| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Bechterew syndrome, Marie-Strümpell disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002556 |
| E.1.2 | Term | Ankylosing spondylitis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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| 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 demonstrate that the efficacy of Secukinumab 150 mg s.c. (with NSAID tapering) is superior to placebo based on the proportion of patients achieving an ASAS20 response at week 12. To show superiority, both Secukinumab treatment arms will be pooled and compared against placebo. |
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| E.2.2 | Secondary objectives of the trial |
• change from baseline in ASAS-NSAID score and in total BASDAI at week 12 is superior for Secukinumab 150 mg compared to placebo. Both Secukinumab treatment arms will be pooled.
• efficacy of Secukinumab 150 mg at Week 12 (early and delayed NSAID tapering) and Week 16 (early NSAID tapering) is superior to placebo based on proportion of patients achieving ASAS20 response.
• change from baseline in ASAS-NSAID score at Week 12 is superior for Secukinumab 150 mg (early and delayed NSAID tapering) as compared to placebo.
• efficacy of Secukinumab 150 mg at Week 12 (early and delayed NSAID tapering) and week 16 (early NSAID tapering) is superior to placebo based on change from baseline in total BASDAI.
• efficacy of Secukinumab 150 mg (early and delayed NSAID tapering) at Week 12 is superior to placebo based on change from baseline in health-related QoL as measured by SF-36 PCS.
• compare both Secukinumab regimens concerning change from baseline in ASAS-NSAID score after 12 weeks. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient must be able to understand and communicate with the investigator and comply with the requirements of the study and must give a written, signed and dated informed consent before any study assessment is performed
2. Male or non-pregnant, non-lactating female patients at least 18 years of age
3. Diagnosis of active AS with prior documented radiologic evidence (X-ray or radiologist’s report) fulfilling the Modified New York criteria for AS (Appendix 3)
4. Active AS assessed by total BASDAI ≥ 4 (0-10) at baseline
5. Spinal pain as measured by BASDAI Question 2 ≥ 4 cm on a 0-10 cm numeric rating scale at baseline
6. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at baseline
7. Patients should have been on at least 2 different NSAIDs at the highest recommended dose for at least 4 weeks in total in the past, prior to randomization, with an inadequate response or failure to respond, or less if therapy had to be reduced due to intolerance, toxicity or contraindications
8. Patients must report regular intake of NSAIDs of at least 50% of the highest recommended dose at Screening. Patients with prior TNFα inhibitor therapy must report regular intake of NSAIDs of at least 50% of the highest recommended dose at baseline after the appropriate washout
9. Patients are required to be on a stable dose of NSAIDs for at least 2 weeks before randomization
10. Patients who have previously been on a TNFα inhibitor will be allowed entry into study after an appropriate wash-out period prior to randomization:
• 4 weeks for Enbrel® (etanercept) – with a terminal half-life of 102 ± 30 hours (s.c. route)
• 8 weeks for Remicade® (infliximab) – with a terminal half-life of 8.0-9.5 days (i.v. infusion)
• 10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days (average 2 weeks) (s.c. route)
• 10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days
• 10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days
11. Patients who have been on a TNFα inhibitor (not more than two) must have experienced an inadequate response to previous or current treatment given at an approved dose for at least 3 months prior to randomization or have been intolerant to at least one administration of an anti-TNFα agent. No more than 40% of patients may have previously received anti-TNFα agents
12. Patients taking MTX (≤ 25 mg/week) or sulfasalazine (≤ 3 g/day) are allowed to continue their medication and must have taken it for at least 3 months and be on a stable dose for at least 4 weeks prior to randomization
13. Patients on MTX must be on stable folic acid supplementation before randomization
14. Patients who are on a DMARD other than MTX or sulfasalazine must discontinue the DMARD 4 weeks prior to randomization, except for leflunomide, which has to be discontinued for 8 weeks prior to randomization unless a cholestyramine washout has been performed
15. Patients taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/day prednisone or equivalent for at least 2 weeks before randomization
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| E.4 | Principal exclusion criteria |
1. Chest X-ray or MRI with evidence of ongoing infectious or malignant process, obtained within 3 months of screening and evaluated by a qualified physician
2. Patients taking high potency opioid analgesics
3. Previous exposure to Secukinumab or any other biologic drug directly targeting IL-17 or IL-17 receptor
4. Use of any investigational drug and/or devices within 4 weeks of randomization, or a period of 5 half-lives of the investigational drug, whichever is longer or participation in another clinical study (interventional or non-interventional) in the same indication during enrollment in this study
5. History of hypersensitivity to the study drug or its excipients or to drugs of similar chemical classes
6. Any therapy by intra-articular injections within 4 weeks before randomization
7. Any intramuscular corticosteroid injection within 2 weeks before randomization
8. Patients previously treated with any biological immunomodulating agents, except those targeting TNFα
9. Patients who have taken more than two anti-TNFα agents
10. Previous treatment with any cell-depleting therapies including but not limited to anti-CD20 or investigational agents 11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin laboratory test
12. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during entire study or longer if required by locally approved prescribing information.
In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
13. Active ongoing inflammatory diseases other than AS that might confound the evaluation of the benefit of Secukinumab therapy, including inflammatory bowel disease or uveitis
14. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions, which in the opinion of the investigator immunocompromises the patient and/or places the patient at unacceptable risk for participation in an immunomodulatory therapy
15. Significant medical problems or diseases, including but not limited to the following: uncontrolled hypertension (≥ 160/95 mmHg), congestive heart failure (New York Heart Association status of class III or IV), uncontrolled diabetes, or very poor functional status unable to perform self-care
16. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, or serum bilirubin.
17. History of renal trauma, glomerulonephritis, or patients with one kidney only, or a serum creatinine level exceeding 1.5 mg/dL (132.6 µmol/L)
18. Screening total WBC count <3,000/µL, or platelets <100,000/µL or neutrophils <1,500/µL or hemoglobin <8.5 g/dL (85 g/L)
19. Active systemic infections during the last two weeks prior to randomization (exception: common cold)
20. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection as defined by either a positive purified protein derivative (PPD) skin test (the size of induration will be measured after 48-72 hours, and a positive result is defined as an induration of ≥ 5 mm or according to local practice/guidelines) or a positive QuantiFERON TB-Gold test as indicated in the assessment schedule in Table 6-1. Patients with a positive test may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the patient has no evidence of active tuberculosis. If presence of latent tuberculosis is established, then treatment according to local country guidelines must have been initiated
21. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at screening or randomization
22. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years (except for basal cell carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed)
Other protocol-defined exclusion criteria may apply. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To demonstrate that the efficacy of Secukinumab 150 mg s.c. (with NSAID tapering) is superior to placebo based on the proportion of patients achieving an ASAS20 response at week 12. To show superiority, both Secukinumab treatment arms will be pooled and compared against placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. To demonstrate that the change from baseline in ASAS-NSAID score at week 12 is superior for Secukinumab 150 mg s.c. as compared to placebo. To show superiority, both Secukinumab treatment arms will be pooled and compared against placebo.
2. To demonstrate that the efficacy of Secukinumab 150 mg s.c at week 12 is superior to placebo based on the change from baseline in the total BASDAI. To show superiority, both Secukinumab treatment arms will be pooled and compared against placebo.
3. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 0 with NSAID tapering allowed from week 4; “delayed tapering”) at Week 12 is superior to placebo based on the proportion of patients achieving an ASAS20 response.
4. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 with NSAID tapering allowed from week 4; “early tapering”) at Week 12 is superior to placebo based on the proportion of patients achieving an ASAS20 response.
5. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 with NSAID tapering allowed from week 4; “early tapering”) at Week 16 is superior to placebo based on the proportion of patients achieving an ASAS20 response.
6. To demonstrate that the change from baseline in ASAS-NSAID score at Week 12 is superior for Secukinumab 150 mg s.c. (Secukinumab from week 0 with NSAID tapering allowed from week 4; “delayed tapering”) as compared to placebo.
7. To demonstrate that the change from baseline in ASAS-NSAID score at Week 12 is superior for Secukinumab 150 mg s.c . (Secukinumab from week 4 with NSAID tapering allowed from week 4; “early tapering”) as compared to placebo.
8. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 0 with NSAID tapering allowed from week 4; “delayed tapering”) at Week 12 is superior to placebo based on the change from baseline in the total BASDAI.
9. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 with NSAID tapering allowed from week 4; “early tapering”) at Week 12 is superior to placebo based on the change from baseline in the total BASDAI.
10. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 with NSAID tapering allowed from week 4; “early tapering”) at Week 16 is superior to placebo based on the change from baseline in the total BASDAI.
11. To demonstrate that the efficacy of Secukinumab 150 mg s.c. at week 12 is superior to placebo based on the change from baseline in health-related Quality of Life as measured by the SF-36 PCS.
12. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 0 with NSAID tapering allowed from week 4; “delayed tapering”) at Week 12 is superior to placebo based on the change from baseline in health-related Quality of Life as measured by the SF-36 PCS.
13. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 with NSAID tapering allowed from week 4; “early tapering”) at Week 12 is superior to placebo based on the change from baseline in health-related Quality of Life as measured by the SF-36 PCS.
14. To compare between both Secukinumab regimens concerning the change from baseline in ASAS-NSAID score after 12 weeks of Secukinumab exposure (ASAS-NSAID index at Week 12 for “delayed tapering” vs. Week 16 for “early tapering”). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 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 | 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) | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 54 |
| 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 | No |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
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