| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
|
| 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 objective of this study is to evaluate the effect of AZD5672 (20, 50, 100 and 150 mg once daily) on the signs and symptoms of rheumatoid arthritis (RA) in patients on background methotrexate therapy, as measured by American College of Rheumatology 20% response criteria (ACR20) at 12 weeks. Both the treatment effect compared with placebo and the dose-response relationship will be evaluated. |
|
| E.2.2 | Secondary objectives of the trial |
1.To further evaluate the effect of AZD5672 on the signs and symptoms of rheumatoid arthritis in patients on background methotrexate therapy·
2.To evaluate the safety and tolerability of AZD5672 in patients on background methotrexate therapy
3.To evaluate the effects of AZD5672 on physical function and quality of life (QoL) as measured by the HAQ (one of the ACR response criteria), individual dimensions of the HAQ, the SF-36 Questionnaire and the Rheumatoid Arthritis QoL Questionnaire (RAQoL)
4.To investigate the plasma pharmacokinetics (PK) of AZD5672 in the study population (to be reported separately)
5.To investigate possible relationships between systemic AZD5672 concentrations/exposures and adverse events (AEs), safety parameters and efficacy measurements (to be reported separately).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Provision of informed consent (including PK subset consent, as applicable).
2.Male or female aged 18 or over.
Note: Women of child-bearing potential may be included only if highly effective contraception is in place (see Section 3.3.4 and Appendix K) and patients are fully aware of the information relating to the potential for reprotoxicity as detailed in the informed consent form. Males who are involved in the study must agree to abstain from procreative sex during the study and for 12 weeks after the last dose of study medication.
3.Diagnosis of RA after the age of 16 according to the revised (1987) criteria of the American College of Rheumatology (see Appendix E).
4.Have active RA defined as:
-³4 swollen joints and ³6 tender/painful joints
and either:
ESR ≥28 mm/h or, CRP ≥10 mg/L.
5.At least one of the following:
-Documented history of positive rheumatoid factor
-Current presence of rheumatoid factor
-Baseline radiographic erosion
-Presence of serum anti-cyclic citrullinated peptide antibodies (anti-CCP).
6.Oral or subcutaneous or intramuscular methotrexate for at least 6 months prior to randomisation. The dose and means of administering methotrexate must have been stable between 5 mg and 25 mg per week for at least 6 weeks prior to randomisation. |
|
| E.4 | Principal exclusion criteria |
1.Pregnant or lactating females
2.Any systemic inflammatory condition in addition to RA that may interfere with the interpretation of the outcome data (examples include but are not limited to polymyalgia rheumatica, giant cell [including temporal] arteritis, reactive arthritis).
3.Current chronic pain disorders, including fibromyalgia and chronic fatigue syndromes.
4.American College of Rheumatology functional class IV (see Appendix F) or wheelchair/bed-bound.
5.Patient unable to comply with the local approved product information for etanercept. Note: any patients randomised to receive etanercept will be confirmed as negative for LTBI prior to initiation of treatment. If the patient has had a negative TB test in the month prior to Visit 1, the result of that test will stand and the test does not need to be repeated. Patients who have a positive test result should be discontinued, see Section 3.3.5.1).
Note: Where a local label is not available, then the label applicable to the supplied drug will apply.
6.Patients who have previously failed to respond to treatment with more than 1 biological agent.
7.Patients who in the opinion of the investigator have active TB as defined by clinical history and/or chest X-ray.
8.Patients who fail to comply with or are unlikely to stay compliant with the restrictions on prior and concomitant medication usage as provided in Section 3.7.
9.Clinical or biochemical evidence of active infection with hepatitis B or hepatitis C (carriers ie, those with positive serology but no evidence of active disease may be included).
10.Values of aspartate aminotransferase (AST), alanine aminotransferase (ALT) or bilirubin >2 x upper limit of normal (ULN) at Visit 1.
Note: If a potential patient has liver function only marginally outside these limits (as judged by the investigator), the patient may at the investigator’s discretion be brought back to study centre and retested not less than 2 weeks later and may be enrolled in the trial if the test(s) is then within the prescribed limit.
11.History of excessive alcohol consumption or chronic alcohol induced disease.
12.Patients who, in the opinion of the investigator, are at increased risk of ventricular arrhythmias, as suggested by (but not limited to):
-QTc at enrolment >450 ms, persistent on 2 repeated ECG recordings 30 minutes apart (subject to cardiological review if clinical doubt over machine calculated value)
-Other clinically significant ECG abnormality suggestive of clinically important underlying cardiovascular disease, including previous myocardial infarction; lack of sinus rhythm (ventricular ectopics allowed unless previously documented to be >100 per hour)
-Personal or familial history of long QT syndrome
-Personal history of clinical coronary heart disease (including angina) or congestive heart failure
-Clinical history of non-sustained or sustained ventricular tachycardia
-Visit 1 potassium outside normal range (subject to repeat if haemolysis etc, is suspected). Hypokalaemia may be treated if clinically indicated by potassium supplementation and patients may be included provided this is adequately corrected within the allowed screening period
-Patients with a clinically significant left ventricular hypertrophy, as determined by ECG, ie, V1/2 + V5/6 ≥35 mm
-Patients with brady-tachy syndrome that is not under satisfactory control
-Patients who, in the opinion of the investigator, have a history of clinically significant valvular heart disease.
13.Chronic or acute renal disease – patients may be included if the plasma/serum creatinine is within the normal range or if abnormal the calculated (using the original Cockroft Gault formula) or measured GFR must be >50 mL/min (see Appendix G).
14.History of malignancy or neoplastic disease, except successfully treated basal or squamous cell carcinoma of the skin >5 years ago.
15.Any other clinically significant disease or disorder, which in the opinion of the investigator (by its nature or by being inadequately controlled) might put the patient at risk due to participation in the study, or may influence the results of the study, or the patient’s ability to participate in the study, including chronic liver disease and significant history of recurrent infections.
16.Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site).
17.Previous enrolment in the present study.
18.Recent participation in a clinical study involving an investigational compound within the 3 months prior to randomisation or 5 half-lives of the investigational product (whichever is longer). Patients involved in non-drug methodology studies (either invasive or non-invasive) may be included without delay, at the discretion of the investigator.
19.Patients who in the opinion of the investigator should not participate in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable of this trial is the proportion of patients who achieve an ACR20 response at Week 12. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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
|
| The end of the study is defined as database lock after which time no patient will be exposed to study-related activities |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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