| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 and the safety of 3 dose levels of oral ERB-041 administered daily for 12 weeks versus palcebo in subjects with active RA who had a suboptimal response to therapy with stable doses of methotrexate. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess health outcome measures and concentrations of ERB-041 and explore the potential exposure-response relationshipTo search for biomarkers that may correlate with severity of RA and/or clinical response to ERB-041 |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. The American College of Rheumatology (ACR) criteria for RA (see Attachment 1). Note: Radiographs of the hand and feet may be performed at screening only if required to establish the diagnosis of RA.
2. ACR functional class I-III (see Attachment 2).
3. Disease duration of at least 6 months.
4. Disease onset at > 16 years of age.
5. Aged 18 to 80 years.
6. Must be treated with a stable, well-tolerated dose of MTX (7.5 to 20 mg, oral [PO], intramuscular [IM] or subcutaneous [SC]) weekly for at least 12 weeks prior to the baseline visit, and be willing to remain on this fixed dose for the duration of the study.
7. Have active RA consisting of ≥ 5 swollen and ≥ 5 painful joints (28-joint count) and meet at least 1 of the following 3 criteria: ·Erythrocyte sedimentation rate (ESR) (Westergren) ≥ 28 mm/hr.·C-reactive protein (CRP) ≥ 15 mg/L. ·Morning stiffness ≥ 45 minutes.
8. Women of childbearing potential, who must have a negative pregnancy test, and all male subjects, must agree and commit to use a medically acceptable nonhormonal method of birth control during the study and for at least 12 weeks after the last dose of test article.
a) Women of childbearing potential are women who are biologically capable of becoming pregnant, including women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
b) Women of nonchildbearing potential are:
i) Postmenopausal women with a history of amenorrhea for ³ 12 months and with serum FSH > 40 IU/L.
ii) Women who are surgically sterile, such as after a hysterectomy, bilateral oophorectomy, or tubal ligation (procedure performed at least 1 year before screening). This information must be documented in subject’s study file. |
|
| E.4 | Principal exclusion criteria |
1. Any prior use of total lymphoid irradiation, rituximab, receipt of anti-CD4 or diphtheria interleukin-2 fusion protein.
2. Inability to satisfy baseline exclusion criteria concerning prior use of RA therapies for times stipulated (See Baseline Exclusion Criteria, Section 12.2.2 points 1 through 9) at anticipated time of the baseline visit.
3. Clinically significant findings from a chest radiograph (posteroanterior [PA] and lateral views).Note: A report from a chest X-ray radiographs performed in the previous 12 months is acceptable for the screening evaluation.
4. Men with abnormal PSA levels, testicular mass or symptomatic benign prostatic hypertrophy
5. Women with clinically significant findings on the following:
a. Mammogram with suspicious abnormality or abnormality suggestive of malignancy if age ³ 40 years.
b. Findings suggestive of neoplasia during the gynecologic examination.
c. Papanicolau (Pap) test result with high-grade intraepithelial lesions or malignancy. Note: Reports from mammogram, gynecologic examination and Pap test performed in the previous 9 months must be available in the subject’s study file and the results must satisfy the screening criteria above.
d. Women with abnormal vaginal bleeding within 6 months before screening.
6. Pregnant or breastfeeding women or women planning to become pregnant during the study or within 12 weeks after the last dose of test article.
7. History of poor compliance or history of drug abuse/alcohol abuse, or excessive alcoholic beverage consumption (ie, 3 or more alcohol-containing drinks per day) that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
8. Any cardiovascular, neurologic, metabolic, immunologic, infectious, hepatic, or renal condition that the physician judges could be detrimental to subjects participating in this study, including any clinically important deviations from normal clinical laboratory values or important concurrent medical events. Significant medical conditions include:
a) Cancer, or a history of cancer:
i. Women with a history of breast, cervical, ovarian, vaginal, or uterine cancer at any time will be excluded.
ii. Men with a history of breast, prostate, or testicular cancer at any time will be excluded.iii.Other cancers, or their history (other than successfully resected cutaneous basal and squamous cell carcinoma) within 5 years before screening.
b) Cardiovascular disease:
i. History or presence of congestive heart failure (CHF) (New York Heart Association classification for CHF: Class III or IV).
ii. History of myocardial infarction within 1 year before screening.
iii. Unstable angina pectoris within 6 months before screening visit.
iv. Cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormality, such as ischemia.
v. Clinically significant peripheral artery disease.vi.History of stroke or transient ischemic attack within 1 year before screening.vii.History of deep vein thrombosis or pulmonary embolism.
c) Poorly controlled diabetes.
d) History of clinically significant pulmonary disease.
e) Liver cirrhosis or fibrosis.
f) History of human immunodeficiency virus (HIV) infection.
g) Immunodeficiency syndromes including Felty’s syndrome, large granular lymphocyte syndrome, or connective tissue diseases other than RA (eg, psoriatic arthritis, systemic lupus erythematosus, primary Sjögren’s syndrome).
h) Antiphospholipid syndrome.
i) Renal disease (including serum creatinine level that exceeds 2 mg/dL [SI units: 175 mmol/L]).
j) Significant neurologic disorder, including history of multiple sclerosis or other central demyelinating disorders.
9. Any medical or surgical condition that might interfere with drug absorption, distribution, metabolism, or excretion.
10. Presence or history of confirmed blood dyscrasias.
11. Any clinically significant laboratory abnormality, in addition to those listed below
a) Anemia (hemoglobin < 8.5 g/dL [SI units: < 85 g/L].
b) Leukopenia (white blood cells < 3.50 x 103/mm3 [SI units: < 3.50 x 109/L]).c)Thrombocytopenia or thrombocytosis (platelets < 125,000/mm3 or ≥ 1,000,000/mm3 [SI units: < 125 x 109/L or ≥ 1,000 x 109/L], respectively).
d) Liver function abnormality (total bilirubin, aspartate aminotransferase [AST/ SGOT], or alanine aminotransferase [ALT/SGPT]: > 1.5 x upper limit of normal).
e) Renal function abnormality, including serum creatinine > 2 mg/dL [SI units: > 175 mmol/L]).
12. History of any clinically significant drug-induced liver injury at any time before screening.
13. Presence of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (Hep. C Ab).
14. Any major surgery, including joint surgery, within 3 months before screening visit.
15. Scheduled elective surgery during study participation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ACR 20 at 12 weeks according to the criteria defined by the American College of Rheumatology |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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.8.5 | 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| 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 | 2 |
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