| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ankylosing Spondylitis (AS) |
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| E.1.1.1 | Medical condition in easily understood language |
| Ankylosing Spondylitis (AS) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| 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 |
Objective 1: To compare the effects of etoricoxib 90 mg once daily to naproxen 1000 mg in the treatment of ankylosing spondylitis as measured by Spinal Pain Intensity (0- to 100-mm VAS, Question 2 of Bath Ankylosing Spondylitis Disease Activity Index, BASDAI) over 6-weeks of treatment in Part I.
Objective 2: To compare the effects of etoricoxib 60 mg once daily to naproxen 1000 mg in the treatment of ankylosing spondylitis as measured by Spinal Pain Intensity (0- to 100-mm VAS, Question 2 of Bath Ankylosing Spondylitis Disease Activity Index, BASDAI) over 6-weeks of treatment in Part I.
Objective 3: To evaluate the overall tolerability of etoricoxib (90 mg and 60 mg once daily) in ankylosing spondylitis patients. |
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| E.2.2 | Secondary objectives of the trial |
Objective 1: To evaluate the treatment effect between etoricoxib doses (90 mg, 60 mg once daily) on Spinal Pain Intensity (VAS) over 6-weeks of treatment in Part I as assessed by the time-weighted average (TWA) change from baseline.
Objective 2: To compare the incremental benefit in those who are considered nonresponders to etoricoxib 60 mg in Part I, and who subsequently increase their dose to etoricoxib 90 mg in Part II, to those non-responders on etoricoxib 60 mg in Part I who subsequently remain on etoricoxib 60 mg in Part II as measured by the
average change from Week 6 to Weeks 10 and 12 in Spinal Pain Intensity (VAS).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female, ≥18 years of age on the day of signing informed consent.
2. Female patients of reproductive potential must demonstrate a serum β-hCG level consistent with a nongravid state at the screening visit (Visit 1) and agree to remain abstinent, use oral, barrier, intramuscular, or implanted contraceptives from Visit 1 until 28 days after the last dose of study medication. Women who are postmenopausal or have had a hysterectomy or bilateral tubal ligation or bilateral oophorectomy are exempt from this requirement. Postmenopausal is defined as no menses for the previous 1 year prior to Visit 1; women with cessation of menses within the previous 1 year prior to Visit 1 must have FSH tested at Visit 1.
Note: If a patient’s Visit 1 FSH result is not within the postmenopausal range (as defined by the central laboratory), serum β-hCG must be tested based on the blood sample from Visit 1 and urine β-hCG must be tested at Visits 2, 5, 8, and 9 (or discontinuation).
3. Patient has a definite diagnosis of AS per Modified New York Criteria at Visit 1, including at least 1 of the following clinical criteria documented as being present for >=6 months prior to visit 1:
a) low back pain and stiffness which improves with exercise, but is not relieved by rest.
b) limitation of motion of the lumbar spine in both the sagittal and frontal planes.
c) limitation of chest expansion relative to normal values corrected for age and sex.
4. Patient has a history of positive therapeutic benefit with NSAIDs and has taken an
NSAID on a regular basis and at a therapeutic dose level for at least 30 days prior to study enrollment (regular basis is defined as greater than 20 of the previous 30 days, including 7 of the last 10 days).
5. If patient is currently using a non-study AS therapy other than NSAIDs, patient's approved non-study AS therapy has been at stable dosing relative to Visit 2 for the required time periods listed below AND is not anticipated to undergo a change within the first 6 weeks of the protocol. Similarly, patients must not have discontinued such therapy within the timeframe given below:
Adalimumab 3 months
Azathioprine 3 months
Bucillamine 8 weeks
Cyclosporin A 3 months
Etanercept 3 months
Golimumab 3 months
Hydroxychloroquine 8 weeks
Infliximab 3 months
Leflunomide 3 months
Methotrexate 2 months
Pamidronate 3 months
d-Penicillamine 3 months
Sulfasalazine 6 weeks
Thalidomide 3 months
Note: The use of other locally approved AS therapies will be considered on a case-by-case basis and require prior discussion with the SPONSOR (or its delegates) before the patient is enrolled in the study.
6. Patient has a score on BASDAI Question 2 at Visit 1 that is <77mm
7. Patient meets Flare Criteria at Visit 2. Patients are assessed after "washout" of prestudy NSAID and must satisfy flare criteria before randomization. The minimum and maximum washout duration depends upon the particular prestudy NSAID
Flare Criteria: Patients must demonstrate sufficient "flare" or worsening of AS pain defined as a score on BASDAI Question 2 at Visit 2 that is:
a) >=40 mm, AND
b) >=30% higher than the BASDAI Question 2 score at Visit 1, AND
c) >=12 mm higher than the BASDAI Question 2 score at Visit 1.
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| E.4 | Principal exclusion criteria |
1. Patient is legally incompetent (e.g., a minor or mentally incapacitated), or has active psychosis, or significant emotional problems at the time of the study which in the view of the investigator are sufficient to interfere with the conduct of the study.
2. Patient has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might confound the results of the study, or interfere with the patient’s participation for the full duration of the study, such that it is not in the best interest of the patient/subject to participate.
3. Patient has a concurrent medical/arthritic disease that could confound or interfere with evaluation of efficacy including, but not limited to: Inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, crystalinduced arthritis, spondyloarthropathy other than AS, DISH (Diffuse idiopathic skeletal hyperostosis)), polymyalgia rheumatica, a history of septic arthritis or intra-articular fracture of the study joint, Wilson’s disease, hemachromomatosis, ochronosis, or primary osteochondromatosis.
4. Patient has acute peripheral articular disease (defined as onset within 4 weeks prior to study) of an active (painful or swollen) peripheral arthritis (note: hip and shoulder are not considered to be peripheral joints).
Note: Patients with a history of chronic peripheral arthritis are permitted to enroll into the study provided that spine pain is the primary source of pain.
5. Patient has a history of gastric or biliary surgery (including gastric bypass surgery), or small intestine surgery that causes clinical malabsorption. Note: Patients who have had gastric banding or patients with cholecystectomy not resulting in malabsorption are allowed to participate.
6. Patient has an active peptic (gastric or duodenal) ulcer or a history of inflammatory bowel disease.
7. Patient has confirmed medical diagnosis of ischemic heart disease, cerebrovascular disease, or peripheral artery occlusive disease. In countries in which the use of COX-2 inhibitors has not been contraindicated in patients with these conditions, patients can otherwise participate (with the exception of those patients who have undergone coronary artery bypass graft surgery, angioplasty, or had a cerebrovascular accident or transient ischemic attack within the past 6 months).
8. Patient has Class II-IV congestive heart failure
9. Patient has uncontrolled hypertension (systolic >160 mm Hg or diastolic > 90 mm Hg) at Visit 1 or Visit 2. Investigators are encouraged to maximize blood pressure control according to local guidelines. Note: Local product labeling should be followed. In countries where the use of etoricoxib is contraindicated in patients with blood pressure values that are persistently elevated above 140/90 mm Hg, this definition of uncontrolled hypertension should be used. Note: Patients may be rescreened one time if blood pressure at Visit 1 is outside of the ranges listed above. Patients must be excluded if blood pressure at Visit 2 is outside of the ranges listed above.
10. Patient has a history of neoplastic disease; Exceptions: (1) patients with adequately treated basal cell carcinoma or carcinoma in situ of the cervix may participate; (2) patients with other malignancies which have been successfully treated ≥ 5 years prior to screening, where in the judgment of both the investigator and treating physician, appropriate follow-up has revealed no evidence of recurrence from the time of treatment through the time of screening. However, patients with a history of leukemia, lymphoma, malignant melanoma, and myeloproliferative disease are ineligible for the study regardless of the time since treatment, and in such cases, no exceptions will apply.
11. Patient is allergic to, or has a history of a significant clinical or laboratory adverse experience associated with etoricoxib or naproxen or any of their constituents; is allergic to acetaminophen/paracetamol, or has hypersensitivity (e.g., bronchoconstriction in association with nasal polyps) to aspirin or NSAIDs. Note: Patients with a history of a potential idiosyncratic allergic reaction (e.g., rash) to a single NSAID in the past but who have tolerated at least 2 other NSAIDs without hypersensitivity reactions may participate.
12. Patient has a personal or family history of an inherited or acquired bleeding disorder.
13. Patient has a history of any illness, which in the opinion of the investigator, might confound the results of the study or pose additional risk to the patient.
14. Patient is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last 5 years) of drug or alcohol abuse or dependence.
15. Patient is considered morbidly obese (defined as having a BMI≥40 kg/m2) and demonstrates significant health problems stemming from their obesity, which would confound study participation or interpretation of study results.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time weighted average change from baseline in Spinal Pain Intensity (VAS) over 6 weeks in Part I is the primary endpoint of this study. It will be analyzed using an analysis of covariance model (ANCOVA) with factors for treatment group, stratum(presence/absence of chronic peripheral arthritis), and baseline value as a one-degree-of-freedom covariate. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assessment according to protocol |
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| E.5.2 | Secondary end point(s) |
| Average change from week 6 in Spinal Pain Intensity (VAS) over weeks 10 and 12 among non-responders. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assessment according to protocol |
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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 | 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 | 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) | No |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 93 |
| 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 | No |
| 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 |
| Argentina |
| Austria |
| Belgium |
| Canada |
| Colombia |
| Czech Republic |
| Estonia |
| Finland |
| France |
| Germany |
| Hungary |
| India |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Taiwan |
| United Kingdom |
| United States |
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| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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