| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Ankylosing Spondylitis (AS) |
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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 |
| To compare the efficacy of etanercept 50 mg once weekly with SSZ 3 g daily in the treatment of AS subjects over 16 weeks. The study hypothesis is that etanercept 50 mg once weekly will demonstrate superior clinical efficacy, as determined by the proportion of responders achieving a 20% improvement on the Assessment of AS (ASAS) response criteria (ASAS 20; Attachment 2) at 16 weeks, compared with SSZ 3 g daily in the treatment of AS subjects. |
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| E.2.2 | Secondary objectives of the trial |
1. To compare the effect of etanercept 50 mg once weekly with SSZ 3 g daily on the quality of life over 16 weeks.
2. To evaluate the safety of etanercept 50 mg once weekly over 16 weeks.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Subject must fulfil all of the following conditions or characteristics in order to be considered for study enrolment:
1. Diagnosis of AS, as defined by Modified New York Criteria for Ankylosing Spondylitis (Attachment 1).
2. Active AS, defined on a scale of 0 to 100 by:
· Average duration and intensity of morning stiffness visual analogue scale (VAS) of nlt 30;
· At least 2 of the following:
- Patient global assessment VAS nlt 30 (Attachment 6);
- Average nocturnal and total pain VAS nlt 30 (Attachment 7);
- Bath Ankylosing Spondylitis Functional Index (BASFI; Attachment 3) VAS nlt 30.
3. Presence of peripheral arthritis, defined as nlt 1 tender/painful and swollen peripheral joint or nlt 1 tender/painful hip or shoulder joint.
4. Treatment failure to at least one NSAID of at least three months duration at the maximal recommended or tolerated anti-inflammatory dose, unless NSAIDs are contraindicated.
5. 18 years of age or older at time of consent.
6. Negative serum pregnancy test taken at screening in all women except those who were surgically sterile or at least 1 year postmenopausal. Sexually active women of childbearing potential participating in the study must use a medically acceptable form of contraception (which include oral contraception, injectable or implantable methods, intrauterine devices, or properly used barrier contraception). A woman of childbearing potential is defined as one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
7. Agreement by male subjects who are not surgically sterile and female subjects who are not surgically sterile or postmenopausal to use reliable methods of birth control for the duration of the study.
8. Ability to self-inject drug or have a designee who can do so.
9. Capable of understanding and willing to provide signed and dated written voluntary informed consent before any protocol specific procedures are performed.
10. Ability to store injectable test article at 2 C to 8 C.
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| E.4 | Principal exclusion criteria |
Subjects with any of the following conditions or characteristics will be excluded from study enrolment:
1. Complete ankylosis (fusion) of spine.
2. Previous treatment with etanercept, antibody to tumour necrosis factor a (TNFa), or other TNFa inhibitors or other biologic agents.
3. Treatment with SSZ within 6 months of screening.
4. History of treatment with SSZ associated with significant toxicity or significant lack of response.
5. Contraindication to SSZ including:
· Hypersensitivity to SSZ, its metabolites, sulfonamides, or salicylates
· History or presence of intestinal or urinary obstruction
· History or presence of porphyria
· Current treatment with digoxin
6. Failure to respond to treatment to more than one DMARD.
7. Use of DMARDs other than methotrexate or hydroxychloroquine within 4 weeks of baseline. Subjects on methotrexate or hydroxychloroquine must have been on a stable dose for at least 4 weeks prior to randomisation.
8. Receipt of more than one DMARD concurrently at screening.
9. Previous use of intravenous bisphosphonate.
10. Receipt of more than one NSAID concurrently at baseline.
11. Dose of NSAID changed within 2 weeks of baseline.
12. Dose of prednisone >10 mg/day (or equivalent) or changed within 2 weeks of baseline.
13. Receipt of intra-articular, intravenous, intramuscular, or subcutaneous corticosteroid within 4 weeks of screening.
14. Abnormality in haematology or chemistry profiles: haemoglobin nmt 85 g/L; haematocrit nmt 27%; platelet count nmt 125 x 10 power 9 /L; white blood cell count nmt 3.5 x 10 power 9 /L; serum creatinine nlt 175 mmol/L; aspartate aminotransferase (AST [SGOT]) and alanine aminotransferase (ALT [SGPT]) nlt 2 times the laboratory’s upper limit of normal.
15. Significant concurrent medical events including:
· Uncontrolled hypertension (defined as screening systolic blood pressure > 160 mm Hg or screening diastolic blood pressure > 100 mm Hg)
· Myocardial infarction within 12 months of the screening visit
· Unstable angina pectoris
· Class III or IV congestive heart failure as defined by the New York Heart Association classification (16) or uncompensated congestive heart failure
· Severe pulmonary disease requiring hospitalisation or supplemental oxygen
· Diagnosis of multiple sclerosis or other central demyelinating diseases
· Presence or history of confirmed blood dyscrasias
· Uncontrolled diabetes mellitus
· Rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or polymyositis
· Cancer or history of cancer (other than resected cutaneous basal cell or squamous cell carcinoma)
· Serious infection (infection associated with hospitalisation and/or intravenous antibiotics) within 1 month of test article administration or active infection at screening
· Open cutaneous ulcers
· Known human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) positive
· Tuberculosis (TB) infection (Note: follow local country guidelines for appropriate screening and treatment of tuberculosis in the setting of anti-TNF therapy)
· Any condition that, in the investigator’s judgment, might cause this study to be detrimental to the subject
16. Receipt of any live (attenuated) vaccine within 4 weeks prior to baseline
17. Known contraindication or hypersensitivity to etanercept or its excipients.
18. Pregnant or breast-feeding women.
19. Reasonable expectation that the subject will not be able to satisfactorily complete the study
20. History of or current psychiatric illness that would interfere with the subject’s ability to comply with protocol requirements or give informed consent.
21. History of alcohol or drug abuse that would interfere with the subject’s ability to comply with protocol requirements.
22. Receipt of any investigational drug within 3 months of screening visit.
23. Employment by the investigator or reporting directly or indirectly to the investigator.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the proportion of subjects who achieve ASAS 20 at Week 16 relative to baseline. |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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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| The end of the study is the last visit of the last subject. |
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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