Pancreatic CancerMIRABILENCT06258824
MicroRNAs as Bile-based Biomarkers in Pancreaticobiliary Cancers
An observational study of Pancreatic Cancer and Cholangiocarcinoma, run by Imperial College London at 1 site in United Kingdom.
Trial summary
pancreatic or biliary-tract cancer can be a serious diagnosis, as many patients present too late for surgery. Cancer cells have been found to release small messenger molecules called that regulate cancer genes called microRNAs (miRNAs). Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Pancreatic Cancer, Cholangiocarcinoma, Ampullary Cancer
- What is being tested?
- Small RNA Sequencing and Validation of candidate miRNAs
- How many people
- 229 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 1 Jan 2018to 27 Jul 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Patients (>18 years old) undergoing ERCP for benign and malignant pancreatico-biliary disease/strictures.
Who may be able to join
- Age ≥ 18 years.
- Scheduled for clinical reason to undergo an ERCP (endoscopic retrograde cholangiopancreatography).
- WHO performance status 0, 1 or 2.
- Willing and mentally able to provide written informed consent.
- Suspected of having benign pancreaticobiliary disease (e.g. chronic pancreatitis, primary sclerosing cholangitis, common bile duct gallstones (choledocholithiasis), sphincter of Oddi dysfunction); or suspected of having PDAC or BTC.
- Presenting with obstructive jaundice and/or an indeterminate biliary stricture.
Who cannot join
- Age <18years old.
- Patients undergoing ERCP post-bariatric surgery, hepatico-jejunostomy or Bilroth II .
- Pregnancy.
- WHO performance status 3 or 4.
- Not willing or able to sign informed consent.
- Not scheduled for endoscopic procedures for clinical reasons.
- No clinical or image data suggestive of pancreaticobiliary disease and need for endoscopic intervention or investigation.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Imperial College Healthcare NHS Trust
London, W12 0HS
About this study
pancreatic or biliary-tract cancer can be a serious diagnosis, as many patients present too late for surgery. Cancer cells have been found to release small messenger molecules called that regulate cancer genes called microRNAs (miRNAs).
The goal of this observational study is to learn about the role of miRNAs from bile and blood samples in patients with pancreatic cancer and bile duct cancer. The main question[s] it aims to answer are:
- Can this detect patients presenting with jaundice (yellow-skin) undergoing endoscopy?
- Can this distinguish between the types of cancer? Participants will have blood and bile samples collected prior to diagnosis and their clinical pathway will be followed up for 6 months.
Read the detailed description
Biliary strictures may be benign or malignant. The major aetiology of a malignant biliary stricture includes a primary tumour or local extension, such as cholangiocarcinoma (CCA) or pancreatic ductal adenocarcinoma (PDAC). There is still ongoing debate about adequate diagnostics in bile duct strictures of unknown aetiology. The application of endoscopic retrograde cholangio-pancreatography (ERCP) is considered to be an essential tool in bile duct strictures. The advantage of ERCP is the ability to achieve biliary decompression and take transpapillary specimens for histological or cytological analysis at the same time. Unfortunately, biliary brush cytology and/or biopsies are often insensitive at detecting malignancy, especially PDAC. MicroRNAs (miRNAs) are newly recognised, small pieces of genetic code that are crucial for regulating cancer genes. It has been previously shown that miRNA "signatures" in tissue and biofluids can be used to detect and prognosticate PDAC. Bile is potentially a rich source of novel biomarkers for PDAC and BTC due to its intimate proximity to the malignant lesion.
This prospective, non-randomised, observational, single-blinded study will investigate, as its primary endpoint, whether candidate biliary miRNAs can differentiate between benign and malignant pancreaticobiliary disease/strictures in patients undergoing ERCP. In order to also generate hypotheses, this study also has several exploratory endpoints for translational research. This will focus on patients with presenting with PDAC, correlating miRNA levels with clinicopathologic factors and survival outcomes, in order to establish bile miRNAs as predictive and prognostic biomarkers. Moreover, the study will aim to elucidate the molecular mechanisms and source of the dysregulated biliary miRNAs in PDAC.
