A Study to Assess Inflammation in Rheumatoid Arthritis Using Molecular Imaging Techniques

An Adaptive Design Open Label Pilot Study in Rheumatoid Arthritis Patients to Assess Inflammation Using Molecular Imaging Techniques

This is an adaptive Positron Emission Tomography/ Computed Tomography (PET/CT) and Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) open-label study design for the investigation of inflammation in adult rheumatoid arthritis (RA) patients, not involving therapeutic intervention. Each study participant will undergo two half body PET/CT scans from the pelvis to the bottom of the feet (including hands and wrists) with an additional bed position centred on the shoulders. One scan will be conducted with 18F-FDG and the other with 18F-GE-180. The first PET/CT scan (PET1) will be performed 4 weeks (28 +/- 2 days) after the first screening visit, whereas the second PET/CT scan (PET2) will be carried out within 2 weeks (7 +/- 7 days) after PET1. The order of PET/CT scans for each subject will be based on a computer generated randomisation schedule after the screening visit. A sub-group of study participants will be invited to undergo an additional dynamic 18F-GE-180 PET scan of a selected joint (knee or wrist) prior to their 18F-GE-180 PET/CT half body scan. The primary objective of the study is to quantify inflammation in joints of RA patients by determining 18F-FDG and 18F-GE-180 uptake using PET, and DCE-MRI parameters.

Inclusion Criteria:

• Subjects must be aged between 30 and 85 years inclusive at the time of signing the consent form.
• Stable, moderate to severe RA, based on either the 1987 American College of Rheumatology definition or the 2010 American College of Rheumatology/ European league Against Rheumatism (ACR/EULAR) classification criteria for RA (functional classes II and II).
• Disease activity score (DAS)28-erythrocyte sedimentation rate >3.2 at screening.
• Patients with at least one painful and swollen wrist or knee joint as assessed by a rheumatologist.
• Male subjects are eligible for enrolment in the study OR female subjects of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy (for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records) or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli international unit per milliliter (MIU/mL) and estradiol <40 picogram/mL (pg/mL) (<147 picomole per liter [pmol/L]) is confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use two of the contraception methods listed in the protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method OR female subjects of child-bearing potential with negative pregnancy test as determined by serum human chorionic gonadotropin (hCG) test at screening and 4-7 days prior to dosing and agrees to use two different contraception methods listed in the protocol. Use must be established a minimum of 1 month prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception from at least one month prior to the first dose through to follow up. Contraception requirements do not apply to women with only same-sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis.
• Subjects must be capable of giving informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

• Subjects who meet diagnostic criteria for any other rheumatic disease (e.g., lupus erythematosus).
• Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac (including ischemic heart disease), neurological, or cerebral disease, or other medical conditions that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study and/or evidence of an uncooperative attitude.
• Patients not on stable medication for RA for at least 4 weeks prior to screening.
• Subjects receiving treatment with biologics will not be eligible for inclusion.
• Subjects exceeding 159 kilogram (kg) body weight.
• Subjects exceeding 195 centimeter (cm) in height.
• History of regular alcohol consumption within 6 months of the study, defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• History of sensitivity to any of the study procedures or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• Subjects with creatinine clearance levels <60 milliliter per minute (mL/min).
• A positive pre-study alcohol screen (alcohol breath test).
• Pregnant females as determined by positive serum HCG test at screening or prior to imaging-related procedures.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Lactating females.
• Exposure to more than four new chemical entities within 12 months prior to the first imaging-related procedures.
• Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations with significant radiation burden (a significant radiation burden being defined as 10 milliSievert [mSv] in addition to natural background radiation, in the previous 3 years including the dose from this study).
• History of, or suffers from, claustrophobia or feel that they will be unable to lie still in the PET or MRI scanner for a period of 1-2 hours or fit in the PET or MRI scanner due to body size.
• Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) which includes, but is not limited to, intracranial aneurysm clips or other metallic objects, history of intra-orbital metal fragments that have not been removed by a medical doctor MD), presence of a cardiac pacemaker, non-magnetic resonance (MR) compatible heart valves or other electronic device or ferromagnetic metal foreign bodies, inner ear implants or history of cancer in first degree relatives diagnosed before age of 55.
• Presence of Ala147Thr polymorphism in translocator protein (TSPO) (which confers low affinity binding of 18F-GE-180) following confirmation by genotyping assay.
• Subjects receiving treatment with Disulfiram.