| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis (RA) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | <Manually entered code. Term in E.1.1> |
|
| 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 vs. placebo after 6 weeks of
treatment
Objective 2: To compare the effects of etoricoxib 60 mg vs. placebo after 6 weeks of
treatment in Part I
Obejctive 3: To assess the safety and tolerability profile of etoricoxib 60 mg and 90 mg in the treatment of RA |
|
| E.2.2 | Secondary objectives of the trial |
Objective 1: To compare the effects between etoricoxib 90 mg and etoricoxib 60 mg
daily after 6 weeks of treatment in Part I
Objective 2: To evaluate 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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is a male or female ≥ 18 years of age on the day of signing informed consent.
2. Patient understands the study procedures, the alternative treatments available, the risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
3. Patient is able to read, understand and complete study questionnaires, including
questions requiring a visual analog scale (VAS) response.
4. Female patients of reproductive potential must demonstrate a serum β-hCG level
consistent with a nongravid state at the prestudy visit and agree to remain abstinent, use oral, barrier, intramuscular, or implanted contraceptives from the prestudy 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).
Note: Serum FSH sample will be obtained only from women with cessation of menses within 1 year prior to Visit 1. 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. The patient must demonstrate a serum β-hCG level consistent with a nongravid state at the screening to continue in the study.
5. Patient is willing to limit alcohol intake to 2 drinks or equivalent per day for the duration of the study and follow-up period (one drink is defined as 2 oz. of hard alcohol, 5 oz. of wine, or 12 oz. of beer) and avoid unaccustomed physical activity (e.g., weight lifting) for the duration of the study.
6. Excepting RA, patient is judged to be in otherwise general good health based on
medical history, physical examination, and routine laboratory tests.
7. Patient has satisfied (for RA diagnosis) at least 4 of 7 ARA 1987 revised criteria for
the diagnosis of RA.
8. Patient is ACR Functional Class I, II, or III.
9. Patient has had a diagnosis of RA made at least 6 months prior to study start and was ≥ 16 years of age when diagnosed.
10. Patient global assessment of disease activity (VAS of 100 mm) at Visit 1 is less than 80 mm.
11. 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 (see Appendix 6.1) prior to study enrollment ( basis is defined as greater than 20 of the previous 30
days, including 7 of the last 10 days).
12. Patient’s approved nonstudy antirheumatic therapy has been at stable dosing for the required time periods listed below AND is not anticipated to undergo a change during the study. Similarly, patients must not have discontinued such therapy within the timeframe given below.
Abatacept: 6 months; Adalimumab: 6 months; Anakinra: 2 months; Antimalarials: 6 weeks; Azathioprine: 3 months; Certolizumab pegol: 6 months; Cyclosporin A: 3 months; d-Penicillamine: 3 months; Etanercept: 6 months; Gold salts (oral or injectable): 3 months; Golimumab: 6 months; Infliximab: 6 months; Leflunomide: 3 months; Methotrexate: 2 months; Sulfasalazine: 6 weeks; Tocilizumab: 6 months;
Note: Treatment with rituximab or epratuzumab is not allowed within 12 months
prior to enrollment. Note: The use of other locally approved RA medications 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.
13. At Visit 2, patient is assessed after "washout" of prestudy NSAID and must satisfy both activity and flare criteria before randomization. The minimum and maximum washout durations depends upon the particular prestudy NSAID.
Disease Flare and Activity Criteria to be Met at Visit 2
Criteria 1 to 3 are required:
1) ≥ 6 tender joints and an increase in number of tender joints of at least 20% (or a
minimum of 2 tender joints, whichever is greater) over the number at Visit 1. and
2) ≥ 3 swollen joints and an increase in number of swollen joints of at least 20%
(or a minimum of 2 swollen joints, whichever is greater) over the number at Visit 1. and
3) Investigator’s global assessment of disease activity must be "fair", "poor" or "very poor". and
One of the following two criteria (4 or 5) is required:
4) Duration of morning stiffness ≥ 45 minutes, and an increase in duration of morning stiffness of at least 15 minutes over Visit 1. or
5) Patient’s assessment of pain > 40 mm and an increase of at least 10 mm in
patient’s assessment of pain over the value at Visit 1. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria cannot participate in the study.
Previous or Concurrent Diseases
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 concurrent medical/arthritic disease that could confound or interfere
with evaluation of efficacy including, but not limited to: inflammatory arthritis (e.g.,
systemic lupus erythematosus, spondyloarthropathy, polymyalgia rheumatica), recent
acute attacks of gout or pseudogout, Paget’s disease affecting the study joint, a
history of septic arthritis or intra-articular fracture of the study joint, osteochondritis desiccans or osteonecrosis of the study joint, Wilson’s disease, hemachromomatosis,
ochronosis, or primary osteochondromatosis and inflammatory muscle diseases (e.g.
polymyositis, dermatomyositis).
3. 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 are allowed to participate.
4. Patient has an active gastric ulcer or history of inflammatory bowel disease.
5. Patient has established ischemic heart disease, cerebrovascular disease, or peripheral vascular disease. In countries in which the use of selective 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).
6. Patient has class II-IV congestive heart failure (See Appendix 6.5).
7. Patient has uncontrolled hypertension (systolic >160 mm Hg or diastolic
> 90 mm Hg) at Visit 1 and/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.
8. 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.
9. Patient is allergic to, or has a history of a significant clinical or laboratory adverse
experience associated with etoricoxib; has hypersensitivity (e.g., bronchoconstriction
in association with nasal polyps) to aspirin or NSAIDs, or is allergic to acetaminophen/paracetamol. 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 two other NSAIDs without hypersensitivity reactions may participate.
10. Patient is currently participating in a study with an investigational drug or device
within 4 weeks of signing informed consent.
11. 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.
12. Patient has a personal or family history of an inherited or acquired bleeding disorder.
13. Patient has a history of any illness that, in the opinion of 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
16. Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The Primary Hypotheses 1 and 2 will be evaluated by comparing etoricoxib (90 mg,
60 mg) to placebo on the proportion of patients achieving the ACR20 Responder Index Criteria and completing Part I, and the time-weighted average change from baseline over the 6 weeks in Part I in Patient Global Assessment of Pain (VAS). An etoricoxib dose (90 mg, 60 mg) will be declared superior to placebo if it demonstrates significantly greater efficacy than placebo in both of these endpoints (alpha= 0.05, 2-sided). |
|
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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