In summary, there is currently no effective method to differentiate malignant from benign biliary strictures, or the ability to stratify these tumours pre-operatively based on their biological subtype and aggressiveness. The proposed study aims to improve the speed and accuracy of diagnosing these tumours by using measuring bile-based miRNA signatures. Importantly, it has been shown that biliary miRNAs can be easily extracted and analysed, and these molecules are stable in clinical settings. The development of clinically useful biliary miRNA biomarkers will result in considerable patient benefits.
- Conditions
- Pancreatic Cancer, Cholangiocarcinoma, Ampullary Cancer, Biliary Stricture, Gallstone Disease
- Being tested
- Small RNA Sequencing and Validation of candidate miRNAs
- Keywords
- microRNA, ERCP, biomarker
- Medical subject headings
- Pancreatic Neoplasms, Cholangiocarcinoma, Cholelithiasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Small RNA Sequencing and Validation of candidate miRNAsDiagnostic test
Samples were prepared for small RNA sequencing using Qiagen's QIAseq small RNA Library Prep kit, quality controlled using an Agilent Bioanalyzer 2100 and sequenced on an NextSeq 500 system (Illumina, San Diego, USA) using the default single-end 75 base pair protocol to include integrated unique molecular indices (UMIs). Validation was undertaken using Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) either using target-specific stem-loop primer assays (TaqMan) or universal reverse transcription (RT) and locked nucleic acid (LNA) enhanced specific primers with SYBR green I assay detection
| Study group | Role | What they receive |
|---|---|---|
| Pancreatic Cancer (PDAC) | A clinical diagnosis of PDAC was defined by results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histopathologist and consultant radiologist. ERCP findings, endoscopic ultrasound findings, biliary brushing cytology, and fine needle aspiration cytology were anonymised and recorded. The combination of a pancreatic mass on radiographic imaging without acute cholangiopathy, and clinical or radiographic progression after ≥12 months of follow-up, or death clinically and radiographically determined to be due to pancreatic cancer. For surgical resection and biopsy specimens, diagnoses and staging were rendered based on standard histo-morphological criteria. For the purposes of analysis, pathological staging was used in preference to clinical staging where possible. Receives: Diagnostic Test: Small RNA Sequencing and Validation of candidate miRNAs | |
| Cholangiocarcinoma (CCA) | A clinical diagnosis of CCA was defined by radiological criteria according to results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histopathologist and consultant radiologist. ERCP findings, endoscopic ultrasound findings, biliary brushing cytology, and fine needle aspiration cytology were anonymised and recorded. This was also determined based on clinical or radiographic progression after ≥12 months of follow-up, or death clinically and radiographically determined to be due to cancer. For surgical resection and biopsy specimens, diagnoses and staging were rendered based on standard histo-morphological criteria. For the purposes of analysis, pathological staging was used in preference to clinical staging where possible. Receives: Diagnostic Test: Small RNA Sequencing and Validation of candidate miRNAs | |
| Benign | A clinical diagnosis of benign disease was defined by assessment at ERCP as well as results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histopathologist and consultant radiologist. Any patients with a benign aetiology were either clinically determined on the basis of no further progression after ≥12 months follow-up with either documented resolution or stability of prior ductal abnormalities or no further intervention as documented in electronic hospital records at 12 months. Receives: Diagnostic Test: Small RNA Sequencing and Validation of candidate miRNAs |
What is being measured
The primary outcome is the main question the study is designed to answer.
Diagnostic Value as measured by Area under the Curve (AUC) for candidate miRNAs
Expression values for each miRNA is calculated and used to undertake Multiple logistic regression was undertaken for candidates individually and in combination using GraphPad Prism. Data was prepared as a binary outcome and all main effects are included in the model. Optimum cut-offs were determined using thresholds obtained from the ROC curve at the maximum Youden index. Youden's J statistic (also called Youden's index) is a single statistic that ranges from 0 to 1 and is determined by the formula (Specificity + Sensitivity -1). Where multiple hypotheses were tested, an appropriate Benjamini-Hochberg (False Discovery Rate) correction was applied to give an adjusted p-value. A p (adjusted) value of <0.05 was considered to be statistically significant.
Measured: On the day of ERCP
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Feb 2024
- Study start1 Jan 2018
- Primary completion11 Mar 2020
- Study completion27 Jul 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Pancreatic CancerStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 229 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Collaborators
- Royal Surrey County Hospital NHS Foundation Trust, Royal Free Hospital NHS Foundation Trust
- Responsible party
- Sponsor
- Investigators
- Adam E Frampton, MB BS FRCS PhD, Principal investigator, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06258824
- Sponsor's protocol ID
- MIRABILE
- Acronym
- MIRABILE
- Status last verified
- Feb 2024
- First submitted
- 6 Feb 2024
- Last updated
- 14 Feb 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- MicroRNAs as Bile-based Biomarkers in Pancreaticobiliary Cancers
- ClinicalTrials.gov ID
- NCT06258824
- Acronym / sponsor ID
- MIRABILE / MIRABILE
- Conditions
- Pancreatic Cancer, Cholangiocarcinoma, Ampullary Cancer, Biliary Stricture, Gallstone Disease
- Keywords
- microRNA, ERCP, biomarker
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 229 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Collaborators
- Royal Surrey County Hospital NHS Foundation Trust, Royal Free Hospital NHS Foundation Trust
- Study start
- 1 Jan 2018 (actual)
- Primary completion
- 11 Mar 2020 (actual)
- Study completion
- 27 Jul 2020 (actual)
- First posted
- 14 Feb 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
pancreatic or biliary-tract cancer can be a serious diagnosis, as many patients present too late for surgery. Cancer cells have been found to release small messenger molecules called that regulate cancer genes called microRNAs (miRNAs).
The goal of this observational study is to learn about the role of miRNAs from bile and blood samples in patients with pancreatic cancer and bile duct cancer. The main question[s] it aims to answer are:
- Can this detect patients presenting with jaundice (yellow-skin) undergoing endoscopy?
- Can this distinguish between the types of cancer? Participants will have blood and bile samples collected prior to diagnosis and their clinical pathway will be followed up for 6 months.
Detailed description
Biliary strictures may be benign or malignant. The major aetiology of a malignant biliary stricture includes a primary tumour or local extension, such as cholangiocarcinoma (CCA) or pancreatic ductal adenocarcinoma (PDAC). There is still ongoing debate about adequate diagnostics in bile duct strictures of unknown aetiology. The application of endoscopic retrograde cholangio-pancreatography (ERCP) is considered to be an essential tool in bile duct strictures. The advantage of ERCP is the ability to achieve biliary decompression and take transpapillary specimens for histological or cytological analysis at the same time. Unfortunately, biliary brush cytology and/or biopsies are often insensitive at detecting malignancy, especially PDAC. MicroRNAs (miRNAs) are newly recognised, small pieces of genetic code that are crucial for regulating cancer genes. It has been previously shown that miRNA "signatures" in tissue and biofluids can be used to detect and prognosticate PDAC. Bile is potentially a rich source of novel biomarkers for PDAC and BTC due to its intimate proximity to the malignant lesion.
This prospective, non-randomised, observational, single-blinded study will investigate, as its primary endpoint, whether candidate biliary miRNAs can differentiate between benign and malignant pancreaticobiliary disease/strictures in patients undergoing ERCP. In order to also generate hypotheses, this study also has several exploratory endpoints for translational research. This will focus on patients with presenting with PDAC, correlating miRNA levels with clinicopathologic factors and survival outcomes, in order to establish bile miRNAs as predictive and prognostic biomarkers. Moreover, the study will aim to elucidate the molecular mechanisms and source of the dysregulated biliary miRNAs in PDAC.
