E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
subjects with moderate to severe rheumatoid
arthritis. |
|
E.1.1.1 | Medical condition in easily understood language |
Moderate to Severe Rheumatoid Arthritis |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039076 |
E.1.2 | Term | Rheumatoid arthritis and other inflammatory polyarthropathies |
E.1.2 | System Organ Class | 100000004859 |
|
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 investigate the safety and tolerability of 60 mg three daily doses of GSK2982772 in subjects with moderate to severe Rheumatoid Arthritis. |
|
E.2.2 | Secondary objectives of the trial |
-To investigate the plasma concentrations of GSK2982772 following 60 mg three
daily doses of GSK2982772 in subjects with moderate to severe Rheumatoid
Arthritis.
-To investigate the effect of 60 mg three daily doses of GSK2982772 on
inflammatory biomarkers in blood subjects with moderate to severe
Rheumatoid Arthritis.
-To investigate the effect of 60 mg three daily doses of GSK2982772 on bone and
synovial parameters as measured by MRI and DCE-MRI in subjects with moderate to severe Rheumatoid Arthritis.
-To investigate the effect of 60 mg three daily doses of GSK2982772 on clinical
disease activity in subjects with moderate to severe Rheumatoid Arthritis.
-To investigate the effect of 60 mg three daily dosing of GSK2982772 on
methotrexate (MTX) concentrations |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
AGE
1.Between 18 and 75 years of age inclusive, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects that do not have any medical conditions, other than moderate to severe RA, that in the opinion of the Investigator put the subject at unacceptable risk or interfere with study assessments or integrity of the data. These medical conditions should be stable at the time of screening and are expected to remain stable for the duration of the study.
3. Subject has had a confirmed diagnosis of rheumatoid arthritis according to the revised
2010 American College of Rheumatology/European League Against Rheumatism ACR-EULAR classification criteria.
4. Disease duration of ≥ 12 weeks (time from onset of patient-reported symptoms of either pain or stiffness or swelling in hands, feet or wrists) at screening.
5. Swollen joint count of ≥4 (28-joint count) and tender joint count ≥ 4 (28-joint count) at screening.
6. Subject has a DAS28 CRP disease activity score of ≥ 3.2 and CRP ≥ 5.0 mg/L ( ≥ 4.76 nmol/L) at screening.
7. Subject must have received at least 12 weeks of non-biologic DMARD monotherapy or methotrexate (MTX)/DMARD combination therapy prior to screening AND must be on stable dose throughout the study.
8. Subject is naive to any biological therapies for RA
OR
Subject may have had previous exposure to a single anti-TNF biologic agent which was discontinued for reasons other than primary non-response more than 8 weeks (or 5 half lives whichever is longer) from first dose. Note: Exposure to a single anti-TNF is not required in addition to Inclusion #7 above.
9. For subjects who have consented to synovial joint biopsy:
a. Subject has an involved knee, wrist, or ankle suitable for biopsy, as assessed by a rheumatologist at screening.
WEIGHT
10. A body mass index (BMI) within range of 18.5 - 35 kg/m2 (inclusive) at screening.
SEX
11. Male and female subjects
Males:
Male subjects with female partners of child bearing potential must comply with the following contraception requirements in Appendix 6.
Females:
A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential as defined in Appendix 6.
b. Reproductive potential and agrees to follow one of the options listed in the Modified
List of Highly Effective Methods for Avoiding Pregnancy in Females of
Reproductive Potential (FRP) (see Appendix 6) from 30 days prior to the first dose of study medication and until at least 30 days after the last dose of study medication and completion of the follow-up visit.
The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
INFORMED CONSENT
12. Capable of giving signed informed consent as described in Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
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|
E.4 | Principal exclusion criteria |
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER
FUNCTION AND QTc INTERVAL)
1. Subject with a positive anti-double stranded deoxyribonucleic acid and confirmed diagnosis of systemic lupus erythematosus (SLE)
2. Subject with current history of Suicidal Ideation Behaviour (SIB) as measured using the Columbia Suicide Severity Rating Scale (C-SSRS) or a history of attempted suicide
3. An active infection, or a history of infections as follows:
- Hospitalisation for treatment of infection within 60 days before first dose
- Currently on any suppressive therapy for a chronic infection
- Use of parenteral antibiotics for an infection within 60 days before first dose
- A history of opportunistic infections within 1 year of screening. This does not include infections that may occur in immunocompetent individuals, such as fungal nail infections or vaginal candidiasis, unless it is of an unusual severity or recurrent nature
- Recurrent or chronic infection or other active infection that, in the opinion of the Investigator might cause this study to be detrimental to the patient
- History of TB, irrespective of treatment status
- A positive diagnostic TB test at screening defined as a positive QuantiFERON-TB Gold test or T-spot test. In cases where the QuantiFERON or T-spot test is indeterminate, the subject may have the test repeated once, but they will not be eligible for the study unless the second test is negative. In cases where the QuantiFERON or T-spot test is positive, but a locally-read follow up chest x-ray, shows no evidence of current or previous pulmonary tuberculosis, the subject may be eligible for the study at the discretion of the Investigator and GSK Medical Monitor
4. QTc > 450msec or QTc > 480msec for subjects with bundle branch block at screening.
The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual over read
The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined and documented prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial. For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP)
5. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if
bilirubin is fractionated and direct bilirubin <35%) at screening
6. Current active or chronic history of liver or biliary disease
7. Current or history of renal disease or estimated glomerular filtration rate (GFR) by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) calculation <60 mL/min/1.73m2 at screening
8. Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency
9. A major organ transplant or hematopoietic stem cell/marrow transplant
10. Any planned surgical procedures including surgical joint during the study
11. A history of malignant neoplasm within the last 5 years, except for adequately treated non-metastatic cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix that has been fully treated and shows no evidence of recurrence
12. Has undergone surgery including synovectomy or arthroplasty on the joint chosen for biopsy and/or magnetic resonance imaging
13. The subject has a history of any other joint disease other than RA at the knee, wrist or ankle joint chosen for biopsy and/or MRI
14. Has undergone intra-articular corticosteroid injection, arthrocentesis or synovial biopsy on any joint within 6 weeks of screening
15. A known allergy to lidocaine or other local anaesthetics
16. Contraindication to MRI scanning which includes but are not limited to:
- Intracranial aneurysm clips or other metallic objects,
- History of intra-orbital metal fragments that have not been removed by a medical professional
- Pacemakers or other implanted cardiac rhythm management devices and non-MR compatible heart valves,
- Inner ear implants,
- History of claustrophobia which may impact participation
Refer to Protocol:- RELEVANT HABITS, CONTRAINDICATIONS & DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective is to investigate safety and tolerability of 60 mg twice daily doses of GSK2982772 in subjects with moderate to severe rheumatoid arthritis. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Days 1, 8, 15, 29, 43, 57, 71 and 85. |
|
E.5.2 | Secondary end point(s) |
The secondary end points are: To investigate the effect of 60 mg twice daily doses on the pharmacokinetics, inflammatory biomarkers in blood, bone and synovial parameters, disease activity, and methotrexate concentrations. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Days 1, 8, 15, 29, 43, 57, 71 and 85. |
|
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 | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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
|
|
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 | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |