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The Use of Biomarkers to Guide Management of Patients Treated With Radiofrequency Ablation for Early Oesophageal Neoplasia (PROBAN)

Primary Purpose

Barrett's Oesophagus

Status
Recruiting
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Cytosponge test
Assessment of the panel of molecular biomarkers: IM-SCORE, TFF3 protein expression, methylation panel, p53 mutation
Oesophagogastroduodenoscopy
Sponsored by
University of Cambridge
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Barrett's Oesophagus focused on measuring Barrett's oesophagus, Radiofrequency ablation, Early Oesophageal Neoplasia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  1. Previous RFA for dysplastic BE or following EMR for BE-related neoplasia
  2. No definite endoscopic evidence of BE defined as at least 1cm tongue of columnar oesophagus or oesophageal BE islands larger than 5mm.
  3. No histological evidence of oesophageal IM including buried BE at first post RFA follow up. GOJ IM is allowed
  4. No evidence of suspicious lesions with dysplasia at the GOJ.

Exclusion criteria

  1. Evidence of BE requiring additional RFA
  2. Anticoagulant or antiplatelet therapy for high risk conditions, whereby discontinuation of the treatment is not recommended.
  3. Individuals with a diagnosis of an oro-pharynx, oesophageal or gastro-oesophageal tumour (T2 staging and above), or symptoms of dysphagia,
  4. Oesophageal varices, stricture or requiring dilatation of the oesophagus
  5. Individuals who have had a myocardial infarction or any cardiac event less than six months ago
  6. Patients whose primary previous ablative treatment was different from RFA, such as Photodynamic therapy (PDT), APC or Cryotherapy
  7. Participants who are unable to provide informed consent.
  8. Participants under age 18.
  9. Endoscopy is generally avoided in pregnant women and therefore it is unlikely that any pregnant women will be included although pregnancy would not be an absolute contraindication. Pregnancy/ pregnancy test will not be recorded as part of the trial.

Sites / Locations

  • MRC Cancer UnitRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Study group

Arm Description

As part of the post RFA treatment follow up patients will receive a Cytosponge test followed by an endoscopy with NBI magnification and biopsies. Four endoscopies will be performed during 2 years of active follow up together with up to 2 Cytosponge procedures. Molecular biomarkers including a methylation panel on DNA and immunohistochemical markers on formalin fixed paraffin embedded samples obtained during the examinations will be assessed. Patients will be then followed up for up to 3 years with standard endoscopy to assess for relapse of Barrett's oesophagus/IM/dysplasia.

Outcomes

Primary Outcome Measures

Diagnostic accuracy of methylation panel for diffuse IM at the GOJ
Diagnostic accuracy of a panel of methylation markers (ZNF345, ZNF569 and TFPI2 loci) for diffuse IM at the GOJ assessed by Methylight on DNA extracted from GOJ biopsies (separately random and targeted biopsies) and Cytosponge samples.

Secondary Outcome Measures

Proportion of patients developing true BE recurrence
Number of patients with GOJ IM with different IM score that will develop true BE recurrence during the observation period defined as oesophageal IM or dysplasia.
Biomarker score for BE recurrence
The accuracy of a biomarker panel to predict risk of BE recurrence. The following biomarkers will be assessed: P53 status by immunohistochemistry TFF3 expression by immunohistochemistry IM-SCORE (defined in the Study Description section) methylation markers (defined in the Outcome 1 Description section).
Accuracy of Light Blue Crest sign
Diagnostic accuracy of a Light Blue Crest (LBC) sign in NBI for the diagnosis of GOJ IM. During each performed endoscopy, NBI magnification will be used to assess systematically the mucosal pit pattern at the GOJ and to look for the LBC sign. In order to assess the accuracy of LBC, targeted biopsies will be taken from all the areas with LBC.
Safety of Cytosponge
Number of participants with Cytosponge procedure-related serious adverse events defined as an event that: Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Consists of a congenital anomaly or birth defect Is otherwise considered medically significant by the investigator (eg. a further procedure is required for the patient).

