| 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 the study is to assess the efficacy of RO4402257 in adult patients with RA who currently have an inadequate clinical response to MTX therapy.
|
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety profile of RO4402257 in patients.
To select potentially efficacious and safe dose(s) for future studies.
To investigate by a population analysis approach the pharmacokinetics (PK) of RO4402257 in the target RA patient population, including the influence of covariates such as age, gender, and concomitant medications on PK parameters such as the apparent oral clearance (CL/F) and the apparent volume of distribution (V/F).
To explore by a population analysis the exposure-response relationship (PK-PD) of RO4402257 in the target RA patient population for the clinical endpoints and the safety parameters.
To better understand the efficacy, dose response, safety, and mode of action of RO4402257, and the progression of RA and diseases associated with RA (e.g., osteopenia) through collection and analysis of biomarker samples.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Able and willing to give written informed consent and to comply with the study protocol
Active RA as diagnosed by the 1987 American College of Rheumatology (ACR; formerly American Rheumatism Association) criteria (Appendix 2)
Age greater than or equal to 18 years
Receiving treatment for RA on an outpatient basis
Has received MTX for at least 24 weeks, of which the last 8 weeks prior to baseline was at a single dose level between 10 mg and 25 mg weekly; the route of administration also remained unchanged for the 8 weeks prior to baseline
If taking either hydroxychloroquine (HCQ) or chloroquine (CQ), dose must be stable for 8 weeks prior to baseline
Swollen joint count (SJC) greater than or equal to 6 (66 joint count) and tender joint count (TJC) greater than or equal to 8 (68 joint count) at screening and baseline
At screening, either high sensitivity C-reactive protein (hs-CRP) greater than or equal to 0.6 mg/dL (6 mg/L) or erythrocyte sedimentation rate (ESR) ≥ 28 mm/h or morning stiffness greater than 45 minutes
Females of child-bearing potential and nonsterilized males with female partners of child-bearing potential only if willing to use a reliable means of contraception (e.g., physical barrier, contraceptive pill, patch, or IUD) during the study and for 4 weeks following the last dose of study drug
If female and of childbearing potential, must have a negative pregnancy test within 3 weeks prior to randomization and at baseline
|
|
| E.4 | Principal exclusion criteria |
Major surgery (including joint surgery) within 8 weeks prior to screening or any planned surgery within 3 months after randomization
Rheumatic autoimmune disease other than RA (including systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis), or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, Felty’s syndrome); Sjögren’s Syndrome with RA is allowed
Bed-ridden or confined to a wheelchair
Prior history of, or current inflammatory joint disease other than RA (e.g., tophaceous gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease)
Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including asthma), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or gastrointestinal disease
History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured)
One of the following:
• History of active tuberculosis
• Chest radiographic findings consistent with active or latent tuberculosis
• Positive PPD (greater than or equal to 10 mm induration) unless there is a history of BCG immunization and the investigator ascertains that there is no recent history of tuberculosis exposure
Known active bacterial (including mycobacterial), viral (including HIV), fungal, or other infections (excluding fungal infections of nail beds)
Any episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks prior to baseline or oral antibiotics within 2 weeks prior to baseline
History of recurrent bacterial infections as an adult
History of hereditary or acquired immune deficiency disorder
Immunization with a live vaccine within 4 weeks prior to baseline
Pregnant women or nursing (breastfeeding) mothers
History of alcohol, drug or chemical abuse within the six months prior to screening
Neuropathies or other conditions that might interfere with pain evaluation
Current DMARD therapy other than MTX , HCQ or CQ
Previous treatment with a biologic agent
Treatment with another investigational agent within 6 weeks of screening, or 5 half-lives of the drug, whichever is longer
Previous treatment with any cell depleting therapies, including investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20)
Previous treatment with alkylating agents
Greater than 10 mg/day of prednisone (or equivalent; please refer to Appendix 1) < 4 weeks prior to the baseline visit
Intraarticular or parenteral corticosteroids < 4 weeks prior to the baseline visit
Sulfasalazine, azathioprine, cyclosporine, thalidomide, D-penicillamine, or tacrolimus within 8 weeks prior to baseline, and leflunomide within 12 weeks (or 4 weeks after 11 days of standard cholestyramine washout) prior to baseline
Gold compounds if less than 8 weeks prior to baseline; immunoadsorption columns if less than 6 months prior to baseline
Screening CPK > 2 x ULN
Screening alanine aminotransferase (ALT/SGPT) or aspartate aminotransferase (AST/SGOT) > 1.5 x ULN
Screening calculated creatinine clearance (Cockroft-Gault) < 50 mL/minute (refer to Appendix 3 for Cockroft-Gault formula)
Screening platelet count < 100,000 cells/mm3
Screening hemoglobin < 9 g/dL
Screening white blood cells < 3000 cells/mm3
Positive Hepatitis B surface antigen or Hepatitis C antibody
History of positive HIV antibody or HIV RNA above detectable limit
Repeated measurement of the QTcB interval at screening greater than or equal to 450 msec
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy parameter is the proportion of patients with an ACR20 response at Week 12.
Achievement of an ACR20 response requires at least a 20% improvement, compared to baseline, in both tender and swollen joint counts, as well as in 3 out of the 5 following parameters: physician’s global assessment of disease activity, patient’s global assessment of disease activity, patient’s assessment of pain, HAQ, and an acute phase reactant, either hs-CRP or ESR.
|
|
| 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 | 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 | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | Yes |
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
Print
