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.
Name: Gadobutrol
Name: 18F-FDG
Name: 18F-GE-180
Description: Half body and shoulder images from 18F-FDG and 18F-GE-180 will be visually inspected by two nuclear medicine physicians with respect to the clarity and ease of identifying abnormal high uptake in joints suspected to have inflammation. A subjective scale of abnormality will be applied to each image as follows: 3 = excellent quality; 2 = intermediate quality; 1 = poor quality but still interpretable; 0 = poor quality, not interpretable.
Measure: Evaluator's assessment of image quality and potential to define abnormality Time: Week 8Description: SUV will be derived from PET static imaging for 18F-FDG and 18F-GE-180 in selected joints. Using normalisation by weight and body surface area, SUVmax, SUVpeak and SUVmean (average of voxel values above a 75% iso-contour of SUVmax) will be calculated within the joint volume.
Measure: Standardised Uptake Value (SUV) of 18F-FDG and 18F-GE-180 Time: Week 8Description: TR will be derived from PET static imaging for 18F-FDG and 18F-GE-180 in selected joints. TR will be determined using the mean image value within each joint volume, and either the blood concentration decay-corrected to the start of the PET acquisition or the mean image value within non-inflamed muscle as reference.
Measure: Tissue-to-reference Ratio (TR) of 18F-FDG and 18F-GE-180 Time: Week 8Description: TIV will be derived from PET static imaging for 18F-FDG and 18F-GE-180 in selected joints.
Measure: Total Inflammatory Volume (TIV) of 18F-FDG and 18F-GE-180 Time: Week 8Description: Ktrans will be derived from DCE-MRI in selected joints
Measure: Exchange Rate (Ktrans) Time: Week 8Description: Ve will be derived from DCE-MRI in selected joints
Measure: Interstitial Volume (Ve) Time: Week 8Description: IRE will be derived from DCE-MRI in selected joints
Measure: Initial Rate of Enhancement (IRE) Time: Week 8Description: ME will be derived from DCE-MRI in selected joints
Measure: Maximal Signal Intensity Enhancement (ME) Time: Week 8Description: 18F-FDG and 18F-GE-180 static images will be evaluated by experienced observers with respect to the ease of identifying high uptake in joints suspected to have inflammation. Images will be assessed on the basis of a 4-point visual scale of abnormality/discernibility (0=poor quality - 4=excellent quality) and the number of abnormal joints will be counted.
Measure: Visual assessment of static 18F-FDG and 18F-GE-180 images using a 4-point visual analysis scale and abnormal joint counts Time: Week 8Description: The correlation between PET static imaging parameters (SUV, TR and TIV) of 18F-FDG and 18F-GE-180 will be determined
Measure: PET static imaging parameters (SUV, TR and TIV) of 18F-FDG and 18F-GE-180 in selected joints Time: Week 8Description: In order to verify static imaging parameters for scans, the pharmacokinetic profile of 18F-GE-180 will be determined, using dynamic PET scanning, blood sampling and HPLC analysis in a sub-cohort of RA study patients. 18F-GE-180 radio-PK parameters will be correlated with 18F-GE-180 static imaging metrics (SUV, TR and TIV)
Measure: 18F-GE-180 radio-PK modelling indices (total distribution volume; VT) and 18F-GE-180 static imaging metrics (SUV, TR and TIV) Time: Week 8Description: Number of AEs and SAEs as a measure of safety and tolerability of 18F-GE-180 and 18F-FDG
Measure: Adverse events (AEs) and serious adverse events (SAEs) assessment Time: Week 8Allocation: Randomized
Crossover Assignment
There is one SNP
- 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. --- Ala147Thr ---