Full Information

First Posted
October 25, 2019
Last Updated
November 3, 2020
Sponsor
University of Cambridge
Collaborators
University of Nottingham
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1. Study Identification

Unique Protocol Identification Number
NCT04155242
Brief Title
The Use of Biomarkers to Guide Management of Patients Treated With Radiofrequency Ablation for Early Oesophageal Neoplasia
Acronym
PROBAN
Official Title
Prospective Study on the Use of Biomarkers to Guide Management of Patients Treated With Radiofrequency Ablation for Early Oesophageal Neoplasia
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Recruiting
Study Start Date
September 1, 2020 (Actual)
Primary Completion Date
December 1, 2024 (Anticipated)
Study Completion Date
December 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cambridge
Collaborators
University of Nottingham

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This prospective cohort study aims to assess the utility of a panel of molecular biomarkers for predicting the risk of relapse of Barrett's Oesophagus after endoscopic treatment of early oesophageal neoplasia with RadioFrequency Ablation (RFA). Patients who received endoscopic treatment of early oesophageal neoplasia with RFA and achieved endoscopic remission will be recruited. During the surveillance visits patients will receive a Cytosponge test followed by an endoscopy with Narrow Band Imaging (NBI) magnification and biopsies. Patients will receive an endoscopy every 6 months and Cytosponge every 12 months for at least 2 years. Molecular biomarkers including a methylation panel on DNA and immunohistochemical markers on formalin fixed paraffin embedded samples. After 2 years of intensive endoscopic follow up, patients will be prospectively tracked for up to 3 years. The investigators will also evaluate: The risk of progression to dysplasia or oesophageal intestinal metaplasia (IM) in patients with IM at the GOJ post RFA in the absence of retreatment the diagnostic accuracy of NBI for IM/dysplasia at the GOJ .
Detailed Description
The panel of predetermined molecular biomarkers includes: IM-SCORE - a score quantifying the extent of intestinal metaplasia at GOJ, which uses a 4-tier system based on the number of glands and the number of biopsies with features of IM. The score has been developed in a pilot study (manuscript under submission) and will be validated in this study Methylation markers- assessed by a PCR-based method (Methylight) on Cytosponge samples. P53 status. TFF3 protein expression.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Barrett's Oesophagus
Keywords
Barrett's oesophagus, Radiofrequency ablation, Early Oesophageal Neoplasia

