| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid arthritis (RA) |
|
| 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 |
| The primary objective for this study is to determine whether AMG 108, at a monthly dose of 250 mg subcutaneous (SC) or less, in combination with methotrexate (MTX) demonstrates a higher frequency in clinical response (ACR20) than that observed with placebo (MTX alone) in RA subjects at Week 16 of therapy. |
|
| E.2.2 | Secondary objectives of the trial |
To determine whether AMG 108, at a monthly dose of 250 mg SC or less, in combination with methotrexate (MTX) demonstrates 20% or higher frequency in clinical response (ACR20) above that observed with MTX alone at Week 16.
To evaluate the short term safety profile of AMG 108 in combination with MTX in RA subjects at doses up to 250 mg subcutaneous (SC) per month.
To determine whether the clinical response in subjects treated with AMG 108 at one or more doses with concomitant MTX, comparing Week 16 with baseline, is superior to that of MTX alone based on:·
1. The proportion of subjects achieving an ACR50 and ACR70 response ·
2. DAS28 score and change in DAS28 score from baseline (EULAR28 response)·
3. ACRn measure and AUC ACRn
To determine AMG 108 pharmacokinetic parameters in RA subjects after SC administration. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Subjects must be diagnosed with RA as determined by meeting 1987 American College of Rheumatology (ACR) classification criteria
Active disease defined as ≥ 6 swollen joints and ≥ 6 tender/painful joints and at least one of the following: ESR ≥ 28 mm/hr, CRP > 2.0 mg/dL, or duration of morning stiffness ≥ 45 minutes at time of screening
Duration of RA for at least 6 months·
Men or women ≥18 and ≤ 70 years old·
Subjects with active disease after a minimum of 4 weeks of MTX or 2 weeks of sulfasalazine or hydroxychloroquine treatment.
Stable use of oral or subcutaneous methotrexate at 10-25 mg weekly (≥4 weeks prior to screening) ·
If using NSAIDS or oral corticosteroids, subjects must be on stable use of NSAIDS or oral corticosteroids (≤10 mg prednisone or equivalent) ≥4 weeks prior to screening
Before any study-specific procedure, the appropriate written informed consent must be obtained. |
|
| E.4 | Principal exclusion criteria |
Previous receipt of commercial or experimental biologic therapies including AMG 108, anakinra (Kineret®), AMG 719, soluble IL-1 type II receptor, etanercept, infliximab, adalimumab, onercept, pegsunercept, abatacept, or rituximab or any other biologic therapy used to treat an inflammatory disease
Uncontrolled, clinically significant systemic disease other than RA such as diabetes mellitus, cardiovascular disease or hypertension
Malignancy within 5 years (except treated in-situ cervical cancer or squamous or basal cell carcinoma)·
Presence of a serious infection, defined as requiring hospitalization or frequent, acute or chronic infections within 8 weeks before screening·
Prior or current history of M. tuberculosis infection or exposure·
Class IV RA (Hochberg 1992) according to ACR revised response criteria or radiographic end stage disease ·
Prosthetic joint infection within 5 years of screening or native joint infection within 1 year of screening·
Felty’s syndrome·
Major chronic inflammatory disease or connective tissue disease other than RA, with the exception of secondary Sjögren’s syndrome·
Known to be positive for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV) or HIV·
White blood cell count <3.0x10e3/μl, absolute neutrophil count (ANC) of <2.5x10e3/μl, or platelet count of <125x10e3/μl at screening
Elevated AST/ALT > 1.5 x upper limit of normal ·
Elevated serum creatinine > 1.5 x upper limit of normal or > 2 mg/dL at screening
Laboratory abnormality which, in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results·
Intra-articular or systemic corticosteroid injections within 4 weeks of screening·
Any DMARD other than methotrexate within 6 weeks of screening·
Cyclophosphamide within 6 months of screening·
Received live vaccines within 3 months of first dose of IMP
Any investigational therapy within 4 weeks of screening·
Pregnant or nursing ·
Sexually active subjects and their partners who are of childbearing potential and not using adequate contraception·
Known sensitivity to mammalian cell derived drug products·
Any physical or psychiatric disorder which, in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results ·
Any disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures·
Active substance abuse (within 24 weeks of screening)·
Requiring or having a condition that may be expected to require strong narcotic analgesics (except hydro codone, codeine, dextropropoxyphene, propoxyphene, or oxycodone) or morphine derived medication for analgesic relief at screening |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the ACR20 response at Week 16.
The secondary endpoints are:·
ACR50 and ACR70 responses at Week 16·
DAS28 score and change in DAS28 score from baseline (EULAR28 response) at Week 16·
ACRn and AUC ACRn at Week 16·
AMG 108 PK parameters (such as Cmax, Tmax, and AUC0-t) after the 1st dose (on Day 1) and after the 4th dose (at Week 12) for the intensive sampling group.
The safety endpoints include:·
Treatment-emergent adverse events and infectious adverse events·
Serious adverse events (SAEs) and serious infectious events (SIEs)·
Severity of injection site reactions (ISRs)·
Significant changes in laboratory values and vital signs·
Changes in anti-AMG 108 antibody status |
|
| 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 | 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
|
| The end of the study is defined as the last visit of the last subject off the study. |
|
| 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 | 4 |
| 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 | 4 |
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