| 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 | 12.0 |
| 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 this study is to evaluate the efficacy of golimumab + MTX in reducing signs and symptoms of RA (as assessed by the American College of Rheumatology [ACR] 20) at Week 14 in patients with inadequate disease control despite treatment with etanercept + MTX or adalimumab + MTX. |
|
| E.2.2 | Secondary objectives of the trial |
The 3 major secondary objectives of this study are to assess the following:
• The onset of response to golimumab 50 mg SC every 4 weeks + MTX as defined by the proportion of patients who achieve an ACR 20 response within 2 weeks of initiating therapy
• The persistence of response to golimumab 50 mg SC every 4 weeks + MTX as defined by the proportion of patients who achieve a DAS28 “good” response by Week 16 and maintain this response through Week 52
• The efficacy of golimumab 2 mg/kg intravenous (IV) therapy + MTX defined by the relative proportions of randomized patients in the golimumab IV group (with a loading dose) and the golimumab SC groups who achieve an ACR 20 response at Week 52 relative to Week 16 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Are women or men 18 years of age or older.
2. Have inadequate RA disease control (defined as an ESR-based DAS28 ≥ 3.6 and
≥ 6 swollen and ≥ 6 tender joints) prior to the first administration of study agent
despite treatment with:
− Etanercept at the approved and stable dose of 50 mg SC once weekly or
25 mg SC injections twice weekly in combination with MTX, or
− Adalimumab at the approved and stable dose of 40 mg SC injection every
2 weeks in combination with MTX
Patients must have received etanercept or adalimumab in combination with MTX for a
minimum of 3 months prior to the first screening visit (Week –6). The last dose of
etanercept must be administered no less than 7 days before the first golimumab injection at Week 0, and the last dose of adalimumab must be administered no less than 14 days before the first golimumab injection at Week 0.
3. Must have received a stable dose of MTX ≥ 7.5 mg/week to ≤ 25 mg/week for at
least 4 consecutive weeks prior to the first screening visit (Week –6) and must plan
to maintain that dose throughout the study as described in Section 7.3.1.
4. If using NSAIDs for RA, must be on a stable dose (not to exceed the normal or
usual approved prescribing dose) for at least 4 consecutive weeks before the first
screening visit (Week –6) and must plan to maintain that dose throughout the study
as described in Section 7.3.4.
5. If using oral corticosteroids, must be on a stable dose equivalent to ≤ 10 mg of
prednisone/day for at least 4 consecutive weeks before the first screening visit
(Week –6) and must plan to maintain that dose throughout the study as described in
Section 7.3.3. If currently not using corticosteroids, the patient must have not
received oral corticosteroids for at least 4 weeks before the first screening visit
(Week –6).
6. If using hydroxychloroquine and/or sulfasalazine, must have received a stable dose for at least 4 consecutive weeks before the first screening visit (Week –6) and must plan to maintain that dose throughout the study.
7. Women of childbearing potential or men capable of fathering children must be
using adequate birth control measures (eg, abstinence, oral contraceptives,
intrauterine device, barrier method with spermicide, surgical sterilization) during
the study and for 6 months after receiving the last administration of study agent.
Female patients of childbearing potential must test negative for pregnancy.
8. Are considered eligible according to the following TB screening criteria:
a. Have no history of latent or active TB prior to screening.
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, will be referred to a physician specializing in TB to
undergo additional evaluation and, if warranted, receive appropriate
treatment as if having latent TB prior to or simultaneously with the first
administration of study agent.
d. Within 6 weeks prior to the first administration of study agent, either have
negative diagnostic TB test results (see Appendix A), or have a newly
identified positive diagnostic TB test result (defined as a positive
QuantiFERON-TB Gold in-tube test) during screening in which active TB
has been ruled out and for which appropriate treatment (see Section 5.1) has
been initiated either prior to or simultaneously with the first administration of
study agent.
e. In the event of 2 indeterminate QuantiFERON-TB Gold in-tube test results,
the patient will be treated as if having latent TB prior to or simultaneously
with the first administration of study agent.
f. Have a chest radiograph (both posterior-anterior and lateral views), read by a
qualified radiologist, whose diagnostic assessment is consistent with no evidence of current active TB or old inactive TB, and taken within 12 months of the study or at the screening visit if the patient has received either etanercept or adalimumab continuously throughout this period. Documentation of the chest radiograph should be provided.
9. Have a screening laboratory test result as follows:
a. Hemoglobin ≥ 8.5 g/dL (International System of Units [SI]: ≥ 85 g/L) or ≥ 5.3 mmol/L.
b. White blood cell (WBC) count ≥ 3.5 × 103 cells/μL (SI: ≥ 3.5 × 109 cells/L).
c. Neutrophils ≥ 1.5 × 103 cells/μL (SI: ≥ 1.5 × 109 cells/L).
d. Platelets ≥ 100 × 103 cells/μL (SI: ≥ 100 × 109 cells/L).
e. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels not exceeding 1.5 times the upper limit of normal (ULN) for the central laboratory conducting the test.
f. Serum creatinine not exceeding 1.5 mg/dL (SI: ≤ 133 μmol/L).
10. Are willing and able to adhere to the study visit schedule and other protocol
requirements.
11. Are capable of providing informed consent, which must be obtained prior to any
study-related procedures. |
|
| E.4 | Principal exclusion criteria |
1. Have a history of latent or active granulomatous infection, including TB,
histoplasmosis, or coccidioidomycosis, prior to the first screening visit (Week –6)
or during the Screening Period, or are frequently in contact with individuals who
carry active TB infection.
2. Have had a Bacille Calmette-Guérin (BCG) vaccination within 12 months of screening.
3. Have a chest radiograph within 3 months prior to the first administration of study
agent that shows an abnormality suggestive of a malignancy or current active
infection, including TB, histoplasmosis, or coccidioidomycosis.
4. Have had a nontuberculous mycobacterial infection or opportunistic infection (eg,
cytomegalovirus, Pneumocystis, aspergillosis, cryptomycosis) within 6 months
prior to the first screening visit (Week –6) or during the Screening Period.
5. Have inflammatory diseases other than RA, including but not limited to psoriatic
arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary Sjogren’s
or Lyme disease, which might confound the evaluation of the benefit of golimumab
therapy.
6. Have been treated with DMARDs/systemic immunosuppressive agents (eg,
leflunomide, azathioprine, cyclosporine, mycophenolate mofetil) during the
4 weeks prior to the first administration of study agent. Patients may have received
MTX, sulfasalazine, or hydroxychloroquine.
7. Have received intra-articular, intramuscular or IV corticosteroids, including
adrenocorticotropic hormone, during the 4 weeks prior to the first administration of
study agent.
8. Have demonstrated a discernible improvement in disease activity as demonstrated
by an ESR-based DAS28 response and as defined by the EULAR criteria between
Week –6 (screening) and prior to the first golimumab injection at Week 0.
9. Have a known hypersensitivity to human immunoglobulin proteins or other
components of golimumab.
10. Have had a clinically serious adverse reaction to a biologic anti-TNFα agent.
11. Have received infliximab, golimumab, or certolizumab prior to the first
administration of the study agent.
12. Have received natalizumab, rituximab, or efalizumab prior to the first
administration of the study agent.
13. Have received anakinra during the 4 weeks prior to the first administration of study agent.
14. Have received alefacept within the 3 months prior to the first administration of the study agent.
15. Have used cytotoxic agents, including chlorambucil, cyclophosphamide, nitrogen
mustard, or other alkylating agents.
16. Have received any investigational anti-TNFα agent including but not limited to
lenercept or onercept.
17. Have been treated with the investigational agents ocrelizumab, ofatumumab, or
janus kinase 3 inhibitor (CP-690550) at any time, or any other investigational drug
within 5 half-lives of that drug prior to the first administration of study agent.
18. Are pregnant, nursing, or planning a pregnancy or fathering a child within 6 months after receiving the last administration of the study agent.
19. Have received, or are expected to receive, any live virus or bacterial vaccination
within 3 months prior to the first administration of study agent, during the trial, or
within 6 months after the last administration of study agent.
20. Have a history of an infected joint prosthesis, or have received antibiotics for a
suspected infection of a joint prosthesis, if that prosthesis has not been removed or
replaced.
21. Have had a serious infection (eg, hepatitis, pneumonia, or pyelonephritis), have
been hospitalized for an infection, or have been treated with IV antibiotics for an
infection within 2 months prior to the first administration of study agent. Less
serious infections (eg, acute upper respiratory tract infection, simple urinary tract
infection [UTI]) need not be considered exclusionary at the discretion of the
investigator.
22. Have a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to: chronic renal infection; chronic chest infection (eg, bronchiectasis);
sinusitis; recurrent UTI (eg, recurrent pyelonephritis, chronic nonremitting cystitis);
an open, draining, or infected skin wound; or an ulcer.
23. Are known to be infected with human immunodeficiency virus (HIV), hepatitis B,
or hepatitis C.
24. Have a history of known demyelinating diseases such as multiple sclerosis or optic neuritis.
25. Have current signs or symptoms of severe, progressive, or uncontrolled renal,
hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic,
psychiatric, or cerebral disease. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of patients who achieve an ACR 20 response at Week 14. |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| First part open, second part double blind |
|
| 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.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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
|
| The end of study is defined as the last follow-up assessment (or visit) for the last patient after his or her last study agent administration. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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