In summary, there is currently no effective method to differentiate malignant from benign biliary strictures, or the ability to stratify these tumours pre-operatively based on their biological subtype and aggressiveness. The proposed study aims to improve the speed and accuracy of diagnosing these tumours by using measuring bile-based miRNA signatures. Importantly, it has been shown that biliary miRNAs can be easily extracted and analysed, and these molecules are stable in clinical settings. The development of clinically useful biliary miRNA biomarkers will result in considerable patient benefits.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Pancreatic Cancer (PDAC) | – | Diagnostic Test: Small RNA Sequencing and Validation of candidate miRNAsA clinical diagnosis of PDAC was defined by results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histopathologist and consultant radiologist. ERCP findings, endoscopic ultrasound findings, biliary brushing cytology, and fine needle aspiration cytology were anonymised and recorded. The combination of a pancreatic mass on radiographic imaging without acute cholangiopathy, and clinical or radiographic progression after ≥12 months of follow-up, or death clinically and radiographically determined to be due to pancreatic cancer. For surgical resection and biopsy specimens, diagnoses and staging were rendered based on standard histo-morphological criteria. For the purposes of analysis, pathological staging was used in preference to clinical staging where possible. |
| Cholangiocarcinoma (CCA) | – | Diagnostic Test: Small RNA Sequencing and Validation of candidate miRNAsA clinical diagnosis of CCA was defined by radiological criteria according to results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histopathologist and consultant radiologist. ERCP findings, endoscopic ultrasound findings, biliary brushing cytology, and fine needle aspiration cytology were anonymised and recorded. This was also determined based on clinical or radiographic progression after ≥12 months of follow-up, or death clinically and radiographically determined to be due to cancer. For surgical resection and biopsy specimens, diagnoses and staging were rendered based on standard histo-morphological criteria. For the purposes of analysis, pathological staging was used in preference to clinical staging where possible. |
| Benign | – | Diagnostic Test: Small RNA Sequencing and Validation of candidate miRNAsA clinical diagnosis of benign disease was defined by assessment at ERCP as well as results of a multidisciplinary team meeting consisting of at least a consultant hepatopancreaticobiliary surgeon, consultant hepatopancreaticobiliary physician, consultant histopathologist and consultant radiologist. Any patients with a benign aetiology were either clinically determined on the basis of no further progression after ≥12 months follow-up with either documented resolution or stability of prior ductal abnormalities or no further intervention as documented in electronic hospital records at 12 months. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Patients (>18 years old) undergoing ERCP for benign and malignant pancreatico-biliary disease/strictures.
Key inclusion criteria (6 listed)
- Age ≥ 18 years.
- Scheduled for clinical reason to undergo an ERCP (endoscopic retrograde cholangiopancreatography).
- WHO performance status 0, 1 or 2.
- Willing and mentally able to provide written informed consent.
- Suspected of having benign pancreaticobiliary disease (e.g. chronic pancreatitis, primary sclerosing cholangitis, common bile duct gallstones (choledocholithiasis), sphincter of Oddi dysfunction); or suspected of having PDAC or BTC.
Key exclusion criteria (7 listed)
- Age <18years old.
- Patients undergoing ERCP post-bariatric surgery, hepatico-jejunostomy or Bilroth II .
- Pregnancy.
- WHO performance status 3 or 4.
- Not willing or able to sign informed consent.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Small RNA Sequencing and Validation of candidate miRNAsSamples were prepared for small RNA sequencing using Qiagen's QIAseq small RNA Library Prep kit, quality controlled using an Agilent Bioanalyzer 2100 and sequenced on an NextSeq 500 system (Illumina, San Diego, USA) using the default single-end 75 base pair protocol to include integrated unique molecular indices (UMIs). Validation was undertaken using Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) either using target-specific stem-loop primer assays (TaqMan) or universal reverse transcription (RT) and locked nucleic acid (LNA) enhanced specific primers with SYBR green I assay detection | Diagnostic test | Benign, Cholangiocarcinoma (CCA), Pancreatic Cancer (PDAC) |
Primary outcome
Diagnostic Value as measured by Area under the Curve (AUC) for candidate miRNAs
Time frame: On the day of ERCP
Expression values for each miRNA is calculated and used to undertake Multiple logistic regression was undertaken for candidates individually and in combination using GraphPad Prism. Data was prepared as a binary outcome and all main effects are included in the model. Optimum cut-offs were determined using thresholds obtained from the ROC curve at the maximum Youden index. Youden's J statistic (also called Youden's index) is a single statistic that ranges from 0 to 1 and is determined by the formula (Specificity + Sensitivity -1). Where multiple hypotheses were tested, an appropriate Benjamini-Hochberg (False Discovery Rate) correction was applied to give an adjusted p-value. A p (adjusted) value of <0.05 was considered to be statistically significant.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Feb 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Adam E Frampton, MB BS FRCS PhD principal investigator
Imperial College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pancreatic Cancer and Cholangiocarcinoma, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Diagnostic Value as measured by Area under the Curve (AUC) for candidate miRNAs (time frame: On the day of ERCP). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Feb 2024.