E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
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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 |
1. To assess the change in inflammatory biomarkers in the synovial tissue of subjects with rheumatoid arthritis (RA) on a background of methotrexate after administration of a single, intravenous dose of GSK315234, as compared to placebo 2. To assess the safety and tolerability of a single, intravenous dose of GSK315234 in subjects with RA on a background of methotrexate, as compared to placebo, under the conditions of this study
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E.2.2 | Secondary objectives of the trial |
1. To assess the change in bone and synovial parameters (as measured by MRI) in subjects with RA on a background of methotrexate after administration of a single, intravenous dose of GSK315234 or placebo 2. To assess pharmacodynamic activity (as measured by effects on serum/plasma and urine biomarkers) in subjects with RA on a background of methotrexate after administration of a single, intravenous dose of GSK315234 or placebo 3. To assess clinical activity (as measured by effects on rheumatological endpoints) in subjects with RA on a background of methotrexate after administration of a single, intravenous dose of GSK315234 or placebo 4. To assess pharmacokinetic/pharmacodynamic correlations in subjects with RA on a background of methotrexate after administration of a single, intravenous dose of GSK315234 5. To assess the immunogenicity of GSK315234 in subjects with RA on a background of methotrexate after administration of a single, intravenous dose of GSK315234
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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 |
There is no separate protocol. See main protocol Section 7.10. Objectives: 1. Evaluate the immune response after one month of treatment with GSK315234 (TH1/TH2, TH17, Treg), 2. Establish the correlation between the immune and the clinical responses 3. Establish the correlation between the immune response and immunohistological parameters.
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E.3 | Principal inclusion criteria |
1. Males or females between 18 and 75 years of age, inclusive 2. Using acceptable contraception to ensure that no pregnancies occur during the course of the study and for at least 12 weeks after receiving the last dose for male subjects and for 32 weeks after receiving the last dose for female subjects (see Section 8.1 of the protocol on contraception for more details) 3. Body mass index within the range 18.5 - 35 kg/m2 inclusive 4. Capable of giving informed consent and can comply with the study requirements and timetable 5. Diagnosis of RA according to the revised 1987 criteria of the ACR 6. DAS28 disease activity score of greater than 3.2 at screening and prior to dosing 7. CRP level >0.5 mg/dL at screening and prior to dosing 8. Inflamed knee or ankle, as shown by clinical examination or ultrasound 9. Has never received a biological (marketed compounds or experimental treatments) or has been treated with a biological and failed due to lack of efficacy (adequate wash-out is required based on the half-life of the previously administered biological; wash-out time should be discussed with GSK Medical Monitor) 10. Must have received at least three months of methotrexate (MTX) prior to screening and must be on a stable dose of MTX (up to 25 mg/week) for at least four weeks prior to randomization and be willing to remain on this dose throughout the study 11. Must be on a stable dose of folate supplements (a minimum of 5 mg/week) for at least four weeks prior to randomization and throughout the course of the study 12. If sulfasalazine is being taken in addition to MTX, the subject must be on a stable dose for at least four weeks prior to screening and be willing to remain on this dose throughout the study 13. If hydoxychloroquine or chloroquinine is being taken in addition to MTX, the subject must be on a stable dose for at least three months prior to screening and be willing to remain on this dose throughout the study 14. If other oral anti-rheumatic therapies are being taken [e.g., non steroidal anti inflammatory drugs (NSAIDs), cyclo-oxygenase type -2 (COX-2) inhibitors, oral glucocorticoids (e.g. prednisolone </=10mg/day)], the subject must be on stable dosing regimens for at least four weeks prior to screening and be willing to remain on this regime throughout the study. 15. Subjects receiving intramuscular glucocorticoids (e.g., methylprednisolone </=120 mg/month) must be on a stable dosing regimen for at least three months prior to screening and be willing to remain on this regimen throughout the study. 16. Must have liver function tests including ALT and AST within 1.5 times the ULN and ALP within 3 times ULN at screening. The subject must also have total bilirubin within the ULN at screening. 17. QTc<450 msec or QTc<480 msec for subjects with Bundle Branch Block based on either single ECG values or triplicate ECG averaged QTc values obtained over a brief recording period
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E.4 | Principal exclusion criteria |
1. Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination, or ECG (12-lead or Holter); at the discretion of the investigator 2. Positive Hepatitis B surface antigen or Hepatitis C antibody at screening 3. History of human immunodeficiency virus or other immunodeficiency disease at screening 4. A history of elevated liver function tests on more than one occasion (ALT, AST and ALP > 3 times the ULN; total bilirubin > 1.5 times the ULN) in the 6 months prior to screening 5. Previous exposure or past infection caused by mycobacterium tuberculosis, unless adequately treated (documentation of treatment must be provided to the investigator and reviewed by the investigator and GSK Medical Monitor) 6. An acute infection 7. A history of repeated, chronic or opportunistic infections that, in the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as a participant in this trial 8. A history of malignancy, except for adequately treated, non-invasive cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix (an exception would be adequately treated cancer >10 years prior to screening; documentation of treatment must be provided to the investigator and reviewed by the investigator and GSK Medical Monitor) 9. Calculated creatinine clearance< 50mL/min 10. Significant cardiac, pulmonary, metabolic, renal, hepatic or GI conditions that, in the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as a participant in this trial 11. Has taken cyclosporine, leflonomide, cyclophosphamide or azathioprine within one month of screening. Subjects who have taken cyclosporine, leflonomide, cyclophophamide or azathioprine in the past must have recovered from all drug related AEs. 12. Has taken gold salts or d-penicillamine within one month prior to screening. Subjects that have taken gold salts or d-penicillamine in the past must have recovered from all drug related AEs. 13. Has received intra-articular or intra-muscular glucocorticoids within one month of screening 14. Has received cell-depleting therapy (e.g., rituximab) 15. Has received a live vaccine within three months of dosing 16. Recent history (within six months of screening) of bleeding disorders, anaemia, peptic ulcer disease, haematemesis or GI bleeding 17. Serum iron AND ferritin below the lower limit of the reference range at screening and prior to dosing 18. History of B12 or folate deficiency 19. A history of haematological disease or acquired platelet disorders, including drug-induced thrombocytopaenia, acute idiopathic thrombocytopaenia or von Willebrand’s disease 20. A known risk of intra-cranial hemorrhage including central nervous system surgery within 12 months prior to screening, arterial vascular malformations, aneurysms, significant closed head trauma within 6 months prior to screening or any other incident the investigator and/or medical monitor considers to be relevant 21. Hb <10 g/dL and platelet count < 150 x 10 power9 /L 22. Donation of blood in excess of 500 mL within a 56 day period prior to dosing 23. An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the male subject to use a condom with spermicide in addition to having their female partner use another form of contraception [such as an intra-uterine device (IUD), diaphragm, oral contraceptives, injectable progesterone, subdermal implants of levonorgestrel] if the female partner could become pregnant for at least 12 weeks after receiving the last dose of study medication. 24. An unwillingness of female subject of child bearing potential to use adequate contraception for at least 32 weeks after receiving the last dose of study medication. If necessary, women of non-child bearing potential will be confirmed. Surgical sterility will be defined as females who have had a documented hysterectomy, tubal ligation or bilateral oophorectomy. 25. History of use of drugs of abuse within 12 months prior to screening 26. History of regular alcohol consumption exceeding average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). Subjects who regularly consume more than 12 units of alcohol in a 24 hour period will also be excluded. 27. Positive pregnancy test or lactating at screening or pre-dose 28. Participation in a trial with any investigational drug within 3 months or 5 half-lives (whichever is longer) before the start of the study and within 4 months if the study drug was new chemical entity. Exposure to more than three new chemical entities in a clinical study setting within 12 months prior to dosing
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E.5 End points |
E.5.1 | Primary end point(s) |
• Synovial infiltration of sub-lining CD68+ macrophage, expressed as change relative to baseline • Spontaneous and elicited adverse events (AEs), vital signs, electrocardiograms (ECGs) and clinical laboratory values
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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 | Yes |
E.6.11 | Pharmacogenomic | No |
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 | Yes |
E.8.1.4 | Double blind | No |
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 | 5 |
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 | Information not present in EudraCT |
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 the trial will be the last visit of the last subject. |
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |