E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
JNJ-38518168 is being developed for the treatment of Rheumatoid Arthritis. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10039075 |
E.1.2 | Term | Rheumatoid arthritis and associated conditions |
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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 assess the safety, tolerability, and efficacy (in terms of change in DAS28 [using C-Reactive Protein (CRP)] from baseline) of JNJ-38518168 at a dose of 100 mg/day for up to 12 weeks compared to placebo in subjects with active Rheumatoid Arthritis (RA) despite methotrexate (MTX) therapy |
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E.2.2 | Secondary objectives of the trial |
To assess the efficacy of JNJ-38518168 as measured by ACR 20, 50, 70, 90 response rates at Week 12 and other efficacy assessments.
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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 |
The synovial biopsy substudy will be performed at selected sites in a subset of approximately up to 18 subjects (JNJ-38518168 100 mg/day [n=12] or placebo [n=6]). Synovial tissue samples collected via biopsy performed during the arthroscopy or ultrasound-guided biopsy of one or more of the inflamed joints. Synovial inflammation will be assessed via immunohistochemistry and digital imaging analysis. RNA and epigenomic profiles will be analyzed in synovial tissues using microarray and other technologies.
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E.3 | Principal inclusion criteria |
1. Man or woman between 18 - 75 yrs, inclusive.
2.2 Have a diagnosis of RA according to the revised 1987 criteria of the ARA for at least 6 m at screening.
3.3 Have active RA defined for the purpose of this study as persistent disease activity with both of the following criteria: a. Serum CRP ≥6 mg/L at screening only. Serum CRP between 5.5 and 6.0 mg/L can be rounded to 6 mg/L. b. 66/68 Joint Count as follows: • Primary study subjects: at least 6 swollen and 6 tender joints using a 66/68 joint count. • Synovial biopsy substudy subjects: at least 4 swollen and 4 tender joints using a 66/68 joint count with a clinically inflamed knee, or ankle joint.
4. Have been treated with and tolerated MTX treatment at dosages between 7.5 to 25 mg/wk inclusive, for a minimum of 4 m prior to screening and must have a stable MTX dose for a minimum of 4 wks prior to the first study drug dose. In addition, based on the Investigator’s assessment, an adequate supply of MTX as needed throughout the subject’s participation in the study.
5.1. If using NSAIDs or other analgesics regularly for RA, subjects must have been on a stable dose for at least 2 wks prior to the first dose of study medication. If not using NSAIDs or other analgesics for RA at study initiation, the patient must have not received NSAIDs or other analgesics for at least 2 wks prior to the first dose of study medication.
6. If using oral corticosteroids, must be on a stable dose of ≤10 mg/day of prednisone or an equipotent dose of another oral corticosteroid for at least 4 weeks prior to the first dose of study medication, and continue with the same dose throughout the study. If not using corticosteroids at study initiation, the subject must have not received oral corticosteroids for at least 4 weeks prior to the first dose of study medication.
7. Currently treated with folic acid at a minimum dose of 5 mg/wk.
8.3. Are considered eligible according to the following TB screening criteria: a. Have no history of latent or active TB at screening. An exception is made for subjects who have a history of latent TB (defined for the purposes of this study as having had a positive result from either the tuberculin skin test or the QuantiFERON-TB Gold test prior to screening) and documentation of having completed an adequate treatment regimen for latent TB prior to the first administration of study agent under this protocol. b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination. c. Have had no recent close contact with a person with active TB or if there has been such contact, have been evaluated by a physician specializing in TB and found not to have evidence of, or require treatment for latent TB. d. Within 6 wks prior to the first administration of study medication, have negative TB screening test results e. Have a TB-negative chest X-ray, within 3 months prior to screening, and read by a qualified radiologist.
9.2 At screening, the results of the following laboratory tests performed at the central laboratory must be within the limits specified in Protocol.
10. Except for signs and symptoms of active RA, subjects should be free from any significant health condition on the basis of the physical examination, medical history, laboratory tests, vital signs, 12-lead ECG, and all other assessments performed at screening.
11. Women must be one of the following: a)Postmenopausal; b)Surgically sterile, c)Sexually abstinent or If, sexually active, be practicing a highly effective method of birth control and must agree to continue to use the same method of cantraception throughout the study.
12.2 All women of child bearing potential must have a negative pregnancy test at screening (from serum) and at baseline (from urine).
13. Male subjects must consent to utilize a medically acceptable method of contraception throughout the study and for three months after the last dose of study drug and to not donate sperm during the study and for 3 months after receiving the last dose of study drug.
