Application of Advanced MRI Techniques to Clinical Trials
Pharmaceutical companies looking to make quicker GO/NO GO decisions about their drugs are increasingly using advanced MRI techniques in their clinical trials. Many of the studies we work on use sophisticated imaging techniques to examine target engagement and to obtain new information about the anatomy being targeted. While some of these techniques will not progress beyond early phase studies, some methods are being used more widely and offer the opportunity for establishing drug efficacy on smaller cohorts of subjects than traditional assessment methods.
- Resting state fMRI and diffusion tensor imaging in Alzheimer's Disease (AD)
- fMRI for assessment of response to visual stimulus in cerebral amyloid angiopathy (CAA)
- DCE-MRI for the pharmacokinetic modelling of the synovium and structural MRI for quantifying disease progression in rheumatoid arthritis.
- Quantification of liver fat content using MRI and spectroscopy
While the specific challenges in setting up and running these projects are dependent on the application, there are some general considerations that must be made.
- Site Selection
Not all sites will have the technical capability or know-how to produce the required data. It is important to establish this early on, before sites are enrolled on their ability to recruit patients!
- Acquisition Design
We perform optimization and standardization of sequences across all major vendors using our local imaging centres and experts, prior to rolling out in a study. We consider stability, image quality, suitability for analysis and patient comfort.
- Project management
Studies using advanced MRI techniques typically require a higher level of engagement with the Sponsor and sites; we like to work in a collaborative way to ensure we meet the study objectives. Project managers, typically with a PhD in imaging science, are assigned to these projects and pull in both in-house experts and our external scientific advisors as necessary.
- Quality control
Site specific methods for rapid detection of protocol violations, positioning errors, or poor data quality are developed for each study.
- Image Analysis
Often the analysis of images requires a bespoke solution tailored to the study endpoints. We will source the appropriate software packages or develop solutions in-house.
Resting State fMRI and Diffusion Tensor Imaging in AD
These MRI techniques provide measures of the connectivity of the brain fibres. IXICO has qualified dozens of sites globally using these techniques and has established QC and analysis pipelines in place to cope with the growing demand for these analysis endpoints. However, there still remains challenges with selecting and training sites to ensure a consistent quality of data and we recommend early engagment with sites to avoid delays to a study.
fMRI to Assess Visual Response in CAA
fMRI is widely used in the research setting to assess a response to various types of stimuli. In this project we focused on applying a visual stimulus to patients with CAA, a disease which is known to affect the visual cortex of the brain. Finding sites with the necessary equipment and know-how is particularly challenging with task based fMRI, as standardization of both the stimulus and sequences is required.
DCE MRI for Rheumatiod Arthritis
Dynamic contrast enhanced (DCE) MRI is increasingly being used to model the concentration of contrast agent as it moves from the blood vasculature to the extra cellular interstitial space. This technique is already widely used in the assessment of anti-angiogenic therapies. Research has indicated that the dynamics of the contrast agent in the synovium in rheumatoid arthritis patients change significantly following administration of disease modifying therapies. For longer term assessment of disease progression, structural MRI is used to quantify bone erosion and bone oedema changes.
Liver Fat Quantification
Percentage fat in the liver can be used as an efficacy biomarker for treatment of conditions such as non-alcoholic steatohepatitis (NASH) and as a safety biomarker for therapies which may have fat deposition as a side effect. Quantification of the fat accumulation in the liver is currently achieved in the clinic by biopsy analysis. MR imaging (variations on the DIXON method) and spectroscopy provide non-invasive alternatives but imaging fatty liver disease in clinical trials poses several challenges. In particular, the anatomy of the liver and the surrounding structures can lead to profound artefacts and tight management is needed in multi-centre trials to avoid inconsistency in the data, particularly when the scanning equipment is from multiple vendors. Proton spectroscopy is a valuable quantitative tool, but it requires careful site selection and training, and the transfer of data in proprietary formats.