
7) Previous treatment with any investigational agent within 28 days ( or less than 5 terminal half-lives of elimination) of day 1 dose
8) Previous treatment with i.v. immunoglobulins
9) Receipt of a live vaccine within 4 weeks prior to treatment
10) Intra-articular or parenteral corticosteroids within 4 weeks prior to screening visit
Exclusion criteria related to lab findings:
1) Haemoglobin < 8.5 g/dl
2) Neutrophil counts < 2.000 / µl
3) Platelet count < 125.000 / µl
4) Lower than 1 x 1000/µl lymphopenia for more than three months prior to inclusion.
5) Serum creatinine > 1.4 mg/dl for women or 1.6 mg/dl for men.
6) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times upper limit of normal
7) Positive HIV, hepatitis B or C serology
8) Any other laboratory test result that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study.
Exclusion criteria related to formal aspects:
1) Patients who participate currently in another clinical trial or patients who participated in another clinical trial during the last 30 days.
2) Patients who are underage or patients who are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (according to § 40 Abs. 4 and § 41 Abs. 2 und Abs. 3 AMG). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpint will be the ASAS40 response rate in TNF-blocker naïve and in TNF-blocker failure patients at week 24. We postulate that at least 30% of the patients will achieve an ASAS40 response. Given the good efficacy of the TNF-blocking agents, abatacept would not be an interesting treatment if the response rate were lower. |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.7.1.3.1 | Other trial type description |
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| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| 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 | No |
| 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 | 2 |
| 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 | Information not present in EudraCT |
| 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
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All patients will undergo a screening examination prior to entering the study to confirm eligibility (first visit to collect baseline data, screening examination).
Patients will return to the investigating center for 9 further visits. Thus, patients return to the investigating center at week 0, 2, 4, 8, 12, 16, 20, 24 / ET (early termination) and 36.
The study ends, when the last patient underwent the contol visit in week 36.
A |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
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