14. Willing and able to adhere to all of the procedures, prohibitions and restrictions specified in this protocol.
15. Before any screening procedure is undertaken, subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
16. To participate in the optional pharmacogenomic (PG)component of this study (where local regulations permit), subjects must have signed the informed consent form for PG research indicating willingness to participate in the PG component of the study. Refusal to give consent for this component does not exclude a subject from participation in the clinical study
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E.4 | Principal exclusion criteria |
1. Diagnosis of RA Functional Class IV according to the ACR criteria which has been ongoing for at least 6 m.
2. Inflammatory diseases other than RA. At the discretion of the Investigator, certain inflammatory may be acceptable after discussion with the Medical Monitor.
3. Current signs or symptoms of liver or renal insufficiency or cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, psychiatric, or metabolic disturbances that are severe, progressive or uncontrolled in the Investigator’s discretion.
4.2 Except for MTX, have been treated with the following approved or investigational non-biologic DMARDs: a. Including, D-penicillamine, hydroxychloroquine, chloroquine, oral or parenteral gold salts, sulfasalazine, azathioprine, cyclosporine, tacrolimus, and mycophenolate mofetil within 4 w prior to randomization b. Leflunomide within 4 w prior to randomization, or have received leflunomide from 4 to 12 w prior to randomization and have not undergone a drug elimination procedure. c. Any investigational non-biologic disease-modifying antirheumatic drugs within 4 wks or 5 half-lives prior to randomization, whichever is longer.
5. Received intra-articular, IM, or IV corticosteroids, including adrenocorticotropic hormone, within 4 w prior to the first dose of study medication, or would be expected to need such therapy during the participation in the study.
6.2 Received any approved or investigational antirheumatic agent targeted at inhibiting TNF including: a. Infliximab, golimumab, or certolizumab pegol within 3 months prior to randomization b. Etanercept, or adalimumab within 2 m prior to randomization c. Any other investigational anti-TNFα biologic agent within 3 months or five half lives of the drug prior to randomization, whichever is longer
7.2 Treated with more than either the total of three biologic antirheumatic agents and/or the total of five DMARDs that proved ineffective anytime before the screening.
8.2 Treated with approved or investigational biologic anti-inflammatory or immunosuppressive agents other than anti-TNFα agents during the six months or five half-lives of the drug prior to the first dose of study medication, whichever is longer.
9. Treated with Prosorba column apheresis within 3 m.
10. Treated with any other investigational drug or medical device within 4 wk or 5 half lives of the drug, whichever is longer.
11. Except for MTX, have been treated with a cytotoxic agent anytime before the first dose of study medication.
12. Undergone surgical treatments for RA including synoviectomy and arthroplasty within 3 m.
13.2 Undergone arthrocentesis or synovial biopsy (except the biopsy procedure performed in the substudy) within 1 m prior to the first dose of study medication.
14. Received drugs that potently inhibit or induce CYP450 3A4 isoform or any drug that potently inhibits or induces the PGP within 2 wk or within 5 half-lives of the drug, whichever is longer.
15. Received drugs with a risk of torsades de pointes within 1 wk or within 5 half-lives of the drug, whichever is longer.
16. Have a history of latent or active granulomatous infection, histoplasmosis, or coccidioidomycosis.
17. Have a QTcF interval >450 msec at screening or baseline, or have a history or current evidence of additional risk factors for torsades de pointes.
18. Have received, or are expected to receive, any live virus or bacterial vaccines within 1 m prior to the first dose of study medication, during the trial, or within 3 m after the last administration of study medication.
19. Have a history of an infected joint prosthesis, or have received antibiotics for a suspected infection of a joint prosthesis anytime before the first dose of study med, if that prosthesis has not been removed or replaced.
20. Infection which is serious in the opinion of the Investigator, have been hospitalized for an infection, or have been treated with IV antibiotics for an infection within 2 m prior to the first dose of study medication. At the discretion of the Investigator, subjects with mild acute infections at screening or before the first dose of study medication could be considered eligible.
21. History of, or current evidence of an opportunistic infection.
22.2 Are seropositive for HIV, hepatitis B, or hepatitis C. Prior and resolved infection with Hepatitis C is permitted. Hepatitis B serology consistent with prior resolved infection or vaccination is permitted.
23. Have any known malignancy or a history of malignancy within the previous 5 yrs.
24. Have a transplanted organ.
25. Have a history of or current evidence of substance abuse (drug or alcohol) problem within the previous 2 y.
26. Have known allergies, hypersensitivity, or intolerance to JNJ-38518168 or its excipients.
27. Women who are pregnant or breast-feeding. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in DAS28 (using CRP) score 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 | 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 | No |
E.6.10 | Pharmacogenetic | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 | 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
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |