E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid arthritis (RA) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
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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 evaluate the efficacy of AMG 827 compared with placebo as measured by the proportion of subjects achieving an American College of Rheumatology (ACR) 50 response at week 12. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of AMG 827 as measured by the following: − The proportion of subjects with an ACR 20 and 70 at week 12 − Disease Activity Score 28 joint (DAS28) at week 12 To evaluate the short term safety profile of AMG 827 in subjects with rheumatoid arthritis (RA) To characterize the pharmacokinetics (PK) of AMG 827 in subjects with RA |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
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E.3 | Principal inclusion criteria |
Subject is capable of understanding and giving written, voluntary informed consent before study screening Male or female ≥ 18 and ≤ 70 years of age at time of screening Subject is diagnosed with RA as determined by meeting 1987 American College of Rheumatology (ACR) classification criteria Subject has active RA defined as ≥ 6 swollen joints (out of 66 joints examined) and ≥ 8 tender/painful joints (out of 68 joints examined) at screening and baseline (swollen and tender/painful joint count must not include distal interphalangeal [DIPs] joints) and at least 1 of the following at screening: − ESR ≥ 28 mm − CRP > 15 mg/L Subject has at least 1 of the following at screening: − Rheumatoid factor (RF) positive − Anti-cyclic citrullinated peptide (anti-CCP) antibody positive Subject has had RA for at least 6 months Subject has a negative test for hepatitis B virus (HBV) surface antigen, hepatitis C virus (HCV) antibody, and human immunodeficiency virus (HIV) Subject, if female and not at least 3 years postmenopausal or surgically sterile, has a negative serum pregnancy test within 4 weeks before initiating IP and a negative urine pregnancy test at baseline Subject is currently taking methotrexate consecutively for ≥ 12 weeks and on a stable dose of methotrexate at 15 to 25 mg weekly for ≥ 4 weeks at day -1. A lower methotrexate dose is acceptable (but no lower than 10 mg per week) if it is the highest tolerated dose, however, toxicity documentation by the investigator is required. Toxicities that would permit use of a lower dose of methotrexate include hepatic, gastrointestinal, mucosal, and hematologic. All subjects must take folic acid to minimize toxicity (at least 5 mg per week). If the subject is currently taking non-steroidal anti-inflammatory drugs (NSAIDs), the subject must be on stable use (eg, PRN use of a stable dose) ≥ 4 weeks prior to screening. If the subject is currently taking oral corticosteroids (not to exceed the equivalent of 10 mg of prednisone per day), the subject must be on a stable dose ≥ 4 weeks prior to screening. Subject has had a chest radiograph within 3 months prior to the first administration of IP that does not demonstrate abnormalities suggestive of a malignancy or current active infection, including tuberculosis Subject has a negative purified protein derivative (PPD; Tuberculin) test within 4 weeks before initiating IP. Tuberculin skin tests are considered positive when they have ≥5 mm of induration at 48 to 72 hours after test is placed. Subjects with a positive tuberculin skin test (if ≤14 mm of induration) are allowed if they meet all of the following criteria: - a history of Bacillus Calmette-Guerin vaccination - a negative Quantiferon test in the past year - no symptoms per tuberculosis worksheet - a negative chest radiograph. Note: subjects with a history of a positive PPD may refuse a repeat PPD and be allowed to continue screening for tuberculosis as above. |
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E.4 | Principal exclusion criteria |
Rheumatoid arthritis related Subject had prosthetic joint infection within 5 years of screening or native joint infection within 1 year of screening Subject has Class IV RA according to ACR revised response criteria (see Appendix C) Subject is diagnosed with Felty’s syndrome (RA, splenomegaly and granulocytopenia) Subject has a planned surgical intervention for a pretreatment condition within the duration of the study, including the follow up period Other medical conditions Subject has any active CTC grade 2 or higher infection (including chronic or localized infections) within 30 days prior to screening, at screening, or during screening period prior to first investigational product (IP) dose Subject has a serious infection, defined as requiring hospitalization or IV antibiotics within 8 weeks before screening Subject has recurrent or chronic infections, defined as ≥ 3 infections requiring anti-microbials over the past 12 months prior to screening Subject has one or more significant concurrent medical conditions, including: − Type 1 diabetes − Poorly controlled type 2 diabetes (hemoglobin A1c > 8.0) − Symptomatic heart failure (New York Heart Association class II, III, or IV) − Myocardial infarction within the last year − Current or history of unstable angina pectoris within the last year − Uncontrolled hypertension as defined by a resting blood pressure ≥ 160/95 mmHg prior to randomization (confirmed by a repeat assessment) − Severe chronic pulmonary disease (eg, requiring oxygen therapy) − Major chronic inflammatory disease or connective tissue disease other than RA (eg, systemic lupus erythematosus), with the exception of secondary Sjögren’s syndrome − Multiple sclerosis or any other demyelinating disease − Active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or melanoma, or history of cancer (except successfully treated in situ cervical cancer or squamous or basal cell carcinoma of the skin). − History of alcoholic liver disease − Any condition that, in the opinion of the investigator, might cause this study to be detrimental to the subject Subject is pregnant or breast feeding, or planning to become pregnant while enrolled in the study, up to the subject’s last study visit including the follow-up period Female subject is not willing to abstain from sexual intercourse or use 2 highly effective forms of birth control for the duration of the study including the follow-up period (except women at least 3 years postmenopausal or surgically sterile). Highly effective methods of birth control for women include but are not limited to birth control pills, Depo-Provera® injections, contraceptive implants, or occlusive cap (barrier method) in combination with barrier methods used by the man. Male subject is not willing to abstain from sexual intercourse or use 2 highly effective forms of birth control for the duration of the study including the follow-up period, plus an additional 10 weeks (except for men who are surgically sterile or whose female partners are at least 3 years postmenopausal or surgically sterile). Highly effective methods of birth control include but are not limited to a condom in combination with hormonal birth control or barrier methods used by the woman. Male subject (including vasectomised males) with a pregnant female partner is not willing to use effective methods to ensure that an unborn child is not exposed to AMG 827 via semen. Effective methods to ensure that an unborn child is not exposed to AMG 827 via semen include condoms or abstinence. Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures Laboratory abnormalities Subject has laboratory abnormalities at screening, including: − Elevated aspartate aminotransferase or alanine aminotransferase (> 1.5 ULN) − Serum total bilirubin ≥ 1.5 mg/dL − Hemoglobin < 11 g/dL − Platelet count < 125,000/mm3 − White blood cell count < 3,000cells/mm3 − Absolute neutrophil count (ANC) < 2000/mm3 − Creatinine clearance < 50 mL/min (Cockroft-Gault formula, calculated value to be provided to sites) − Any other laboratory abnormality, which, in the opinion of the investigator, will prevent the subject from completing the study or will interfere with the interpretation of the study results AMG 827 contraindications or precautions Subject has known or suspected sensitivity to mammalian cell-derived (ie, from Chinese hamster ovary) products or any components of the study drug For further exclusion criteria please see protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the ACR 50 response at Week 12. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
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 | No |
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 | No |
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 | 30 |
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 |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |