Ignite Creation Date:
2024-05-06 @ 3:49 PM
Last Modification Date:
2024-10-26 @ 1:57 PM
Study NCT ID:
NCT04760964
Status:
RECRUITING
Last Update Posted:
2024-06-18
First Post:
2021-02-17
Brief Title:
Mitochondrial DAMPs as Mechanistic Biomarkers of Mucosal Inflammation in Crohns Disease and Ulcerative Colitis
Sponsor:
University of Edinburgh
Organization:
University of Edinburgh
Study Overview
Official Title:
Mitochondrial DAMPs as Mechanistic Biomarkers of Mucosal Inflammation in Crohns Disease and Ulcerative Colitis MUSIC
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
Recruiting
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MUSIC
Brief Summary:
The MUSIC study is a multi-centre longitudinal study set in the real world IBD clinical setting to investigate and develop a new biomarker approach that aims to inform both patients and clinicians of the current state of the affected gut lining how inflamed or whether the bowel wall has completely healed
This new biomarker approach will study a panel of molecular signs in IBD patients blood stools and biopsies that will be correlated to the current gold standard of direct gut visual examination using ileo-colonoscopy and flexible sigmoidoscopy tests a fibre-optic examination of the lower small bowel and large bowel Here the state and appearances of IBD patients gut lining will be assessed over one year in response to treatment given to them by their NHS IBD consultant
This approach will focus on the role of damage associated molecular patterns DAMPs also known as danger signals DAMPs are found in our own cells and are released during tissue stress or injury Like signals from bacteria they can trigger inflammation In the MUSIC study blood stool saliva and gut samples obtained from participants during active IBD and in clinical remission will be used in order to understand how DAMPs contribute to the development of gut inflammation
This new biomarker approach will study a panel of molecular signs in IBD patients blood stools and biopsies that will be correlated to the current gold standard of direct gut visual examination using ileo-colonoscopy and flexible sigmoidoscopy tests a fibre-optic examination of the lower small bowel and large bowel Here the state and appearances of IBD patients gut lining will be assessed over one year in response to treatment given to them by their NHS IBD consultant
This approach will focus on the role of damage associated molecular patterns DAMPs also known as danger signals DAMPs are found in our own cells and are released during tissue stress or injury Like signals from bacteria they can trigger inflammation In the MUSIC study blood stool saliva and gut samples obtained from participants during active IBD and in clinical remission will be used in order to understand how DAMPs contribute to the development of gut inflammation
Detailed Description:
The hypothesis is that mitochondrial DAMPs are good mechanistic biomarkers for mucosal inflammation and healing in IBD
Complete mucosal healing total resolution and absence of ulcerations in the gut is the most sought-after treatment target with the best long-term implication in prognosis
Up to now IBD clinicians rely on 1 clinical symptoms how patients feel their bowel habit presence of blood in stools 2 clinical tests such as stool calprotectin FC and blood C-reactive protein CRP to inform both themselves and the patients how well the drug treatment is working and importantly whether the ulcers and inflammation seen in the gut lining have healed or not
Current evidence shows that these approaches are not fully informative For example 30 of patients with significant subjective improvement in their symptoms following treatment of active CD have evidence of active inflammation in their gut lining when further assessed with an ileo-colonoscopy Blood and stool tests to predict mucosal healing are only useful in around 60-70 and very limited in guiding the doctors in how severely inflamed the bowel wall is during active IBD
Direct visualisation using ileo-colonoscopy or flexible sigmoidoscopy is the most accurate approach to assess disease activity and mucosal healing in response to medical treatment By knowing precisely how the gut wall inflammation is responding to treatment the clinician can accurately manage the IBD patient by either changing the dose and type of treatment and whether to carry on with expensive strong medications with potentially serious side effects However in the real world follow-up endoscopic tests are difficult to carry out as they are expensive and we lack the capacity to undertake these examinations within NHS
Project Goals
The main goal for the MUSIC study is to investigate the role of mitochondrial DAMPs in the clinic as an indicator of gut inflammation and subsequent mucosal healing in response to medical treatment in IBD
Secondly further scientific studies will be carried out using blood stool saliva and gut biopsy samples to investigate how mitochondrial DAMPs and all known biomarkers and biological data such as genetics contribute to the abnormal development of gut inflammation in IBD
Primary research questions
Do mitochondrial DAMPs predict the activity and severity of IBD-inflammation
Does normalisation of mitochondrial DAMPs reflect complete endoscopic mucosal healing in IBD
How do mitochondrial DAMPs compare to current biomarkers FC CRP and clinical symptoms HBIMayo Score in assessing IBD inflammation and mucosal healing
Can a simple decision-making model be developed to predict mucosal healing based on mitochondrial DAMPs together with relevant biological data such as genetics blood transcriptomics microbiome and current clinical biomarkers such as calprotectin faecal haemoglobin and blood CRP
Secondary research questions
How are mitochondrial DAMPs released from cells in the IBD gut
What types of cells are important in mitochondrial DAMP release There are many forms of inflammatory cells in affected IBD gut eg macrophage epithelial neutrophils It is possible that different cell types may contain more inflammatory DAMPs
Which type of mitochondrial DAMPs are important in causing inflammation Can mitochondrial DAMPs pinpoint a specific underlying genetic susceptibility eg autophagy or inflammatory mechanism in IBD
Rationale
The focus is to investigate mitochondrial DAMPs utility in two clinically relevant scenarios a How severe or active is the disease b How well are we treating IBD - with endoscopic endpoints of mucosal inflammation and healing respectively The Simple Endoscopic Score for Crohns Disease SES-CD and Endoscopic Mayo Score eMS will be used for CD and UC respectively Both have been validated and used widely in research and in clinical trials By using these objective endoscopic endpoints mtDAMPs and in combination with current biomarkers FC and CRP can be tested across a range of mucosal inflammation full healing to severe
In addition to this it will be investigated if mitochondrial DAMPs can identify a subclinical pathogenic mechanism eg a defective autophagy to clear damaged mitochondria b de-regulated innate immune response to mitochondrial DAMPs These data will pave the way for future use of mitochondrial DAMP biomarkers as part of a stratified approach for new treatments targeted at mitochondrial DAMPs and their downstream inflammatory mechanisms in IBD
Study Population
Presently within usual NHS care all patients with active IBD especially those to be initiated on biologic or immunomodulator treatment are followed up where they will have documentation of disease activity Harvey Bradshaw Index HBI or UC Mayo Score MS stool calprotectin C-reactive protein albumin and blood count to assess their well-being and response to medical treatment
With MUSIC patients will be followed up prospectively aligning the usual NHS clinical care above and will receive additional endoscopic follow-up to assess mucosal healing in response to medical treatment Thus the MUSIC study will incorporate a prospective endoscopic evaluation of mucosal inflammation and mucosal healing into IBD clinics
The recruitment and subsequent clinical data and sample collection will take place at 0 3 6 9 and 12 months
Complete mucosal healing total resolution and absence of ulcerations in the gut is the most sought-after treatment target with the best long-term implication in prognosis
Up to now IBD clinicians rely on 1 clinical symptoms how patients feel their bowel habit presence of blood in stools 2 clinical tests such as stool calprotectin FC and blood C-reactive protein CRP to inform both themselves and the patients how well the drug treatment is working and importantly whether the ulcers and inflammation seen in the gut lining have healed or not
Current evidence shows that these approaches are not fully informative For example 30 of patients with significant subjective improvement in their symptoms following treatment of active CD have evidence of active inflammation in their gut lining when further assessed with an ileo-colonoscopy Blood and stool tests to predict mucosal healing are only useful in around 60-70 and very limited in guiding the doctors in how severely inflamed the bowel wall is during active IBD
Direct visualisation using ileo-colonoscopy or flexible sigmoidoscopy is the most accurate approach to assess disease activity and mucosal healing in response to medical treatment By knowing precisely how the gut wall inflammation is responding to treatment the clinician can accurately manage the IBD patient by either changing the dose and type of treatment and whether to carry on with expensive strong medications with potentially serious side effects However in the real world follow-up endoscopic tests are difficult to carry out as they are expensive and we lack the capacity to undertake these examinations within NHS
Project Goals
The main goal for the MUSIC study is to investigate the role of mitochondrial DAMPs in the clinic as an indicator of gut inflammation and subsequent mucosal healing in response to medical treatment in IBD
Secondly further scientific studies will be carried out using blood stool saliva and gut biopsy samples to investigate how mitochondrial DAMPs and all known biomarkers and biological data such as genetics contribute to the abnormal development of gut inflammation in IBD
Primary research questions
Do mitochondrial DAMPs predict the activity and severity of IBD-inflammation
Does normalisation of mitochondrial DAMPs reflect complete endoscopic mucosal healing in IBD
How do mitochondrial DAMPs compare to current biomarkers FC CRP and clinical symptoms HBIMayo Score in assessing IBD inflammation and mucosal healing
Can a simple decision-making model be developed to predict mucosal healing based on mitochondrial DAMPs together with relevant biological data such as genetics blood transcriptomics microbiome and current clinical biomarkers such as calprotectin faecal haemoglobin and blood CRP
Secondary research questions
How are mitochondrial DAMPs released from cells in the IBD gut
What types of cells are important in mitochondrial DAMP release There are many forms of inflammatory cells in affected IBD gut eg macrophage epithelial neutrophils It is possible that different cell types may contain more inflammatory DAMPs
Which type of mitochondrial DAMPs are important in causing inflammation Can mitochondrial DAMPs pinpoint a specific underlying genetic susceptibility eg autophagy or inflammatory mechanism in IBD
Rationale
The focus is to investigate mitochondrial DAMPs utility in two clinically relevant scenarios a How severe or active is the disease b How well are we treating IBD - with endoscopic endpoints of mucosal inflammation and healing respectively The Simple Endoscopic Score for Crohns Disease SES-CD and Endoscopic Mayo Score eMS will be used for CD and UC respectively Both have been validated and used widely in research and in clinical trials By using these objective endoscopic endpoints mtDAMPs and in combination with current biomarkers FC and CRP can be tested across a range of mucosal inflammation full healing to severe
In addition to this it will be investigated if mitochondrial DAMPs can identify a subclinical pathogenic mechanism eg a defective autophagy to clear damaged mitochondria b de-regulated innate immune response to mitochondrial DAMPs These data will pave the way for future use of mitochondrial DAMP biomarkers as part of a stratified approach for new treatments targeted at mitochondrial DAMPs and their downstream inflammatory mechanisms in IBD
Study Population
Presently within usual NHS care all patients with active IBD especially those to be initiated on biologic or immunomodulator treatment are followed up where they will have documentation of disease activity Harvey Bradshaw Index HBI or UC Mayo Score MS stool calprotectin C-reactive protein albumin and blood count to assess their well-being and response to medical treatment
With MUSIC patients will be followed up prospectively aligning the usual NHS clinical care above and will receive additional endoscopic follow-up to assess mucosal healing in response to medical treatment Thus the MUSIC study will incorporate a prospective endoscopic evaluation of mucosal inflammation and mucosal healing into IBD clinics
The recruitment and subsequent clinical data and sample collection will take place at 0 3 6 9 and 12 months
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None