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
147 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Study group
Arm Type
Experimental
Arm Description
As part of the post RFA treatment follow up patients will receive a Cytosponge test followed by an endoscopy with NBI magnification and biopsies. Four endoscopies will be performed during 2 years of active follow up together with up to 2 Cytosponge procedures. Molecular biomarkers including a methylation panel on DNA and immunohistochemical markers on formalin fixed paraffin embedded samples obtained during the examinations will be assessed. Patients will be then followed up for up to 3 years with standard endoscopy to assess for relapse of Barrett's oesophagus/IM/dysplasia.
Intervention Type
Diagnostic Test
Intervention Name(s)
Cytosponge test
Intervention Description
The Cytosponge will be administered by the study nurse prior to the participant having the endoscopy, usually as part of the same visit to hospital. The capsule along with the string is swallowed by drinking a small glass of water. The participant is asked to hold the Cytosponge in situ for 5 minutes. The sponge contained within expands and is then drawn back by the research nurse up the oesophagus by the attached string, collecting cells as it moves upwards. This device received a letter of no objection by the MHRA for use in the BEST pilot trial (LRQ 0939857) but it is not CE marked. Cytosponge and research endoscopic biopsies will be couriered to the Fitzgerald laboratory, at the MRC Cancer Cell Unit on a regular basis. The specimens will be processed in conjunction with the Cambridge University Hospitals' NHS Foundation Trust tissue bank which is accredited to GLP standards.
Intervention Type
Diagnostic Test
Intervention Name(s)
Assessment of the panel of molecular biomarkers: IM-SCORE, TFF3 protein expression, methylation panel, p53 mutation
Intervention Description
Molecular analysis of the specimen obtained by Cytosponge or endoscopic biopsies - TFF3 protein expression, methylation panel, p53 mutation. Endoscopic biopsies will be assessed for the presence of IM (according to the IM-score).
Intervention Type
Diagnostic Test
Intervention Name(s)
Oesophagogastroduodenoscopy
Intervention Description
Endoscopy will be carried out with white light and NBI with optical magnification or near focus to inspect oesophagus and GOJ. NBI magnification will be used to assess systematically the mucosal pit pattern at the GOJ and to look for light blue crest (LBC) sign. Targeted biopsies will be taken from either areas with LBC or irregular pit pattern on NBI, followed by random biopsies as per clinical standard. A maximum of 6 biopsies will be taken at the GOJ (maximum 4 targeted and 4 random.. During the first 2 post RFA follow up, at discretion of the endoscopists, neo-suqamous biopsies can be taken in line with local policies. Argon plasma coagulation ablation is allowed in a single island up to 5mm or up to 3 islands <3mm within the study endoscopy as long as this does not represent an obstacle to GOJ biopsies.
Primary Outcome Measure Information:
Title
Diagnostic accuracy of methylation panel for diffuse IM at the GOJ
Description
Diagnostic accuracy of a panel of methylation markers (ZNF345, ZNF569 and TFPI2 loci) for diffuse IM at the GOJ assessed by Methylight on DNA extracted from GOJ biopsies (separately random and targeted biopsies) and Cytosponge samples.
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Proportion of patients developing true BE recurrence
Description
Number of patients with GOJ IM with different IM score that will develop true BE recurrence during the observation period defined as oesophageal IM or dysplasia.
Time Frame
5 years
Title
Biomarker score for BE recurrence
Description
The accuracy of a biomarker panel to predict risk of BE recurrence. The following biomarkers will be assessed: P53 status by immunohistochemistry TFF3 expression by immunohistochemistry IM-SCORE (defined in the Study Description section) methylation markers (defined in the Outcome 1 Description section).
Time Frame
5 years
Title
Accuracy of Light Blue Crest sign
Description
Diagnostic accuracy of a Light Blue Crest (LBC) sign in NBI for the diagnosis of GOJ IM. During each performed endoscopy, NBI magnification will be used to assess systematically the mucosal pit pattern at the GOJ and to look for the LBC sign. In order to assess the accuracy of LBC, targeted biopsies will be taken from all the areas with LBC.
Time Frame
5 years
Title
Safety of Cytosponge
Description
Number of participants with Cytosponge procedure-related serious adverse events defined as an event that: Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Consists of a congenital anomaly or birth defect Is otherwise considered medically significant by the investigator (eg. a further procedure is required for the patient).
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Previous RFA for dysplastic BE or following EMR for BE-related neoplasia No definite endoscopic evidence of BE defined as at least 1cm tongue of columnar oesophagus or oesophageal BE islands larger than 5mm. No histological evidence of oesophageal IM including buried BE at first post RFA follow up. GOJ IM is allowed No evidence of suspicious lesions with dysplasia at the GOJ. Exclusion criteria Evidence of BE requiring additional RFA Anticoagulant or antiplatelet therapy for high risk conditions, whereby discontinuation of the treatment is not recommended. Individuals with a diagnosis of an oro-pharynx, oesophageal or gastro-oesophageal tumour (T2 staging and above), or symptoms of dysphagia, Oesophageal varices, stricture or requiring dilatation of the oesophagus Individuals who have had a myocardial infarction or any cardiac event less than six months ago Patients whose primary previous ablative treatment was different from RFA, such as Photodynamic therapy (PDT), APC or Cryotherapy Participants who are unable to provide informed consent. Participants under age 18. Endoscopy is generally avoided in pregnant women and therefore it is unlikely that any pregnant women will be included although pregnancy would not be an absolute contraindication. Pregnancy/ pregnancy test will not be recorded as part of the trial.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Massimiliano Di Pietro, MD
Phone
01223763349
Email
md460@mrc-cu.cam.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Massimiliano Di Pietro, MD
Organizational Affiliation
MRC Cancer Unit, Hutchison-MRC Research Hon. Consultant Gastroenterologist, Addenbrooke's Hospital, Cambridge.
Official's Role
Principal Investigator
Facility Information:
Facility Name
MRC Cancer Unit
City
Cambridge
ZIP/Postal Code
CB2 0XZ
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Massimiliano di Pietro, MD
Phone
01223763349
Email
md460@mrc-cu.cam.ac.uk

12. IPD Sharing Statement

Plan to Share IPD
No

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The Use of Biomarkers to Guide Management of Patients Treated With Radiofrequency Ablation for Early Oesophageal Neoplasia

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