What is the problem? A wrist fracture is a common injury, affecting about 100,000 people in the UK each year. While most people recover well, a significant minority, between 10% and 20%, develop persistent pain and disability that lasts long after the bone has healed. In some cases this leads to a severe chronic pain condition called Complex Regional Pain Syndrome (CRPS). Currently we cannot easily predict who will recover and who may not, making it challenging to provide early targeted support. What are we trying to find out? We want to see if we can identify "signs" in the body, such as genetic markers, chemical messengers in the blood, and heart rate rhythms, that predict a person's recovery. We are also investigating the brain's "internal map" of the body. After an injury, this map can sometimes become "blurred" or less precise, which we believe is linked to ongoing pain. Our goal is to use this information to help in identify patients at high risk of chronic pain so they could receive better treatment in the future. What will happen in the study? We are inviting 250 participants: 200 people with a recent wrist fracture and 50 people who already live with long-term CRPS to act as a comparison group. All participants will first take part in a baseline assessment. This involves completing questionnaires (including a 0-10 pain rating scale), providing a blood sample, and taking part in simple bedside tests. These tests will also measure your internal body map by checking how accurately you can identify finger touches with your eyes closed and how you compare the size or weight of your limbs. Based on the results of these objective tests, we will invite some participants with recent wrist fractures to take part in specific sub-studies: * Brain Scans (24 people): If the bedside tests show changes in your internal map, we will invite you for two fMRI scans, six months apart, to watch the internal map in action whilst performing simple hand tasks. * Fitness Watches (50 people): Based on your pain rating scores, we will invite 25 people with higher pain and 25 people with lower pain to wear a watch for five days, at the beginning and end of their recovery, to track heart rate rhythms. * Virtual Reality (20 people): If you still have ongoing pain or a blurred internal map at 6 months, we may invite you to test at-home VR equipment to see if it helps re-train the brain. Who are we? Our research team includes experts in genetics, brain imaging, pain, and modern digital technologies who have experience in delivering clinical trials. How will we tell people what we found out? We are committed to sharing what we learn with the people who make our research possible. We will therefore inform participants and public. Once the study is complete, we will: * Publish a plain English summary of the results to the public registry ClinicalTrials.gov within 12 months of the study ending * Provide a direct update to participants who have consented to be contacted for future research via email * Offer community sharing of our findings through our sponsor Cambridge Arthritis Research Endeavour (CARE) website * Publish in Academic literature the full scientific results in medical journals to ensure that other doctors and researchers can learn from this study
Study Design Prospective cohort Study Participants (1) Patients aged 18 years and older, with an acute fracture of the distal radius within the past 6 weeks, willing and competent to complete the informed consent process. Patients with multiple trauma; have had an open fracture; have a unilateral sensory deficit; significant neurological disease or patients who would be unable to follow trial procedures will be excluded. (2) Participants with Chronic Complex Regional Pain Syndrome (CRPS), willing and competent to complete the informed consent process. Planned Size of Sample Total of 250 participants * 200 with distal radius fractures * 50 with chronic CRPS Planned Study Period September 2025 - 2029 (4 years) Research Aim The primary aim of this study is to perform multi-domain deep phenotyping of patients following a distal radius fracture, to generate novel hypotheses regarding the biological and physiological mechanisms that predict the transition to chronic pain and Complex Regional Pain Syndrome (CRPS). Key research questions 1. Validate candidate genes and identify molecular biomarkers associated with pain persistence and development of CRPS 2. To characterise the neurobiological and bodily representation changes that occur following a wrist fracture and their impact on the patient experience using fMRI 3. Investigate autonomic nervous system function as a potential predictor of clinical outcomes using Wearable digital technology 4. To assess the feasibility and acceptability of home-based Virtual Reality interventions in body representation disorder and pain persistence patients Domain level objectives Objectives Outcome measures Time point(s) of evaluation 1. Genetic and Molecular biomarkers 1a) Validate candidate genes, previously identified in chronic CRPS cohorts, in a prospective cohort of at-risk patients' post-fracture Frequency of four specific CRPS associated SNPs determined through PCR analysis PCR analysis of genomic DNA extracted from participants whole blood at month 0 n. 200 (DRF patients) 1b) To analyse for molecular biomarkers that may link with development of chronic pain and CRPS Biomarkers (including cytokines TNFα, Il-1 and IL-6, miRNA expression profiles miR-232 and miR-939 and autoantibodies) Biomarker analysis from whole blood samples taken at month 0 for all DRF patients and at month 6 for participants enrolled in sub-studies Month 0 n. 200 (DRF patients) Month 6 n. 50 - 94 (Sub-studies follow up participants) 1c) To compare genetic and molecular biomarker profiles from acute fracture cohort with those from an established chronic CRPS patient cohort Biomarkers (including cytokines TNFα, Il-1 and IL-6, miRNA expression profiles miR-232 and miR-939 and autoantibodies) Biomarker analysis from whole blood samples taken at month 0 n. 50 (chronic CRPS) 2. Neurobiology and Body Representation Disturbance (BRD) 2a) To identify predictive neural signatures in hypothesis-driven regions of interest (e.g. insula, parietal cingulate and ventral premotor cortices) Functional MRI Functional connectivity measures and Brain activation patters measured as Blood-Oxygen-Level-Dependent (BOLD) fMRI performed at month 0 and 6 n. 24 DRF * 2:1 ratio between disturbed and normal body representation (16 BRD Vs 6 non-BRD 2b) To quantify the impact of BRD on pain severity, perception and quality of life in participants following a distal radius fracture Patient reported outcome measures (PROMS) * Bath CRPS Body Perception Disturbance Scale * Neglect-Like Questionnaire * Body disownership scale * Brief Pain Inventory * Fear of Pain Questionnaire - Short form * Pain Catastrophizing Scale * Pain Self Efficacy Questionnaire * Quick Disabilities of the Arm, Shoulder and Hand * Pittsburgh Sleep Quality Index * Edinburgh Handedness Index - Short Form * Hospital Anxiety and Depression Scale PROMS performed at month 0 for all DRF patients and at month 6 for participants enrolled in sub-studies Month 0 n. 200 (DRF) Month 6 n. 50 - 94 (Sub-studies follow up participants) 3. Heart rate variability (wearable digital technology) 3a) To analyse heart rate variability captured via remote wearable technology as a biomarker for predicting outcomes in baseline high vs low pain groups and recovery between high and low pain scores (VAS \>6 and \<3 respectively) Heart rate variability obtained from wearable device worn on non-fractured wrist for 5 days. Months 0 and 6 n. 50 * 1:1 ratio between numerical rating scale \<3 and \>6 (25 \<3 Vs 25 \>6) 4. Virtual Reality intervention feasibility 4a) To evaluate the feasibility, acceptability and preliminary influence on pain and body representation of a home-based virtual reality intervention. Self-reported feasibility and subjectivity questionnaire outcomes and digital wearable variables over 7-day regular usage period. Patient reported outcome measures (PROMS) * Tampa Scale of Kinesiophobia * System Usability Scale * Virtual Reality Subjective Questionnaire * Subjective Experience Survey Month 6 n. 20 (BRD or pain persistence at 6 months)
Study Type
OBSERVATIONAL
Enrollment
200
Addenbrooke's Hospital
Cambridge, Cambridgeshire, United Kingdom
RECRUITINGRare SNPs in genetic analysis
A whole blood sample will be collected from each participant at baseline. DNA will be analysis to identify the presence or absence of pre-specified candidate Single Nucleotide Polymorphisms (SNP) alleles, previously associated with chronic CRPS, via Polymerase Chain Reaction (PCR). Participants will then be categorised as variant positive or negative.
Time frame: 5 years
Functional MRI biomarkers
Structural and functional MRI scans will be performed at month 0 and 6 using 3T MRI facilities at the Wolfson Brain Imaging Centre in Cambridge. This will involve a 1-hour scanning time, including stuctural (T1-weighted and Diffusion Tensor Imaging (DTI)) and functional (task-based and resting-state BOLD) fMRI.
Time frame: 5 years
Nicholas Shenker, BMBCh PhD
CONTACT
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