| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
| 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. |
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| 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
To further evaluate the long-term efficacy and safety of golumimab treatment, a voluntary, open-label, 24-week study extension is held during weeks 53 to 88, consisting of 3 additional visits and a telephone follow-up in week 88. |
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| 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 prior to the first administration of study agent despite treatment with etanercept or adalimumab in combination with MTX for a minimum of 3 months prior to the first screening visit:
- Etanercept at the approved dose of 50 mg SC once weekly or 25 mg SC injections twice weekly in combination with MTX at Week 0, or
- Adalimumab at the approved dose of 40 mg SC injection every 2 weeks in combination with MTX at Week 0
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 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 for at least 4 consecutive weeks before the first screening visit.
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. If currently not using corticosteroids, the patient must have not received oral corticosteroids for at least 4 weeks before the first screening visit.
6. If using hydroxychloroquine and/or sulfasalazine, must have received a stable dose for at least 4 consecutive weeks before the first screening visit 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 during the study and for 6 months after receiving the last administration of study agent. Female patients must test negative for pregnancy.
8. Are considered eligible according to the following TB screening criteria:
- Have no history of latent or active TB prior to screening. An exception is made for patients with a history of latent TB and documentation of having completed appropriate treatment for latent TB within 3 years prior to the first administration of study agent.
- Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
- 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.
- Within 6 weeks prior to the first administration of study agent, either have a negative QuantiFERON-TB Gold test result, or have a newly identified positive QuantiFERON-TB Gold test result in which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of study agent.
- 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.
- Have a chest radiograph, demonstrating 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.
9. Have screening laboratory test result as follows:
- Hemoglobin ≥ 8.5 g/dL (International System of Units [SI]: ≥ 85 g/L) or ≥ 5.3 mmol/L.
- White blood cell (WBC) count ≥ 3.5 x 10^3 cells/μL (SI: ≥ 3.5 x 10^9 cells/L).
- Neutrophils ≥ 1.5 x 10^3 cells/μL (SI: ≥ 1.5 x 10^9 cells/L).
- Platelets ≥ 100 x 10^3 cells/μL (SI: ≥ 100 x 10^9 cells/L).
- 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.
- 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.
12. Patients must undergo screening for HBV.
- Patients who test positive for surface antigen (HBsAg+) are not eligible for this study, regardless of the results of other hepatitis B tests.
- Patients who test negative for surface antigen (HBsAg-) and test positive for core antibody (anti-HBc+) and surface antibody (anti-HBs+) are eligible for this study.
- Patients who test positive only for surface antibody (anti-HBs+) are eligible for this study.
- Patients who test positive only for core antibody (anti-HBc+) must undergo HBV DNA testing. If the HBV DNA test is positive or if the HBV DNA test cannot be performed, the patient is not eligible for this study. If the HBV DNA test is negative, the patient is eligible for this study. |
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| E.4 | Principal exclusion criteria |
1. Have a history of latent or active granulomatous infection, including histoplasmosis, or coccidioidomycosis, prior to the first screening visit or during the Screening Period. Pulmonary calcifications in isolation are not considered indicative of latent histoplasmosis. Refer to inclusion criteria for information regarding eligibility with a history of latent TB.
2. Have had a 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 within 6 months prior to the first screening visit or during the Screening Period.
5. Have inflammatory diseases other than RA which might confound the evaluation of the benefit of golimumab therapy.
6. Have been treated with DMARDs/systemic immunosuppressive agents during the 4 weeks prior to the first screening visit. Patients may have received MTX, sulfasalazine, or hydroxychloroquine.
7. Have received IA, IM, or IV corticosteroids during the 4 weeks prior to the first screening visit.
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 screening and prior to the first golimumab injection at Week 0.
9. Have a known hypersensitivity to 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, tocilizumab, abatacept, or efalizumab prior to the first administration of the study agent.
13. Have received anakinra during the 4 weeks prior to the first screening visit.
14. Have received alefacept within the 3 months prior to the first screening visit.
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 a janus kinase 3 inhibitor 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, 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 need not be considered exclusionary at the discretion of the investigator.
22. Have a history of, or ongoing, chronic or recurrent infectious disease.
23. Are known to be infected with 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.
26. Have a history of, or concurrent, CHF, including medically controlled, asymptomatic CHF.
27. Have a history of colonic mucosal dysplasia.
28. Have a history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease such as lymphadenopathy of unusual size or location or clinically significant hepatomegaly or splenomegaly.
29. Have any known malignancy or have a history of malignancy within the previous 5 years (with the exception of a nonmelanoma skin cancer that has been treated with no evidence of recurrence).
30. Have a transplanted organ (with the exception of a corneal transplant performed > 3 months prior to the first study agent administration).
31. Have or have had a substance abuse problem within the previous 3 years.
32. Are unwilling or unable to undergo multiple venipunctures because of poor tolerability or lack of easy access.
33. Are participating in another trial with an investigational agent or procedure.
34. Do not meet this study’s inclusion criteria for HBV infection. |
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| 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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- The proportion of patients who achieve an ACR 20 response at Week 2
- The proportion of golimumab SC patients who achieve an ESR-based DAS28 "good" response at Week 16 and maintain that response through Week 52
- The proportion of randomized patients in the golimumab IV group (with a loading dose) compared with the proportion of randomized patients in the golimumab SC group who achieve an ACR 20 response at Week 52 relative to Week 16 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 |
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| 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 | 150 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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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| 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. |
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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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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